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| Publications of Edward D. Levin :chronological alphabetical combined listing:
%% Journal Articles
@article{fds358908,
Author = {Levin, ED},
Title = {What Can Fish Tell Us About Developmental Neurotoxic Risks
of the Sea?},
Journal = {BIRTH DEFECTS RESEARCH},
Volume = {111},
Number = {9},
Pages = {454-454},
Publisher = {WILEY},
Year = {2019},
Month = {May},
Key = {fds358908}
}
@article{fds369158,
Author = {Levin, E and Pippen, E and White, H and Kim, J and Kenou, B and Hawkey, A and Holloway, Z},
Title = {Chronic Steady Low-Dose Prenatal Diazinon Exposure of Rats
Causes Locomotor Hyperactivity, Increased Risk-taking
Behavior and Cognitive Impairment},
Journal = {NEUROTOXICOLOGY AND TERATOLOGY},
Volume = {73},
Pages = {83-83},
Publisher = {PERGAMON-ELSEVIER SCIENCE LTD},
Year = {2019},
Month = {May},
Key = {fds369158}
}
@article{fds369159,
Author = {Holloway, Z and Hawkey, A and Pippen, E and White, H and Kenou, B and Kim,
J and Greengrove, E and Levin, E},
Title = {Chronic paternal THC in rats causes long-lasting behavioral
disruption in the offspring},
Journal = {NEUROTOXICOLOGY AND TERATOLOGY},
Volume = {73},
Pages = {93-94},
Publisher = {PERGAMON-ELSEVIER SCIENCE LTD},
Year = {2019},
Month = {May},
Key = {fds369159}
}
@article{fds358919,
Author = {Kollins, S and Levin, E and Price, T and Murphy, S},
Title = {Delta-9-Tetrahydrocannabinol Exposure Alters Sperm
Methylation Profiles: Concurrent Results From Humans and
Rats},
Journal = {NEUROPSYCHOPHARMACOLOGY},
Volume = {42},
Pages = {S642-S643},
Publisher = {NATURE PUBLISHING GROUP},
Year = {2017},
Month = {November},
Key = {fds358919}
}
@article{fds358920,
Author = {Murphy, SK and Schrott, R and Visco, Z and Huang, Z and Grenier, C and Mitchell, J and Schechter, J and Lucas, J and Levin, ED and Price, T and Kollins, SH},
Title = {Environment and Gametic Epigenetic Reprogramming.},
Journal = {ENVIRONMENTAL AND MOLECULAR MUTAGENESIS},
Volume = {58},
Pages = {S28-S28},
Publisher = {WILEY},
Year = {2017},
Month = {September},
Key = {fds358920}
}
@article{fds358921,
Author = {Levin, ED},
Title = {Neurodevelopmental Toxicity of Tobacco Smoke and
Nicotine},
Journal = {NEUROTOXICOLOGY AND TERATOLOGY},
Volume = {61},
Pages = {153-153},
Publisher = {PERGAMON-ELSEVIER SCIENCE LTD},
Year = {2017},
Month = {May},
Key = {fds358921}
}
@article{fds370329,
Author = {Levin, E and Cauley, M and Hall, B and Abreu-Villaca, Y and Junaid, S and White, H and Kiany, A},
Title = {Prenatal exposure to tobacco smoke extract and some of its
constituents in rats cause persisting neurobehavioral
effects in the offspring},
Journal = {NEUROTOXICOLOGY AND TERATOLOGY},
Volume = {61},
Pages = {156-156},
Publisher = {PERGAMON-ELSEVIER SCIENCE LTD},
Year = {2017},
Month = {May},
Key = {fds370329}
}
@article{fds358922,
Author = {Murphy, SK and Keyhan, S and Guo, L and Tomins, K and Taylor, M and Joglekar, R and Huang, Z and Grenier, C and Liao, Y and Massarsky, A and Soubry, A and Lea, A and Burke, EE and Cauley, M and Hall, BJ and Lucas,
JE and Hoyo, C and Di Giulio and RT and Levin, ED and Price,
TM},
Title = {Environmental Influence on Preconceptional and Gestational
DNA Methylation Profiles.},
Journal = {ENVIRONMENTAL AND MOLECULAR MUTAGENESIS},
Volume = {57},
Pages = {S39-S39},
Publisher = {WILEY-BLACKWELL},
Year = {2016},
Month = {September},
Key = {fds358922}
}
@article{fds316075,
Author = {Levin, ED and Rezvani, AH and Xiao, Y and Yenugonda, VM and Brown, ML and Kellar, KJ},
Title = {Nicotinic treatments not only for tobacco, but also other
addictions},
Journal = {Biochemical Pharmacology},
Volume = {97},
Number = {4},
Pages = {635-635},
Publisher = {Elsevier BV},
Year = {2015},
Month = {October},
ISSN = {0006-2952},
url = {http://dx.doi.org/10.1016/j.bcp.2015.08.040},
Doi = {10.1016/j.bcp.2015.08.040},
Key = {fds316075}
}
@article{fds316106,
Author = {Bailey, J and Levin, E},
Title = {The neurobehavioral toxicity of FireMaster 550® in
zebrafish ( Danio rerio ): Chronic developmental and acute
adolescent exposures},
Journal = {Neurotoxicology and Teratology},
Volume = {49},
Pages = {118-118},
Publisher = {Elsevier BV},
Year = {2015},
Month = {May},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2015.04.064},
Doi = {10.1016/j.ntt.2015.04.064},
Key = {fds316106}
}
@article{fds316096,
Author = {Levin, ED},
Title = {Age and sex differences in starting nicotine
self-administration in early, mid or late adolescence vs.
adulthood: Cause and effect relationships determined in a
rat model},
Journal = {Neurotoxicology and Teratology},
Volume = {49},
Pages = {140-140},
Publisher = {Elsevier BV},
Year = {2015},
Month = {May},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2015.04.128},
Doi = {10.1016/j.ntt.2015.04.128},
Key = {fds316096}
}
@article{fds316116,
Author = {Hall, BJ and Cauley, M and Kiany, A and Burke, DA and Levin,
ED},
Title = {Low dose tobacco smoke extract exposure during development
causes long-term behavioral dysfunction in
rats},
Journal = {Neurotoxicology and Teratology},
Volume = {49},
Pages = {121-122},
Publisher = {Elsevier BV},
Year = {2015},
Month = {May},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2015.04.073},
Doi = {10.1016/j.ntt.2015.04.073},
Key = {fds316116}
}
@article{fds316105,
Author = {Oliveri, A and Levin, E},
Title = {Early-life exposure to organophosphate flame retardants
alters behavior in adult zebrafish: A comparison with
organophosphate pesticides},
Journal = {Neurotoxicology and Teratology},
Volume = {49},
Pages = {130-130},
Publisher = {Elsevier BV},
Year = {2015},
Month = {May},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2015.04.096},
Doi = {10.1016/j.ntt.2015.04.096},
Key = {fds316105}
}
@article{fds369160,
Author = {Levin, E and Hall, B and Cauley, M},
Title = {Neurotoxic effects on attention deficit and hyperactivity in
rodent models},
Journal = {Neurotoxicology and Teratology},
Volume = {49},
Pages = {116-116},
Publisher = {Elsevier BV},
Year = {2015},
Month = {May},
url = {http://dx.doi.org/10.1016/j.ntt.2015.04.057},
Doi = {10.1016/j.ntt.2015.04.057},
Key = {fds369160}
}
@article{fds274205,
Author = {Rezvani, AH and Levin, ED},
Title = {Assessment of pregnenolone effects on alcohol intake and
preference in male alcohol preferring (P)
rats.},
Journal = {Eur J Pharmacol},
Volume = {740},
Pages = {53-57},
Year = {2014},
Month = {October},
ISSN = {0145-6008},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000304806000362&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Abstract = {Neuroactive steroids can modulate a variety of
neurobehavioral functions via the GABAergic system. This
study was conducted to determine the importance of the
neurosteroid pregnenolone on the regulation of alcohol
intake. The effects of acute and chronic administration of
pregnenolone on alcohol intake were assessed in alcohol
preferring (P) rats. The rats were injected i.p. with the
vehicle or pregnenolone (25, 50 or 75 mg/kg) and their
alcohol and water intake were recorded at 2, 4, 6 and 24 h.
Also, the chronic effects of 50 mg/kg (i.p.) pregnenolone on
alcohol intake were determined. Our results show that
although the main effect of i.p. injection of pregnenolone
in reducing alcohol intake was not quite significant
compared with the vehicle, pregnenolone at 75 mg/kg
significantly (P<0.025) reduced alcohol intake. Regarding
alcohol preference, acute administration of pregnenolone
both at 50 mg/kg (P<0.05) and at 75 mg/kg (P<0.025)
significantly reduced alcohol preference. In chronic
experiments pregnenolone given for 10 consecutive days did
not show a significant effect on alcohol intake and alcohol
preference. Overall, although pregnenolone given i.p.
acutely and significantly reduced alcohol intake and
preference, the fact that chronic treatment did not show an
effect diminishes its promise to be considered for the
treatment of alcoholism. However, its profile of effects
might be different in human alcoholics.},
Doi = {10.1016/j.ejphar.2014.07.003},
Key = {fds274205}
}
@article{fds316110,
Author = {Zhang, C and Bailey, JM and Oliveri, AN and Frazier, J and Delarosa, A and Crosby, E and Janardhan, S and Mackinnon, S and Levin, ED and Cole,
GJ},
Title = {LONG-TERM BEHAVIORAL EFFECTS OF EMBRYONIC ETHANOL EXPOSURE
IN ZEBRAFISH},
Journal = {ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH},
Volume = {38},
Pages = {176A-176A},
Publisher = {WILEY-BLACKWELL},
Year = {2014},
Month = {June},
ISSN = {0145-6008},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000337523700705&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316110}
}
@article{fds316107,
Author = {Cauley, M and Burke, D and Hall, BJ and Seidler, FJ and Slotkin, TA and Levin, ED},
Title = {Sex-selective interaction of prenatal nicotine with neonatal
chlorpyrifos on novel object recognition in
rats},
Journal = {Neurotoxicology and Teratology},
Volume = {43},
Pages = {88-89},
Publisher = {Elsevier BV},
Year = {2014},
Month = {May},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2014.04.043},
Doi = {10.1016/j.ntt.2014.04.043},
Key = {fds316107}
}
@article{fds369161,
Author = {Hall, B and Cauley, M and Burke, D and Levin, E},
Title = {Neurobehavioral consequences of gestational exposure to a
low dose of tobacco smoke extract in rats},
Journal = {Neurotoxicology and Teratology},
Volume = {43},
Pages = {96-97},
Publisher = {Elsevier BV},
Year = {2014},
Month = {May},
url = {http://dx.doi.org/10.1016/j.ntt.2014.04.065},
Doi = {10.1016/j.ntt.2014.04.065},
Key = {fds369161}
}
@article{fds316104,
Author = {Burke, D and Levin, ED},
Title = {Nicotinic α4β2 antagonist treatment attenuates impairments
in radial-arm maze repeated acquisition caused by
dizocilpine in rats},
Journal = {Biochemical Pharmacology},
Volume = {86},
Number = {8},
Pages = {1231-1231},
Publisher = {Elsevier BV},
Year = {2013},
Month = {October},
ISSN = {0006-2952},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000326007000039&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Doi = {10.1016/j.bcp.2013.08.047},
Key = {fds316104}
}
@article{fds316095,
Author = {Rezvani, AH and Xiao, Y and Brown, ML and Paige, MA and Yenugonda, VM and Kellar, KJ and Levin, ED},
Title = {DESENSITIZATION OF A4 beta 2 NICOTINIC RECEPTORS ATTENUATES
ALCOHOL INTAKE AND PREFERENCE IN ALCOHOL PREFERRING P
RATS},
Journal = {ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH},
Volume = {37},
Pages = {247A-247A},
Publisher = {WILEY-BLACKWELL},
Year = {2013},
Month = {June},
ISSN = {0145-6008},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000318998301130&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316095}
}
@article{fds369162,
Author = {Bailey, J and Oliveri, A and Stapleton, H and Levin,
E},
Title = {Behavioral effects of short-term exposure to Firemaster
550},
Journal = {Neurotoxicology and Teratology},
Volume = {37},
Pages = {86-86},
Publisher = {Elsevier BV},
Year = {2013},
Month = {May},
url = {http://dx.doi.org/10.1016/j.ntt.2013.03.046},
Doi = {10.1016/j.ntt.2013.03.046},
Key = {fds369162}
}
@article{fds316093,
Author = {Yenugonda, VM and Xiao, Y and Levin, ED and Rezvani, AH and Tran, TT and Al-Muhtasib, N and Wells, C and Slade, S and Johnson, JE and Kong, H-S and Dakshanamurthy, S and Tomita, Y and Liu, Y and Paige, MA and Kellar, KJ and Brown, ML},
Title = {Design, synthesis, and characterization of picomolar
selective a4b2 nicotinic acetylcholine receptor
inhibitors},
Journal = {ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL
SOCIETY},
Volume = {244},
Pages = {1 pages},
Publisher = {AMER CHEMICAL SOC},
Year = {2012},
Month = {August},
ISSN = {0065-7727},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000324621805663&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316093}
}
@article{fds369163,
Author = {Levin, E and Cauley, M and Johnson, J and Sexton, H and Gordon, K and Seidler, F and Slotkin, T},
Title = {Does pharmacotherapy of preterm labor sensitize the brain to
neurotoxicants? Sequential exposure to dexamethasone and
chlorpyrifos},
Journal = {Neurotoxicology and Teratology},
Volume = {34},
Number = {3},
Pages = {368-368},
Publisher = {Elsevier BV},
Year = {2012},
Month = {May},
url = {http://dx.doi.org/10.1016/j.ntt.2012.05.002},
Doi = {10.1016/j.ntt.2012.05.002},
Key = {fds369163}
}
@article{fds358923,
Author = {Galici, R and Rezvani, AH and Aluisio, L and Lord, B and Levin, ED and Fraser, I and Boggs, J and Welty, N and Shoblock, JR and Motley, ST and Letavic, MA and Carruthers, NI and Dugovic, C and Lovenberg, TW and Bonaventure, P},
Title = {JNJ-39220675, A NOVEL SELECTIVE HISTAMINE H-3 RECEPTOR
ANTAGONIST, REDUCES THE ABUSE-RELATED EFFECTS OF ALCOHOL IN
RATS},
Journal = {INFLAMMATION RESEARCH},
Volume = {60},
Pages = {S333-S333},
Publisher = {SPRINGER BASEL AG},
Year = {2011},
Month = {September},
Key = {fds358923}
}
@article{fds316076,
Author = {Yen, J and Donerly, S and Levin, E and Linney, E},
Title = {Differing Effects of 3 Organophosphates (Chlorpyrifos,
Diazinon and Parathion) on Developing Zebrafish Nervous
System},
Journal = {Neurotoxicology and Teratology},
Volume = {33},
Number = {4},
Pages = {509-510},
Publisher = {Elsevier BV},
Year = {2011},
Month = {July},
ISSN = {0892-0362},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000294527900059&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Doi = {10.1016/j.ntt.2011.05.062},
Key = {fds316076}
}
@article{fds316102,
Author = {Rezvani, AH and Robinson, E and Eisenberg, L and Levin, ED and Bonaventure, P and Motley, T and Lovenberg, TW and Heilig, M and Thorsell, A and Cippitelli, A},
Title = {EFFECTS OF A NOVEL, SELECTIVE BRAIN NPY Y2 RECPTOR ANATONIST
JNJ-31020028, ON ALCOHOL CONSUMPTION, RELAPSE AND ANXIETY IN
RATS},
Journal = {ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH},
Volume = {35},
Number = {6},
Pages = {68A-68A},
Publisher = {WILEY-BLACKWELL},
Year = {2011},
Month = {June},
ISSN = {0145-6008},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000290804300230&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316102}
}
@article{fds369165,
Author = {White, H and Levin, E and Kellar, K and Aisen, P and Wesnes, K and Newhouse, P},
Title = {Transdermal Nicotine Treatment of Mild Cognitive Impairment:
A Multi-Center Randomized Controlled Trial},
Journal = {JOURNAL OF THE AMERICAN GERIATRICS SOCIETY},
Volume = {59},
Pages = {S11-S11},
Year = {2011},
Key = {fds369165}
}
@article{fds316108,
Author = {Rezvani, AH and Lumeng, L and Li, TK and Xiao, Y and Brown, ML and Paige,
MA and McDowell, BE and Rose, JE and Kellar, KJ and Levin,
ED},
Title = {NICOTINE SELF-ADMINISTRATION IN SELECTIVELY-BRED ALCOHOL
PREFERRING (P) RATS: NICOTINIC INVOLVEMENT},
Journal = {ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH},
Volume = {34},
Number = {6},
Pages = {18A-18A},
Publisher = {WILEY-BLACKWELL PUBLISHING, INC},
Year = {2010},
Month = {June},
ISSN = {0145-6008},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000278107200032&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316108}
}
@article{fds369167,
Author = {Newhouse, P and Levin, E and Kellar, K and Coderre, E and Wilkins, H and Aisen, P and White, H and Wesnes, K},
Title = {Transdermal Nicotine Treatment of Mild Cognitive Impairment
(MCI): A Multi-Center Pilot Study},
Journal = {AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY},
Volume = {17},
Number = {3},
Pages = {A102-A102},
Year = {2009},
Key = {fds369167}
}
@article{fds316091,
Author = {Levin, ED and Hampton, D and Xiao, Y and Kellar, KJ},
Title = {Sazetidine-A, a nicotinic desensitizing agent, decreases
nicotine self-administration in rats},
Journal = {BIOCHEMICAL PHARMACOLOGY},
Volume = {74},
Number = {8},
Pages = {SMA43-SMA44},
Publisher = {PERGAMON-ELSEVIER SCIENCE LTD},
Year = {2007},
Month = {October},
ISSN = {0006-2952},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000250188900096&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316091}
}
@article{fds316101,
Author = {Levin, ED and Linney, E and Slotkin, TA},
Title = {Complementary zebrafish and rat models of developmental
neurobehavioral toxicity: The case of organophosphate
pesticide exposure},
Journal = {Neurotoxicology and Teratology},
Volume = {29},
Number = {3},
Pages = {406-406},
Publisher = {Elsevier BV},
Year = {2007},
Month = {May},
ISSN = {0892-0362},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000247746900043&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Doi = {10.1016/j.ntt.2007.03.038},
Key = {fds316101}
}
@article{fds316078,
Author = {Levin, ED},
Title = {Nicotinic treatment for both symptomatic relief and
attenuation of cognitive decline with aging and Alzheimer's
dementia.},
Journal = {NEUROTOXICOLOGY},
Volume = {27},
Number = {6},
Pages = {1162-1162},
Publisher = {ELSEVIER SCIENCE BV},
Year = {2006},
Month = {December},
ISSN = {0161-813X},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000243211300069&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316078}
}
@article{fds316099,
Author = {Levin, ED and Roegge, C and Timofeeva, O and Seidler, FJ and Slotkin,
TA},
Title = {Low dose early postnatal diazinon exposure causes impaired
working memory on the radial-arm maze in rats during
adulthood.},
Journal = {NEUROTOXICOLOGY},
Volume = {27},
Number = {6},
Pages = {1165-1165},
Publisher = {ELSEVIER SCIENCE BV},
Year = {2006},
Month = {December},
ISSN = {0161-813X},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000243211300075&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316099}
}
@article{fds316117,
Author = {Roegge, C and Timofeva, O and Seidler, F and Slotkin, TA and Levin,
ED},
Title = {Persisting effects of early postnatal diazinon exposure on
emotional reactivity in rats},
Journal = {Neurotoxicology and Teratology},
Volume = {28},
Number = {6},
Pages = {709-709},
Publisher = {Elsevier BV},
Year = {2006},
Month = {November},
ISSN = {0892-0362},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000243168100018&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Doi = {10.1016/j.ntt.2006.09.015},
Key = {fds316117}
}
@article{fds316077,
Author = {Levin, ED and Bencan, Z and Cerutti, DT},
Title = {Assessing stress in zebrafish: Anxiolytic effects of
nicotine},
Journal = {Neurotoxicology and Teratology},
Volume = {28},
Number = {6},
Pages = {709-710},
Publisher = {Elsevier BV},
Year = {2006},
Month = {November},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2006.09.016},
Doi = {10.1016/j.ntt.2006.09.016},
Key = {fds316077}
}
@article{fds316092,
Author = {Levin, ED},
Title = {Cholinergic involvement in neurocognitive function: From
zebrafish to humans.},
Journal = {NEUROTOXICOLOGY},
Volume = {27},
Number = {5},
Pages = {892-893},
Publisher = {ELSEVIER SCIENCE BV},
Year = {2006},
Month = {September},
ISSN = {0161-813X},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000240408800072&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316092}
}
@article{fds316111,
Author = {Rezvani, AH and Levin, ED},
Title = {Nicotine-antipsychotic drugs interaction and sustained
attention in rats},
Journal = {INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY},
Volume = {9},
Pages = {S146-S146},
Publisher = {CAMBRIDGE UNIV PRESS},
Year = {2006},
Month = {July},
ISSN = {1461-1457},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000239495500566&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316111}
}
@article{fds316089,
Author = {Levin, ED},
Title = {Developing nicotinic therapy for cognitive impairment of
schizophrenia and aging-related dementia},
Journal = {INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY},
Volume = {9},
Pages = {S126-S126},
Publisher = {CAMBRIDGE UNIV PRESS},
Year = {2006},
Month = {July},
ISSN = {1461-1457},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000239495500494&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316089}
}
@article{fds316087,
Author = {Levin, ED},
Title = {Clozapine effects on memory function are reversed by
hippocampal damage},
Journal = {NEUROPSYCHOPHARMACOLOGY},
Volume = {30},
Pages = {S197-S197},
Publisher = {NATURE PUBLISHING GROUP},
Year = {2005},
Month = {December},
ISSN = {0893-133X},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000233442100513&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316087}
}
@article{fds316114,
Author = {Levin, ED and Rezvani, AH},
Title = {Adolescent rats show differential effects of nicotine and
alcohol relative to adults.},
Journal = {ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH},
Volume = {28},
Number = {5},
Pages = {175A-175A},
Publisher = {LIPPINCOTT WILLIAMS & WILKINS},
Year = {2004},
Month = {May},
ISSN = {0145-6008},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000221549301009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316114}
}
@article{fds316090,
Author = {Weiser, M and Levin, ED and George, TP and Newhouse, PA and Leonard,
S},
Title = {Nicotinic receptor modulation of attention: An endophenotype
for therapeutic drug development},
Journal = {BIOLOGICAL PSYCHIATRY},
Volume = {55},
Pages = {152S-152S},
Publisher = {ELSEVIER SCIENCE INC},
Year = {2004},
Month = {April},
ISSN = {0006-3223},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000220755300529&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316090}
}
@article{fds316079,
Author = {Levin, ED and Blackwelder, WR and Glasgow, HB and Burkholder, JM and Moeller, PR and Ramsdell, JS},
Title = {Learning impairment caused by infusion of a toxin produced
by Pfiesteria piscicida into the hippocampus of
rats.},
Journal = {TOXICOLOGICAL SCIENCES},
Volume = {72},
Pages = {71-71},
Publisher = {OXFORD UNIV PRESS},
Year = {2003},
Month = {March},
ISSN = {1096-6080},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000181518500347&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316079}
}
@article{fds316088,
Author = {Swain, H and Donerly, S and Chrysanthis, E and Yacsin, K and Linney, E and Levin, ED},
Title = {A zebrafish model for studying the neurobehavioral impacts
of developmental chlorpyrifos exposure.},
Journal = {TOXICOLOGICAL SCIENCES},
Volume = {72},
Pages = {129-129},
Publisher = {OXFORD UNIV PRESS},
Year = {2003},
Month = {March},
ISSN = {1096-6080},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000181518500630&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316088}
}
@article{fds316086,
Author = {LEVIN, ED and TORRY, D},
Title = {NICOTINE EFFECTS ON MEMORY PERFORMANCE},
Journal = {EFFECTS OF NICOTINE ON BIOLOGICAL SYSTEMS
II},
Pages = {329-335},
Publisher = {BIRKHAUSER VERLAG AG},
Editor = {Clarke, PBS and Quik, M and Adlkofer, F and Thurau,
K},
Year = {1995},
Month = {January},
ISBN = {3-7643-5083-0},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:A1995BC71W00043&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316086}
}
%% Papers Published
@article{fds375370,
Author = {Hawkey, AB and Shekey, N and Dean, C and Asrat, H and Koburov, R and Holloway, ZR and Kullman, SW and Levin, ED},
Title = {Developmental exposure to pesticides that disrupt retinoic
acid signaling causes persistent retinoid and behavioral
dysfunction in zebrafish.},
Journal = {Toxicol Sci},
Volume = {198},
Number = {2},
Pages = {246-259},
Publisher = {Oxford University Press (OUP)},
Year = {2024},
Month = {March},
url = {http://dx.doi.org/10.1093/toxsci/kfae001},
Abstract = {Early developmental exposure to environmental toxicants may
play a role in the risk for developing autism. A variety of
pesticides have direct effects on retinoic acid (RA)
signaling and as RA signaling has important roles in
neurodevelopment, such compounds may cause developmental
neurotoxicity through an overlapping adverse outcome
pathway. It is hypothesized that a pesticide's embryonic
effects on retinoid function may correspond with
neurobehavioral disruption later in development. In the
current studies, we determined the effects of RA-acting
pesticides on neurobehavioral development in zebrafish.
Buprofezin and imazalil caused generalized hypoactivity in
the larval motility test, whereas chlorothalonil and
endosulfan I led to selective hypoactivity and
hyperactivity, respectively. With buprofezin,
chlorothalonil, and imazalil, hypoactivity and/or novel
anxiety-like behaviors persisted in adulthood and buprofezin
additionally decreased social attraction responses in
adulthood. Endosulfan I did not produce significant adult
behavioral effects. Using qPCR analyses of adult brain
tissue, we observed treatment-induced alterations in RA
synthesis or catabolic genes, indicating persistent changes
in RA homeostasis. These changes were compound-specific,
with respect to expression directionality, and potential
patterns of homeostatic disruption. Results suggest the
likely persistence of disruptions in RA signaling well into
adulthood and may represent compensatory mechanisms
following early life stage exposures. This study
demonstrates that early developmental exposure to
environmental toxicants that interfere with RA signaling
causes short as well as long-term behavioral disruption in a
well-established zebrafish behavioral model and expand upon
the meaning of the RA adverse outcome pathway, indicating
that observed effects likely correspond with the nature of
underlying homeostatic effects.},
Doi = {10.1093/toxsci/kfae001},
Key = {fds375370}
}
@article{fds376105,
Author = {Marchese, MJ and Zhu, T and Hawkey, AB and Wang, K and Yuan, E and Wen, J and Be, SE and Levin, ED and Feng, L},
Title = {Prenatal and perinatal exposure to Per- and polyfluoroalkyl
substances (PFAS)-contaminated drinking water impacts
offspring neurobehavior and development.},
Journal = {Sci Total Environ},
Volume = {917},
Pages = {170459},
Year = {2024},
Month = {March},
url = {http://dx.doi.org/10.1016/j.scitotenv.2024.170459},
Abstract = {Per- and polyfluoroalkyl substances (PFAS) are persistent
organic pollutants ubiquitous in the environment and humans.
In-utero PFAS exposure is associated with numerous adverse
health impacts. However, little is known about how prenatal
PFAS mixture exposure affects offspring's neurobehavioral
function. This study aims to determine the causal
relationship between in-utero PFAS mixture exposure and
neurobehavioral changes in Sprague-Dawley rat offspring.
Dams were exposed via drinking water to the vehicle
(control), an environmentally relevant PFAS mixture, or a
high-dose PFAS mixture. The environmentally relevant mixture
was formulated to resemble measured tap water levels in
Pittsboro, NC, USA (10 PFAS compounds; sum PFAS
=758.6 ng/L). The high-dose PFAS load was 3.8 mg/L
(5000×), within the range of exposures in the experimental
literature. Exposure occurred seven days before mating until
birth. Following exposure to PFAS-laden water or the vehicle
during fetal development, neurobehavioral toxicity was
assessed in male and female offspring with a battery of
motor, cognitive, and affective function tests as juveniles,
adolescents, and adults. Just before weaning, the
environmentally relevant exposure group had smaller
anogenital distances compared to the vehicle and high-dose
groups on day 17, and males in the environmentally relevant
exposure group demonstrated lower weights than the high-dose
group on day 21 (p < 0.05). Reflex development delays were
seen in negative geotaxis acquisition for both exposure
groups compared to vehicle-exposed controls (p = 0.009).
Our post-weaning behavioral measures of anxiety, depression,
and memory were not found to be affected by maternal PFAS
exposure. In adolescence (week five) and adulthood (week
eight), the high PFAS dose significantly attenuated typical
sex differences in locomotor activity. Maternal exposure to
an environmentally relevant PFAS mixture produced
developmental delays in the domains of pup weight,
anogenital distance, and reflex acquisition for rat
offspring. The high-dose PFAS exposure significantly
decreased typical sex differences in locomotor
activity.},
Doi = {10.1016/j.scitotenv.2024.170459},
Key = {fds376105}
}
@article{fds374240,
Author = {Natarajan, S and Abass, G and Kim, L and Wells, C and Rezvani, AH and Levin, ED},
Title = {Acute and chronic glutamate NMDA antagonist treatment
attenuates dopamine D1 antagonist-induced reduction of
nicotine self-administration in female rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {234},
Pages = {173678},
Year = {2024},
Month = {January},
url = {http://dx.doi.org/10.1016/j.pbb.2023.173678},
Abstract = {Multiple interacting neural systems are involved in
sustaining nicotine reinforcement. We and others have shown
that dopamine D1 receptors and glutamate NMDA receptors both
play important roles in nicotine reinforcement. Blockade of
D1 receptors with the antagonist SCH-23390 (0.02 mg/kg)
both acutely and chronically significantly decreased
nicotine self-administration in rats. Blockade of NMDA
receptors (10 mg/kg) acutely with memantine significantly
increased nicotine self-administration, but chronic blockade
of NMDA receptors with memantine significantly decreased
nicotine self-administration. The current study examined the
interactions of acute and chronic administration of
SCH-23390 and memantine on nicotine self-administration in
female rats. Replicating earlier studies, acute and chronic
SCH-23390 significantly decreased nicotine
self-administration and memantine had a biphasic effect with
acute administration increasing nicotine self-administration
and chronic memantine showed a non-significant trend toward
decreasing it. However, chronic interaction study showed
that memantine significantly attenuated the decrease in
nicotine self-administration caused by chronic SCH-23390.
These studies provide important information that memantine
attenuates the efficacy of D1 antagonist SCH 23390 in
reducing nicotine-self-administration. These two drugs do
not appear to have mutually potentiating effects to aid
tobacco cessation.},
Doi = {10.1016/j.pbb.2023.173678},
Key = {fds374240}
}
@article{fds376269,
Author = {Stickler, A and Hawkey, AB and Gondal, A and Natarajan, S and Mead, M and Levin, ED},
Title = {Embryonic exposures to cadmium and PAHs cause long-term and
interacting neurobehavioral effects in zebrafish.},
Journal = {Neurotoxicol Teratol},
Volume = {102},
Pages = {107339},
Year = {2024},
url = {http://dx.doi.org/10.1016/j.ntt.2024.107339},
Abstract = {Developmental exposure to either polycyclic aromatic
hydrocarbons (PAHs) or heavy metals has been shown to cause
persisting and overlapping neurobehavioral effects in animal
models. However, interactions between these compounds have
not been well characterized, despite their co-occurrence in
a variety of environmental media. In two companion studies,
we examined the effects of developmental exposure to cadmium
(Cd) with or without co-exposure to prototypic PAHs
benzo[a]pyrene (BaP, Exp. 1) or fluoranthene (FA, Exp. 2)
using a developing zebrafish model. Zebrafish embryos were
exposed to Cd (0-0.3 μM), BaP (0-3 μM), FA (0-1.0 μM),
or binary Cd-PAH mixtures from 5 to 122 h post
fertilization (hpf). In Exp. 1, Cd and BaP produced
independent effects on an array of outcomes and interacting
effects on specific outcomes. Notably, Cd-induced deficits
in dark-induced locomotor stimulation were attenuated by BaP
co-exposure in the larval motility test and BaP-induced
hyperactivity was attenuated by Cd co-exposure in the
adolescent novel tank test. Likewise, in Exp. 2, Cd and FA
produced both independent and interacting effects.
FA-induced increases on adult post-tap activity in the tap
startle test were attenuated by co-exposure with Cd. On the
predator avoidance test, FA- and 0.3 μM Cd-induced
hyperactivity effects were attenuated by their co-exposure.
Taken together, these data indicate that while the effects
of Cd and these representative PAHs on zebrafish behavior
were largely independent of one another, binary mixtures can
produce sub-additive effects for some neurobehavioral
outcomes and at certain ages. This research emphasizes the
need for detailed risk assessments of mixtures containing
contaminants of differing classes, and for clarity on the
mechanisms which allow cross-class toxicant interactions to
occur.},
Doi = {10.1016/j.ntt.2024.107339},
Key = {fds376269}
}
@article{fds372839,
Author = {Kozal, JS and Jayasundara, N and Massarsky, A and Lindberg, CD and Oliveri, AN and Cooper, EM and Levin, ED and Meyer, JN and Giulio,
RTD},
Title = {Mitochondrial dysfunction and oxidative stress contribute to
cross-generational toxicity of benzo(a)pyrene in Danio
rerio.},
Journal = {Aquat Toxicol},
Volume = {263},
Pages = {106658},
Year = {2023},
Month = {October},
url = {http://dx.doi.org/10.1016/j.aquatox.2023.106658},
Abstract = {The potential for polycyclic aromatic hydrocarbons (PAHs) to
have adverse effects that persist across generations is an
emerging concern for human and wildlife health. This study
evaluated the role of mitochondria, which are maternally
inherited, in the cross-generational toxicity of
benzo(a)pyrene (BaP), a model PAH and known mitochondrial
toxicant. Mature female zebrafish (F0) were fed diets
containing 0, 12.5, 125, or 1250 μg BaP/g at a feed rate
of 1% body weight twice/day for 21 days. These females were
bred with unexposed males, and the embryos (F1) were
collected for subsequent analyses. Maternally-exposed
embryos exhibited altered mitochondrial function and
metabolic partitioning (i.e. the portion of respiration
attributable to different cellular processes), as evidenced
by in vivo oxygen consumption rates (OCRs). F1 embryos had
lower basal and mitochondrial respiration and ATP
turnover-mediated OCR, and increased proton leak and reserve
capacity. Reductions in mitochondrial DNA (mtDNA) copy
number, increases in mtDNA damage, and alterations in
biomarkers of oxidative stress were also found in
maternally-exposed embryos. Notably, the mitochondrial
effects in offspring occurred largely in the absence of
effects in maternal ovaries, suggesting that PAH-induced
mitochondrial dysfunction may manifest in subsequent
generations. Maternally-exposed larvae also displayed
swimming hypoactivity. The lowest observed effect level
(LOEL) for maternal BaP exposure causing mitochondrial
effects in offspring was 12.5 µg BaP/g diet (nominally
equivalent to 250 ng BaP/g fish). It was concluded that
maternal BaP exposure can cause significant mitochondrial
impairments in offspring.},
Doi = {10.1016/j.aquatox.2023.106658},
Key = {fds372839}
}
@article{fds370723,
Author = {Hawkey, AB and Unal, D and Holloway, ZR and Levin,
ED},
Title = {Developmental exposure of zebrafish to neonicotinoid
pesticides: Long-term effects on neurobehavioral
function.},
Journal = {Neurotoxicology},
Volume = {96},
Pages = {240-253},
Year = {2023},
Month = {May},
url = {http://dx.doi.org/10.1016/j.neuro.2023.05.003},
Abstract = {Neonicotinoid compounds are commonly used insecticides which
have become increasingly used as replacements of older
generations of insecticides, such as organophosphates. Given
the established neurotoxicity of cholinergic toxicants,
developmental neurotoxicity studies are needed to identify
in vertebrate species the potential toxicity of these
insecticides which act on nicotinic cholinergic receptors.
Previously, developmental exposure to a neonicotinoid
insecticide imidacloprid was shown to cause persisting
neurobehavioral toxicity in zebrafish. The current study
evaluated neurobehavioral effects of embryonic exposure to
two other neonicotinoid insecticides, clothianidin
(1-100 µM) and dinotefuran (1-100 µM) in zebrafish
(5-120 h post-fertilization), concentrations below the
threshold for increased lethality and overt
dysmorphogenesis. Neurobehavioral tests were conducted at
larval (6 days), adolescent (10 weeks) and adult (8 months)
ages. Both compounds caused short-term behavioral effects on
larval motility, although these effects were distinct from
one another. At a lower concentration (1 µM) clothianidin
increased dark-induced locomotor stimulation the second time
the lights turned off, while a higher concentration
(100 µM) reduced activity in the dark at its second
presentation. By contrast, dinotefuran (10-100 µM) caused
a general decrease in locomotion. Specific longer-term
neurobehavioral toxicity after early developmental exposure
was also seen. clothianidin (100 µM) reduced locomotor
activity in the novel tank in adolescence and adulthood, as
well as reduced baseline activity in the tap startle test
(1-100 µM) and reduced activity early (1-10 µM) or
throughout the predator avoidance test session (100 µM).
In addition to locomotor effects, clothianidin altered the
diving response in a dose-, age- and time-block-dependent
manner (1 µM, 100 µM), causing fish to remain further
away from a fast predator cue (100 µM) relative to
controls. Dinotefuran produced comparatively fewer effects,
increasing the diving response in adulthood (10 µM), but
not adolescence, and suppressing initial locomotor activity
in the predator avoidance test (1-10 µM). These data
indicate that neonicotinoid insecticides may carry some of
the same risks for vertebrates posed by other classes of
insecticides, and that these adverse behavioral consequences
of early developmental exposure are evident well into
adulthood.},
Doi = {10.1016/j.neuro.2023.05.003},
Key = {fds370723}
}
@article{fds367718,
Author = {Hawkey, AB and Evans, J and Holloway, ZR and Pippen, E and Jarrett, O and Kenou, B and Slotkin, TA and Seidler, FJ and Levin,
ED},
Title = {Developmental exposure to the flame retardant, triphenyl
phosphate, causes long-lasting neurobehavioral and
neurochemical dysfunction.},
Journal = {Birth Defects Res},
Volume = {115},
Number = {3},
Pages = {357-370},
Year = {2023},
Month = {February},
url = {http://dx.doi.org/10.1002/bdr2.2125},
Abstract = {BACKGROUND: Human exposures to organophosphate flame
retardants result from their use as additives in numerous
consumer products. These agents are replacements for
brominated flame retardants but have not yet faced similar
scrutiny for developmental neurotoxicity. We examined a
representative organophosphate flame retardant, triphenyl
phosphate (TPP) and its potential effects on behavioral
development and dopaminergic function. METHODS: Female
Sprague-Dawley rats were given low doses of TPP (16 or
32 mg kg-1 day-1 ) via subcutaneous osmotic minipumps,
begun preconception and continued into the early postnatal
period. Offspring were administered a battery of behavioral
tests from adolescence into adulthood, and littermates were
used to evaluate dopaminergic synaptic function. RESULTS:
Offspring with TPP exposures showed increased latency to
begin eating in the novelty-suppressed feeding test,
impaired object recognition memory, impaired choice accuracy
in the visual signal detection test, and sex-selective
effects on locomotor activity in adolescence (males) but not
adulthood. Male, but not female, offspring showed marked
increases in dopamine utilization in the striatum, evidenced
by an increase in the ratio of the primary dopamine
metabolite (3,4-dihydroxyphenylacetic acid) relative to
dopamine levels. CONCLUSIONS: These results indicate that
TPP has adverse effects that are similar in some respects to
those of organophosphate pesticides, which were restricted
because of their developmental neurotoxicity.},
Doi = {10.1002/bdr2.2125},
Key = {fds367718}
}
@article{fds369719,
Author = {Hawkey, AB and Mead, M and Natarajan, S and Gondal, A and Jarrett, O and Levin, ED},
Title = {Embryonic exposure to PFAS causes long-term,
compound-specific behavioral alterations in
zebrafish.},
Journal = {Neurotoxicol Teratol},
Volume = {97},
Pages = {107165},
Year = {2023},
url = {http://dx.doi.org/10.1016/j.ntt.2023.107165},
Abstract = {Per- and polyfluoroalkyl substances (PFAS) are commonly used
as surfactants and coatings for industrial processes and
consumer products. These compounds have been increasingly
detected in drinking water and human tissue, and concern
over their potential effects on health and development is
growing. However, relatively little data are available for
their potential impacts on neurodevelopment and the degree
to which different compounds within this class may differ
from one another in their neurotoxicity. The present study
examined the neurobehavioral toxicology of two
representative compounds in a zebrafish model. Zebrafish
embryos were exposed to 0.1-100uM perfluorooctanoic acid
(PFOA) or 0.01-1.0uM perfluorooctanesulfonic acid (PFOS)
from 5 to 122 h post-fertilization. These concentrations
were below threshold for producing increased lethality or
overt dysmorphologies, and PFOA was tolerated at a
concentration 100× higher than PFOS. Fish were maintained
to adulthood, with behavioral assessments at 6 days,
3 months (adolescence) and 8 months of age (adulthood).
Both PFOA and PFOS caused behavioral changes in zebrafish,
but PFOS and PFOS produced strikingly different phenotypes.
PFOA was associated with increased larval motility in the
dark (100uM), and enhanced diving responses in adolescence
(100uM) but not adulthood. PFOS was associated with a
reversed light-dark response in the larval motility test
(0.1-1uM), whereby the fish were more active in the light
than the dark. PFOS also caused time-dependent changes in
locomotor activity in the novel tank test during adolescence
(0.1-1.0uM) and an overall pattern of hypoactivity in
adulthood at the lowest concentration (0.01uM).
Additionally, the lowest concentration of PFOS (0.01uM)
reduced acoustic startle magnitude in adolescence, but not
adulthood. These data suggest that PFOS and PFOA both
produce neurobehavioral toxicity, but these effects are
quite distinct from one another.},
Doi = {10.1016/j.ntt.2023.107165},
Key = {fds369719}
}
@article{fds367274,
Author = {Schrott, R and Modliszewski, JL and Hawkey, AB and Grenier, C and Holloway, Z and Evans, J and Pippen, E and Corcoran, DL and Levin, ED and Murphy, SK},
Title = {Sperm DNA methylation alterations from cannabis extract
exposure are evident in offspring.},
Journal = {Epigenetics Chromatin},
Volume = {15},
Number = {1},
Pages = {33},
Year = {2022},
Month = {September},
url = {http://dx.doi.org/10.1186/s13072-022-00466-3},
Abstract = {BACKGROUND: Cannabis legalization is expanding and men are
the predominant users. We have limited knowledge about how
cannabis impacts sperm and whether the effects are
heritable. RESULTS: Whole genome bisulfite sequencing (WGBS)
data were generated for sperm of rats exposed to: (1)
cannabis extract (CE) for 28 days, then 56 days of vehicle
only (~ one spermatogenic cycle); (2) vehicle for
56 days, then 28 days of CE; or (3) vehicle only. Males
were then mated with drug-naïve females to produce F1
offspring from which heart, brain, and sperm tissues
underwent analyses. There were 3321 nominally significant
differentially methylated CpGs in F0 sperm identified via
WGBS with select methylation changes validated via bisulfite
pyrosequencing. Significant methylation changes validated in
F0 sperm of the exposed males at the gene 2-Phosphoxylose
Phosphatase 1 (Pxylp1) were also detectable in their F1
sperm but not in controls. Changes validated in exposed F0
sperm at Metastasis Suppressor 1-Like Protein (Mtss1l) were
also present in F1 hippocampal and nucleus accumbens (NAc)
of the exposed group compared to controls. For Mtss1l, a
significant sex-specific relationship between DNA
methylation and gene expression was demonstrated in the F1
NAc. Phenotypically, rats born to CSE-exposed fathers
exhibited significant cardiomegaly relative to those born to
control fathers. CONCLUSIONS: This is the first
characterization of the effect of cannabis exposure on the
entirety of the rat sperm methylome. We identified
CE-associated methylation changes across the sperm
methylome, some of which persisted despite a "washout"
period. Select methylation changes validated via bisulfite
pyrosequencing, and genes associated with methylation
changes were involved in early developmental processes.
Preconception CE exposure is associated with detectable
changes in offspring DNA methylation that are functionally
related to changes in gene expression and cardiomegaly.
These results support that paternal preconception exposure
to cannabis can influence offspring outcomes.},
Doi = {10.1186/s13072-022-00466-3},
Key = {fds367274}
}
@article{fds363005,
Author = {Hawkey, AB and Pippen, E and Kenou, B and Holloway, Z and Slotkin, TA and Seidler, FJ and Levin, ED},
Title = {Persistent neurobehavioral and neurochemical anomalies in
middle-aged rats after maternal diazinon
exposure.},
Journal = {Toxicology},
Volume = {472},
Pages = {153189},
Year = {2022},
Month = {April},
url = {http://dx.doi.org/10.1016/j.tox.2022.153189},
Abstract = {Diazinon is an organophosphate pesticide that has a history
of wide use. Developmental exposures to organophosphates
lead to neurobehavioral changes that emerge early in life
and can persist into adulthood. However, preclinical studies
have generally evaluated changes through young adulthood,
whereas the persistence or progression of deficits into
middle age remain poorly understood. The current study
evaluated the effects of maternal diazinon exposure on
behavior and neurochemistry in middle age, at 1 year
postpartum, comparing the results to our previous studies of
outcomes at adolescence and in young adulthood (4 months of
age) (Hawkey 2020). Female rats received 0, 0.5 or
1.0 mg/kg/day of diazinon via osmotic minipump throughout
gestation and into the postpartum period. The offspring were
tested on a battery of locomotor, affective, and cognitive
tests at young adulthood and during middle age. Some of the
neurobehavioral consequences of developmental DZN seen
during adolescence and young adulthood faded with continued
aging, whereas other neurobehavioral effects emerged with
aging. At middle age, the rats showed few locomotor effects,
in contrast to the locomotor hyperactivity that had been
observed in adolescence. Notably, though, DZN exposure
during development impaired reference memory performance in
middle-aged males, an effect that had not been seen in the
younger animals. Likewise, middle-aged females exposed to
DZN showed deficient attentional accuracy, an effect not
seen in young adults. Across adulthood, the continued
potential for behavioral defects was associated with altered
dopaminergic function, characterized by enhanced dopamine
utilization that was regionally-selective (striatum but not
frontal/parietal cortex). This study shows that the
neurobehavioral impairments from maternal low dose exposure
to diazinon not only persist, but may continue to evolve as
animals enter middle age.},
Doi = {10.1016/j.tox.2022.153189},
Key = {fds363005}
}
@article{fds362375,
Author = {Rezvani, AH and Cauley, M and Levin, ED},
Title = {Time-dependent effects of nicotine on reversal of
dizocilpine-induced attentional impairment in female
rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {215},
Pages = {173359},
Year = {2022},
Month = {April},
url = {http://dx.doi.org/10.1016/j.pbb.2022.173359},
Abstract = {Nicotine and nicotinic compounds have been found to
attenuate the attentional impairments caused by the
glutamate NMDA antagonist dizocilpine (MK-801). The timing
of the nicotine effect on attention in rodents has not yet
been determined. In the current study, we tested the
interaction of dizocilpine with nicotine. Nicotine was given
at a range of times (30 to 240 min) prior to dizocilpine
administration and before testing on an operant signal
detection task. Each rat was assessed with each dose timing.
This protocol was repeated twice with one week between
phases of testing. In the first phase, correct rejection
performance was significantly impaired by 0.05 mg/kg of
dizocilpine and this impairment was significantly attenuated
by nicotine given sc 30-150 min prior to dizocilpine
administration. The greater dizocilpine-induced percent
correct rejection impairment seen during the first phase of
drug challenge, was significantly attenuated by nicotine
given 30 or 90 min before the start of the 1-h test
session. During the second phase, the dizocilpine-induced
repeated acquisition impairment was more modest. During this
phase of testing nicotine administered 60, 90 or 150 min
before testing significantly attenuated the
dizocilpine-induced impairment. In both phases of testing,
nicotine administration 240 min prior to testing was not
seen to attenuate the dizocilpine-induced impairment. During
the first phase but not the second phase, dizocilpine
administration caused a significant impairment in percent
hit. Nicotine was not found to have a significant effect in
the second phase. Response omissions were significantly
increased by dizocilpine during the first, but not the
second phase. Nicotine was not found to have any significant
effects on response omission. Overall, our data show that
nicotine administration prior to dizocilpine administration
was able to significantly improve dizocilpine-induced
attentional impairment in a time-dependent
manner.},
Doi = {10.1016/j.pbb.2022.173359},
Key = {fds362375}
}
@article{fds361966,
Author = {Joglekar, R and Cauley, M and Lipsich, T and Corcoran, DL and Patisaul,
HB and Levin, ED and Meyer, JN and McCarthy, MM and Murphy,
SK},
Title = {Developmental nicotine exposure and masculinization of the
rat preoptic area.},
Journal = {Neurotoxicology},
Volume = {89},
Pages = {41-54},
Year = {2022},
Month = {March},
url = {http://dx.doi.org/10.1016/j.neuro.2022.01.005},
Abstract = {Nicotine is a neuroteratogenic component of tobacco smoke,
e-cigarettes, and other products and can exert sex-specific
effects in the developing brain, likely mediated through sex
hormones. Estradiol modulates expression of nicotinic
acetylcholine receptors in rats, and plays critical roles in
neurodevelopmental processes, including sexual
differentiation of the brain. Here, we examined the effects
of developmental nicotine exposure on the sexual
differentiation of the preoptic area (POA), a brain region
that normally displays robust structural sexual dimorphisms
and controls adult mating behavior in rodents. Using a rat
model of gestational exposure, developing pups were exposed
to nicotine (2 mg/kg/day) via maternal osmotic minipump
(subcutaneously, sc) throughout the critical window for
brain sexual differentiation. At postnatal day (PND) 4, a
subset of offspring was analyzed for epigenetic effects in
the POA. At PND40, all offspring were gonadectomized,
implanted with a testosterone-releasing capsule (sc), and
assessed for male sexual behavior at PND60. Following sexual
behavior assessment, the area of the sexually dimorphic
nucleus of the POA (SDN-POA) was measured using
immunofluorescent staining techniques. In adults, normal sex
differences in male sexual behavior and in the SDN-POA area
were eliminated in nicotine-treated animals. Using novel
analytical approaches to evaluate overall masculinization of
the adult POA, we identified significant masculinization of
the nicotine-treated female POA. In neonates (PND4),
nicotine exposure induced trending alterations in
methylation-dependent masculinizing gene expression and DNA
methylation levels at sexually-dimorphic differentially
methylated regions, suggesting that developmental nicotine
exposure is capable of triggering masculinization of the rat
POA via epigenetic mechanisms.},
Doi = {10.1016/j.neuro.2022.01.005},
Key = {fds361966}
}
@article{fds359061,
Author = {Levin, ED and Wells, C and Slade, S and Johnson, J and Petro, A and Rezvani, AH and Rose, JE},
Title = {Chronic infusions of mecamylamine into the medial habenula:
Effects on nicotine self-administration in
rats.},
Journal = {Behav Brain Res},
Volume = {416},
Pages = {113574},
Year = {2022},
Month = {January},
url = {http://dx.doi.org/10.1016/j.bbr.2021.113574},
Abstract = {The habenula is an epithalamic structure through which
descending connections go from the telencephalon to the
brainstem, putting it in a key location to provide feedback
control over the ascending projections from the brainstem to
the telencephalon. The medial habenula has a high
concentration of nicotinic receptors. We assessed the role
of medial habenular nicotinic receptors for nicotine
self-administration (SA) in female young adult
Sprague-Dawley rats. The rats had bilateral chronic infusion
cannulae placed into the medial habenula nucleus. Each
cannula was connected to a slow delivery osmotic minipump to
chronically infuse mecamylamine (100 µg/side/day) or
vehicle for four consecutive weeks. The rats were tested for
nicotine SA for the first two weeks of mecamylamine
infusion. Then, they had one week of enforced abstinence,
during which they had no access to the nicotine SA. Finally,
they had one week of resumed nicotine SA access. There was a
significantly differential mecamylamine effects in animals
with lower and higher pretreatment baseline nicotine SA.
Rats with lower baseline nicotine SA levels showed a nearly
significant mecamylamine-induced reduction in SA while those
with higher baseline levels of SA showed a significant
mecamylamine-induced increase in nicotine SA. This study
determined that medial habenular nicotinic receptors are
important for nicotine reinforcement. Baseline level of
performance makes a crucial difference for the involvement
of habenular mechanisms in nicotine reinforcement with
nicotinic activation being important for maintaining
nicotine self-administration for those with lower levels of
baseline self-administration and the opposite effect with
subjects with higher levels of baseline self-administration.},
Doi = {10.1016/j.bbr.2021.113574},
Key = {fds359061}
}
@article{fds363862,
Author = {Levin, ED and Bushnell, S and Newland, MC and Meyer, J and Boyes,
W},
Title = {Introduction: The continuing importance of behavioral
toxicology: In memory of Philip J. Bushnell,
Ph.D.},
Journal = {Neurotoxicol Teratol},
Volume = {92},
Pages = {107107},
Year = {2022},
url = {http://dx.doi.org/10.1016/j.ntt.2022.107107},
Doi = {10.1016/j.ntt.2022.107107},
Key = {fds363862}
}
@article{fds366213,
Author = {Eddins, D and Petro, A and Levin, ED},
Title = {Impact of acute nicotine exposure on monoaminergic systems
in adolescent and adult male and female rats.},
Journal = {Neurotoxicol Teratol},
Volume = {93},
Pages = {107122},
Year = {2022},
url = {http://dx.doi.org/10.1016/j.ntt.2022.107122},
Abstract = {Adolescence is a period of risk for beginning tobacco
addiction. Differential neural response to nicotine in
adolescents vs. adults may help explain the increased
vulnerability to nicotine self-administration seen with
adolescent onset. We indexed the effects of acute nicotine
ditartrate (0.4 mg/kg, salt weight) administration on
dopamine (DA) and serotonin (5HT) as well as the DA
metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in several
brain regions (nucleus accumbens, striatum and frontal
cortex) of 6-week old (adolescent) and 10-week old (young
adult) Sprague-Dawley rats. When nicotine was administered
DA concentrations in the accumbens were significantly higher
in adults than in adolescents, whereas there was no
age-related difference without nicotine. However neither age
group showed a significant effect of nicotine vs.
age-matched controls. DA turnover in the accumbens was
significantly greater in adolescent females in response to
nicotine, but adult females did not show this effect and
neither did males of either age group. DA turnover in the
striatum was significantly higher in adolescents than adults
regardless of nicotine administration. In the frontal
cortex, there was a more complex effect. Without nicotine,
adult male rats had higher DA concentrations than adolescent
males, whereas female rats did not differ from adolescent to
adult ages. When given nicotine, the age effect was no
longer seen in males. However, there was not a significant
effect of nicotine vs. age-matched controls in either age
group. No age or nicotine effects were seen in females. 5HT
in the accumbens was significantly increased by nicotine
administration in adults but not in adolescents. Altered
neural responsivity of adolescents to nicotine-induced
neural effects particularly in accumbens DA and 5HT may be
related to the increased nicotine dose concentrations they
self-administer.},
Doi = {10.1016/j.ntt.2022.107122},
Key = {fds366213}
}
@article{fds366214,
Author = {Hawkey, AB and Piatos, P and Holloway, Z and Boyda, J and Koburov, R and Fleming, E and Di Giulio and RT and Levin, ED},
Title = {Embryonic exposure to benzo[a]pyrene causes age-dependent
behavioral alterations and long-term metabolic dysfunction
in zebrafish.},
Journal = {Neurotoxicol Teratol},
Volume = {93},
Pages = {107121},
Year = {2022},
url = {http://dx.doi.org/10.1016/j.ntt.2022.107121},
Abstract = {Polycyclic aromatic hydrocarbons (PAH) are products of
incomplete combustion which are ubiquitous pollutants and
constituents of harmful mixtures such as tobacco smoke,
petroleum and creosote. Animal studies have shown that these
compounds exert developmental toxicity in multiple organ
systems, including the nervous system. The relative
persistence of or recovery from these effects across the
lifespan remain poorly characterized. These studies tested
for persistence of neurobehavioral effects in AB* zebrafish
exposed 5-120 h post-fertilization to a typical PAH,
benzo[a]pyrene (BAP). Study 1 evaluated the neurobehavioral
effects of a wide concentration range of BAP (0.02-10 μM)
exposures from 5 to 120 hpf during larval (6 days) and
adult (6 months) stages of development, while study 2
evaluated neurobehavioral effects of BAP (0.3-3 μM) from 5
to 120 hpf across four stages of development: larval
(6 days), adolescence (2.5 months), adulthood (8 months)
and late adulthood (14 months). Embryonic BAP exposure
caused minimal effects on larval motility, but did cause
neurobehavioral changes at later points in life. Embryonic
BAP exposure led to nonmonotonic effects on adolescent
activity (0.3 μM hyperactive, Study 2), which attenuated
with age, as well as startle responses (0.2 μM enhanced,
Study 1) at 6 months of age. Similar startle changes were
also detected in Study 2 (1.0 μM), though it was observed
that the phenotype shifted from reduced pretap activity to
enhanced posttap activity from 8 to 14 months of age.
Changes in the avoidance (0.02-10 μM, Study 1) and
approach (reduced, 0.3 μM, Study 2) of aversive/social
cues were also detected, with the latter attenuating from 8
to 14 months of age. Fish from study 2 were maintained into
aging (18 months) and evaluated for overall and
tissue-specific oxygen consumption to determine whether
metabolic processes in the brain and other target organs
show altered function in late life based on embryonic PAH
toxicity. BAP reduced whole animal oxygen consumption, and
overall reductions in total basal, mitochondrial basal, and
mitochondrial maximum respiration in target organs,
including the brain, liver and heart. The present data show
that embryonic BAP exposure can lead to neurobehavioral
impairment across the life-span, but that these long-term
risks differentially emerge or attenuate as development
progresses.},
Doi = {10.1016/j.ntt.2022.107121},
Key = {fds366214}
}
@article{fds359062,
Author = {Holloway, Z and Hawkey, AB and Pippen, E and White, H and Katragadda, V and Kenou, B and Wells, C and Murphy, SK and Rezvani, AH and Levin,
ED},
Title = {Corrigendum to "Paternal cannabis extract exposure in rats:
Preconception timing effects on neurobehavioral effects in
offspring" [Neurotoxicology 81 (2020) 180-188].},
Journal = {Neurotoxicology},
Volume = {87},
Pages = {258},
Year = {2021},
Month = {December},
url = {http://dx.doi.org/10.1016/j.neuro.2021.08.009},
Doi = {10.1016/j.neuro.2021.08.009},
Key = {fds359062}
}
@article{fds359689,
Author = {Slotkin, TA and Levin, ED and Seidler, FJ},
Title = {Paternal Cannabis Exposure Prior to Mating, but Not
Δ9-Tetrahydrocannabinol, Elicits Deficits in Dopaminergic
Synaptic Activity in the Offspring.},
Journal = {Toxicol Sci},
Volume = {184},
Number = {2},
Pages = {252-264},
Year = {2021},
Month = {November},
url = {http://dx.doi.org/10.1093/toxsci/kfab117},
Abstract = {The legalization and increasing availability of cannabis
products raises concerns about the impact on offspring of
users, and little has appeared on the potential contribution
of paternal use. We administered cannabis extract to male
rats prior to mating, with two different 28-day exposures,
one where there was a 56-day interval between the end of
exposure and mating ("Early Cannabis"), and one just prior
to mating ("Late Cannabis"); the extract delivered
4 mg/kg/day of the main psychoactive component,
Δ9-tetrahydrocannabinol. We then assessed the impact on
dopamine (DA) systems in the offspring from the onset of
adolescence (postnatal day 30) through middle age (postnatal
day 150), measuring the levels of DA and its primary
metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) in
various brain regions. Paternal cannabis with either regimen
elicited a profound and persistent deficit in DA utilization
(DOPAC/DA ratio) in the offspring, indicative of subnormal
presynaptic activity. However, the two regimens differed in
the underlying mechanism, with Early Cannabis reducing DOPAC
whereas Late Cannabis increased DA and elicited a smaller
reduction in DOPAC. Effects were restricted to male
offspring. The effects of cannabis were not reproduced by
equivalent exposure to its Δ9-tetrahydrocannabinol, nor did
we see the effects with perinatal exposure to tobacco smoke
or some of its fetotoxic contributors (benzo[a]pyrene
without or with nicotine). Our studies provide some of the
first evidence for adverse effects of paternal cannabis
administration on neurodevelopment in the offspring, and
reinforce the important consequences of paternal drug use in
the preconception period.},
Doi = {10.1093/toxsci/kfab117},
Key = {fds359689}
}
@article{fds359487,
Author = {Levin, ED and Wells, C and Pace, C and Abass, G and Hawkey, A and Holloway,
Z and Rezvani, AH and Rose, JE},
Title = {Self-administration by female rats of low doses of nicotine
alone vs. nicotine in tobacco smoke extract.},
Journal = {Drug Alcohol Depend},
Volume = {228},
Pages = {109073},
Year = {2021},
Month = {November},
url = {http://dx.doi.org/10.1016/j.drugalcdep.2021.109073},
Abstract = {BACKGROUND: Nicotine has reinforcing effects, but there are
thousands of other compounds in tobacco, some of which might
interact with nicotine reinforcement. AIMS: This rat study
was conducted to determine if nicotine self-administration
is altered by co-administration of the complex mixture of
compounds in tobacco smoke extract (TSE). METHODS: Female
Sprague-Dawley rats were tested for self-administration of
low doses of nicotine (3 or 10 µg/kg/infusion) at three
different rates of reinforcement (FR1, FR3 and FR5) over
three weeks either alone or together with the complex
mixture of tobacco smoke extract (TSE). RESULTS: Rats
self-administering 3 µg/kg/infusion of nicotine alone
showed a rapid initiation on an FR1 schedule, but declined
with FR5. Rats self-administering nicotine in TSE acquired
self-administration more slowly, but increased responding
over the course of the study. With 10 µg/kg/infusion rats
self-administered significantly more nicotine alone than
rats self-administering the same nicotine dose in TSE. Rats
self-administering nicotine alone took significantly more
infusions with the 10 than the 3 µg/kg/infusion dose,
whereas rats self-administering nicotine in TSE did not.
Nicotine in TSE led to a significantly greater locomotor
hyperactivity at a dose of 0.1 mg/kg compared to rats that
received nicotine alone. Rats self-administering nicotine
alone had significantly more responding on the active vs.
inactive lever, but rats self-administering the same
nicotine doses in TSE did not. CONCLUSIONS:
Self-administration of nicotine in a purer form appears to
be more clearly discriminated and dose-related than nicotine
self-administered in the complex mixture of
TSE.},
Doi = {10.1016/j.drugalcdep.2021.109073},
Key = {fds359487}
}
@article{fds358892,
Author = {Rezvani, AH and Wells, C and Hawkey, A and Blair, G and Koburov, R and Ko,
A and Schwartz, A and Kim, VJ and Levin, ED},
Title = {Differential behavioral functioning in the offspring of rats
with high vs. low self-administration of the opioid agonist
remifentanil.},
Journal = {Eur J Pharmacol},
Volume = {909},
Pages = {174407},
Year = {2021},
Month = {October},
url = {http://dx.doi.org/10.1016/j.ejphar.2021.174407},
Abstract = {Opioid use disorder (OUD) has a variety of adverse effects
on both the users and their offspring. In the current study,
a random group of Sprague-Dawley rats (25 females and 15
males) were tested for intravenous self-administration of
the opioid agonist remifentanil to determine the range of
acquisition for opioid. One-month after the end of
self-administration of remifentanil, rats with the highest
intake were mated together and rats with lowest intake were
mated together. Then, the offspring of the two groups were
tested for anxiety-like behavior, locomotor activity,
nociception and intravenous remifentanil
self-administration. The parents showed a range of
remifentanil self-administration, especially in the female
rats. The offspring of the parents with low and high
remifentanil self-administration showed significant
differences in specific behavioral functions. On the
hotplate test of nociception, the female offspring parents
with high remifentanil self-administration had significantly
longer hotplate latencies, indicating reduced nociception,
than the female offspring of parents with low
remifentanil-self-administration, whereas there was no
difference in the male offspring of low and high responding
parents. In the elevated plus maze test of anxiety-like
behavior, the offspring of the parents with high
remifentanil intake showed more anxiety-like behavior than
the offspring of the parents with low remifentanil intake
regardless of sex. Locomotor activity was not significantly
different. Interestingly, no significant differences in
remifentanil self-administration in the offspring of parents
with low and high remifentanil self-administration were
detected. Overall, our data suggest a considerable range in
remifentanil self-administration in rats and the offspring
of rats with high opioid self-administration exhibit
different behaviors vs offspring of rats with low opioid
self-administration.},
Doi = {10.1016/j.ejphar.2021.174407},
Key = {fds358892}
}
@article{fds358894,
Author = {Jao, NC and Levin, ED and Simon, MA and Hitsman, B},
Title = {Differences in Cognitive Task Performance, Reinforcement
Enhancement, and Nicotine Dependence Between Menthol and
Nonmenthol Cigarette Smokers.},
Journal = {Nicotine Tob Res},
Volume = {23},
Number = {11},
Pages = {1902-1910},
Year = {2021},
Month = {October},
url = {http://dx.doi.org/10.1093/ntr/ntab120},
Abstract = {INTRODUCTION: Menthol has been shown to target similar brain
regions and neural receptors as nicotine, yet the
association between menthol cigarette use and cognitive
performance remains unknown. AIMS AND METHODS: This study
examined differences in cognitive task performance between
menthol (MS) and nonmenthol (NMS) cigarette smokers after
acute cigarette consumption. Sixty white and black and/or
African American, nonabstinent, MS (n = 30) and NMS (n = 30)
were assessed presmoking and postsmoking their preferred
cigarette on four computerized tasks: Continuous Performance
Task (CPT; alerting attention), N-Back Task (working
memory), Finger Tapping Task (motor control), and Apple
Picker Task (reinforcement enhancement). Self-reported
nicotine dependence and objective smoking topography
measures were also compared between groups. RESULTS: Initial
unadjusted analyses showed a significant effect of cigarette
type × time on CPT speed (p = .042), where MS improved
while NMS group worsened in CPT speed after smoking. After
controlling for baseline cigarette craving and cigarette
nicotine levels, the effect of cigarette type × time for
all cognitive outcomes was statistically nonsignificant (ps
> .05). However, there remained a significant effect of
cigarette type, where MS versus NMS had poorer CPT (p =
.046) and N-Back Task accuracy (p = .006) but faster N-Back
speed (p = .039). There were no statistically significant
differences between groups on reinforcement enhancement,
nicotine dependence, or smoking behavior outcomes (ps >
.05). CONCLUSIONS: Contrary to our hypotheses, results did
not find a significant effect of cigarette type on the
change in cognitive performance after acute smoking in
nonabstinent smokers. Further studies are needed to clarify
the specific pharmacological effects of nicotine and menthol
on cognitive functioning. IMPLICATIONS: The current study is
the first to compare the potential enhancement of cognitive
task performance after acute cigarette smoking between
satiated menthol and nonmenthol cigarette smokers. Study
results suggest that acute menthol cigarette use may not
enhance cognitive function above and beyond nonmenthol
cigarettes to increase dependence among menthol smokers.
However, the contribution of other psychological factors
(eg, craving, mood) and cigarette characteristics (eg,
nicotine content) may be involved in cognitive function
enhancement to perpetuate dependence and smoking persistence
for menthol smokers.},
Doi = {10.1093/ntr/ntab120},
Key = {fds358894}
}
@article{fds357942,
Author = {Holloway, Z and Hawkey, A and Asrat, H and Boinapally, N and Levin,
ED},
Title = {The use of tocofersolan as a rescue agent in larval
zebrafish exposed to benzo[a]pyrene in early
development.},
Journal = {Neurotoxicology},
Volume = {86},
Pages = {78-84},
Year = {2021},
Month = {September},
url = {http://dx.doi.org/10.1016/j.neuro.2021.07.003},
Abstract = {Polycyclic aromatic hydrocarbons (PAHs) are widespread
environmental pollutants created by incomplete combustion.
Benzo(a)pyrene (BaP), the prototypic PAH, is known to exert
toxicity through oxidative stress which is thought to occur
through inhibition of antioxidant scavenging systems. The
use of agents that reduce oxidative stress may be a valuable
route for ameliorating the adverse effects of PAHs on neural
development and behavior. This study was conducted to
determine if tocofersolan (a synthetic water-soluble analog
of vitamin E) supplementation can prevent or reduce
neurobehavioral deficits in zebrafish embryos exposed to BaP
during early development. Newly hatched zebrafish were
assessed on locomotor activity and light responsivity.
Zebrafish embryos were exposed to vehicle (DMSO),
tocofersolan (0.3 μM-3 μM), and/or BaP (5 μM) from
5-120 hours post-fertilization. This concentration range
was below the threshold for producing overt dysmorphogenesis
or decreased survival. One day after the end of exposure the
larval fish were tested for locomotor activity under
alternating light and dark 10 min periods, BaP (5 μM)
was found to cause locomotor hypoactivity in larval fish.
Co-exposure of tocofersolan (1 μM) restored control-like
locomotor function. Based on the findings of this study,
this model can be expanded to assess the outcome of vitamin
E supplementation on other potential environmental
neurotoxicants, and lead to determination if this rescue
persists into adulthood.},
Doi = {10.1016/j.neuro.2021.07.003},
Key = {fds357942}
}
@article{fds358893,
Author = {Levin, ED},
Title = {Invited Perspective: Does Developmental Adaptation Pose
Risks with Changing Toxicant Exposures?},
Journal = {Environ Health Perspect},
Volume = {129},
Number = {8},
Pages = {81302},
Year = {2021},
Month = {August},
url = {http://dx.doi.org/10.1289/EHP9560},
Doi = {10.1289/EHP9560},
Key = {fds358893}
}
@article{fds357590,
Author = {Hawkey, AB and Hoeng, J and Peitsch, MC and Levin, ED and Koshibu,
K},
Title = {Subchronic effects of plant alkaloids on anxiety-like
behavior in zebrafish.},
Journal = {Pharmacol Biochem Behav},
Volume = {207},
Pages = {173223},
Year = {2021},
Month = {August},
url = {http://dx.doi.org/10.1016/j.pbb.2021.173223},
Abstract = {Zebrafish provide a valuable emerging complementary model
for neurobehavioral research. They offer a powerful way to
screen for the potential therapeutic effects of neuroactive
drugs. A variety of behavioral tests for zebrafish have been
developed and validated for assessing neurobehavioral
function. The novel tank diving test is a straightforward,
reproducible way of measuring anxiety-like behavior in
zebrafish. When introduced into a novel tank, zebrafish
normally dive to the bottom of the tank and then gradually
explore the higher levels of the water column as time
progresses. Buspirone is an effective anxiolytic drug in
humans, which has been found, with acute administration, to
reduce this anxiety-like response in zebrafish. The current
study used the zebrafish model to evaluate the potential
anxiolytic effects of alkaloids, commonly found in
Solanaceae plants, with known neuropharmacology relevant to
mood regulation. In line with previous findings, acute
treatment with anxiolytic positive controls buspirone and
the plant alkaloid nicotine reduced the anxiety-like diving
response in the zebrafish novel tank diving test. Further,
both buspirone and nicotine continued to produce
anxiolytic-like effects in zebrafish after 5 days of
exposure. In the same treatment paradigm, the effects of
five other alkaloids-cotinine, anatabine, anabasine,
harmane, and norharmane-were investigated. Cotinine, the
major metabolite of nicotine, also caused anxiolytic-like
effects, albeit at a dose higher than the effective dose of
nicotine. Nicotine's anxiolytic-like effect was not shared
by the other nicotinic alkaloids, anabasine and anatabine,
or by the naturally present monoamine oxidase inhibitors
harmane and norharmane. We conclude that nicotine uniquely
induces anxiolytic-like effects after acute and subchronic
treatment in zebrafish. The zebrafish model with the novel
tank diving test could be a useful complement to rodent
models for screening candidate compounds for anxiolytic
effects in nonclinical studies.},
Doi = {10.1016/j.pbb.2021.173223},
Key = {fds357590}
}
@article{fds355172,
Author = {Levin, ED and Wells, C and Hawkey, A and Holloway, Z and Blair, G and Vierling, A and Ko, A and Pace, C and Modarres, J and McKinney, A and Rezvani, AH and Rose, JE},
Title = {Correction to: Amitifadine, a triple reuptake inhibitor,
reduces self-administration of the opiate remifentanil in
rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {238},
Number = {4},
Pages = {1227},
Year = {2021},
Month = {April},
url = {http://dx.doi.org/10.1007/s00213-021-05794-y},
Doi = {10.1007/s00213-021-05794-y},
Key = {fds355172}
}
@article{fds359690,
Author = {Schrott, R and Murphy, SK and Modliszewski, JL and King, DE and Hill, B and Itchon-Ramos, N and Raburn, D and Price, T and Levin, ED and Vandrey, R and Corcoran, DL and Kollins, SH and Mitchell, JT},
Title = {Refraining from use diminishes cannabis-associated
epigenetic changes in human sperm.},
Journal = {Environ Epigenet},
Volume = {7},
Number = {1},
Pages = {dvab009},
Year = {2021},
url = {http://dx.doi.org/10.1093/eep/dvab009},
Abstract = {Cannabis use alters sperm DNA methylation, but the potential
reversibility of these changes is unknown. Semen samples
from cannabis users and non-user controls were collected at
baseline and again following a 77-day period of cannabis
abstinence (one spermatogenic cycle). Users and controls did
not significantly differ by demographics or semen analyses.
Whole-genome bisulfite sequencing identified 163 CpG sites
with significantly different DNA methylation in sperm
between groups (P < 2.94 × 10-9). Genes associated
with altered CpG sites were enriched with those involved in
development, including cardiogenesis and neurodevelopment.
Many of the differences in sperm DNA methylation between
groups were diminished after cannabis abstinence. These
results indicate that sustained cannabis abstinence
significantly reduces the number of sperm showing
cannabis-associated alterations at genes important for early
development.},
Doi = {10.1093/eep/dvab009},
Key = {fds359690}
}
@article{fds358896,
Author = {Levin, ED and Dow-Edwards, D and Patisaul, H},
Title = {Introduction to sex differences in neurotoxic
effects.},
Journal = {Neurotoxicol Teratol},
Volume = {83},
Pages = {106931},
Year = {2021},
url = {http://dx.doi.org/10.1016/j.ntt.2020.106931},
Doi = {10.1016/j.ntt.2020.106931},
Key = {fds358896}
}
@article{fds355969,
Author = {Hawkey, AB and Holloway, Z and Dean, C and Koburov, R and Slotkin, TA and Seidler, FJ and Levin, ED},
Title = {Neurobehavioral anomalies in zebrafish after sequential
exposures to DDT and chlorpyrifos in adulthood: Do multiple
exposures interact?},
Journal = {Neurotoxicol Teratol},
Volume = {87},
Pages = {106985},
Year = {2021},
url = {http://dx.doi.org/10.1016/j.ntt.2021.106985},
Abstract = {A sequence of different classes of synthetic insecticides
have been used over the past 70 years. Over this period,
the widely-used organochlorines were eventually replaced by
organophosphates, with dichlorodiphenyltrichloroethane (DDT)
and chlorpyrifos (CPF) as the principal prototypes.
Considerable research has characterized the risks of DDT and
CPF individually, but little is known about the toxicology
of transitioning from one class of insecticides to another,
as has been commonplace for agricultural and pest control
workers. This study used adult zebrafish to investigate
neurobehavioral toxicity following 5-week chronic exposure
to either DDT or CPF, to or their sequential exposure (DDT
for 5 weeks followed by CPF for 5 weeks). At the end of
the exposure period, a subset of fish were analyzed for
brain cholinesterase activity. Behavioral effects were
initially assessed one week following the end of the CPF
exposure and again at 14 months of age using a behavioral
test battery covering sensorimotor responses, anxiety-like
functions, predator avoidance and social attraction. Adult
insecticide exposures, individually or sequentially, were
found to modulate multiple behavioral features, including
startle responsivity, social approach, predator avoidance,
locomotor activity and novel location recognition and
avoidance. Locomotor activity and startle responsivity were
each impacted to a greater degree by the sequential
exposures than by individual compounds, with the latter
being pronounced at the early (1-week post exposure) time
point, but not 3-4 months later in aging. Social approach
responses were similarly impaired by the sequential exposure
as by CPF-alone at the aging time point. Fleeing responses
in the predator test showed flee-enhancing effects of both
compounds individually versus controls, and no additive
impact of the two following sequential exposure. Each
compound was also associated with changes in recognition or
avoidance patterns in a novel place recognition task in late
adulthood, but sequential exposures did not enhance these
phenotypes. The potential for chemical x chemical
interactions did not appear related to changes in CPF
metabolism to the active oxon, as prior DDT exposure did not
affect the cholinesterase inhibition resulting from CPF.
This study shows that the effects of chronic adult
insecticide exposures may be relevant to behavioral health
initially and much later in life, and that the effects of
sequential exposures may be unpredictable based on their
constituent exposures.},
Doi = {10.1016/j.ntt.2021.106985},
Key = {fds355969}
}
@article{fds357514,
Author = {Boyda, J and Hawkey, AB and Holloway, ZR and Trevisan, R and Di Giulio,
RT and Levin, ED},
Title = {The organophosphate insecticide diazinon and aging:
Neurobehavioral and mitochondrial effects in zebrafish
exposed as embryos or during aging.},
Journal = {Neurotoxicol Teratol},
Volume = {87},
Pages = {107011},
Year = {2021},
url = {http://dx.doi.org/10.1016/j.ntt.2021.107011},
Abstract = {Organophosphate (OP) compounds comprise one of the most
widely used classes of insecticides worldwide. OPs have been
shown to have negative human health impacts, particularly
developmental neurotoxicity. However, neurotoxic impacts in
later adulthood and during the aging process are relatively
uncharacterized. The present study examined diazinon (DZN),
an OP, to determine the neurobehavioral consequences, in
addition to mitochondrial dysfunction on a macroscale (whole
organism basal respiration) and on a microscale (whole organ
mitochondrial respiration), using zebrafish (ZF) as a model.
One group of 14-month-old adult ZF were exposed acutely as
adults (0.4, 1.25, and 4.0 μM) for five days and tested as
adults, and another group was exposed developmentally
5-120 h post-fertilization (70, 210, and 700 nM) and
tested at larval, adolescent, adult, and aging life stages.
ZF exposed acutely as adults did not display many
significant neurobehavioral impacts or mitochondrial
dysfunction. Conversely, the embryonically exposed ZF showed
altered behavioral functions at each stage of life which
emerged and attenuated as fish transitioned from each
developmental stage to the next. Mitochondrial oxygen
consumptions measurement results for developmentally DZN
exposed ZF showed significant increases in the low and
middle dose groups in organs such as the brain and testes.
Overall, there is an indication that early developmental
exposure to DZN had continuing adverse neurobehavioral and
cellular consequences throughout their lives well into
adulthood and aging periods.},
Doi = {10.1016/j.ntt.2021.107011},
Key = {fds357514}
}
@article{fds362712,
Author = {Vorhees, CV and Williams, MT and Hawkey, AB and Levin,
ED},
Title = {Translating Neurobehavioral Toxicity Across Species From
Zebrafish to Rats to Humans: Implications for Risk
Assessment.},
Journal = {Front Toxicol},
Volume = {3},
Pages = {629229},
Year = {2021},
url = {http://dx.doi.org/10.3389/ftox.2021.629229},
Abstract = {There is a spectrum of approaches to neurotoxicological
science from high-throughput in vitro cell-based assays,
through a variety of experimental animal models to human
epidemiological and clinical studies. Each level of analysis
has its own advantages and limitations. Experimental animal
models give essential information for neurobehavioral
toxicology, providing cause-and-effect information regarding
risks of neurobehavioral dysfunction caused by toxicant
exposure. Human epidemiological and clinical studies give
the closest information to characterizing human risk, but
without randomized treatment of subjects to different
toxicant doses can only give information about association
between toxicant exposure and neurobehavioral impairment. In
vitro methods give much needed high throughput for many
chemicals and mixtures but cannot provide information about
toxicant impacts on behavioral function. Crucial to the
utility of experimental animal model studies is
cross-species translation. This is vital for both risk
assessment and mechanistic determination. Interspecies
extrapolation is important to characterize from experimental
animal models to humans and between different experimental
animal models. This article reviews the literature
concerning extrapolation of neurobehavioral toxicology from
established rat models to humans and from zebrafish a newer
experimental model to rats. The functions covered include
locomotor activity, emotion, and cognition and the
neurotoxicants covered include pesticides, metals, drugs of
abuse, flame retardants and polycyclic aromatic
hydrocarbons. With more complete understanding of the
strengths and limitations of interspecies translation, we
can better use animal models to protect humans from
neurobehavioral toxicity.},
Doi = {10.3389/ftox.2021.629229},
Key = {fds362712}
}
@article{fds352828,
Author = {Holloway, ZR and Hawkey, AB and Torres, AK and Evans, J and Pippen, E and White, H and Katragadda, V and Kenou, B and Wells, C and Murphy, SK and Rezvani, AH and Levin, ED},
Title = {Paternal cannabis extract exposure in rats: Preconception
timing effects on neurodevelopmental behavior in
offspring.},
Journal = {Neurotoxicology},
Volume = {81},
Pages = {180-188},
Year = {2020},
Month = {December},
url = {http://dx.doi.org/10.1016/j.neuro.2020.10.007},
Abstract = {Maternal toxicant exposure during gestation can have
deleterious effects on neurobehavioral development of the
offspring. The potential risks engendered by paternal
toxicant exposure prior to conception have been largely
understudied. Recently, we found that chronic THC exposure
prior to conception in male rats causes long-lasting
behavioral impairment in their offspring. The current study
examined the effects of chronic preconception exposure to
cannabis smoke extract in Sprague-Dawley rats at two
different phases in sperm development. One group received
daily subcutaneous (sc) injections of THC in cannabis
extract at 4 mg/kg/day for 28 days until three days prior to
mating with untreated females (late exposure group). Another
group received the same regimen except they underwent 56
days of drug abstinence prior to mating (early exposure
group). These were compared with a control group treated
with vehicle. The offspring underwent a battery of tests for
behavioral function to assess motor, emotional and cognitive
function. On the elevated plus maze test, the offspring of
both paternal cannabis smoke extract (CSE) exposure groups
had significantly more time on the open arms than control
offspring, indicative of greater risk-taking behavior. No
significant main effects of CSE exposure were seen on
adolescent or adult locomotor activity in the figure-8
apparatus. In the novel object recognition test, there was a
significantly greater drop-off in novel object preference
across the session in the male, but not female offspring of
the late exposure group. There was also a sex-selective
effect of paternal CSE treatment in the 16-arm radial maze
test of memory function. Female offspring of the late
exposure group had significantly more working memory errors
than control females in the first half of the 12-session
training sequence. No significant effects were seen in the
operant visual signal sustained detection test of attention.
This study shows that there are long-lasting behavioral
consequences of preconception CSE exposure through the
paternal lineage in rats.},
Doi = {10.1016/j.neuro.2020.10.007},
Key = {fds352828}
}
@article{fds358897,
Author = {Acharya, KS and Schrott, R and Grenier, C and Huang, Z and Holloway, Z and Hawkey, A and Levin, ED and Murphy, SK},
Title = {Epigenetic alterations in cytochrome P450 oxidoreductase
(Por) in sperm of rats exposed to tetrahydrocannabinol
(THC)},
Journal = {Scientific Reports},
Volume = {10},
Number = {1},
Year = {2020},
Month = {December},
url = {http://dx.doi.org/10.1038/s41598-020-69204-7},
Abstract = {As marijuana legalization is increasing, research regarding
possible long-term risks for users and their offspring is
needed. Little data exists on effects of paternal
tetrahydrocannabinol (THC) exposure prior to reproduction.
This study determined if chronic THC exposure alters sperm
DNA methylation (DNAm) and if such effects are
intergenerationally transmitted. Adult male rats underwent
oral gavage with THC or vehicle control. Differentially
methylated (DM) loci in motile sperm were identified using
reduced representation bisulfite sequencing (RRBS). Another
cohort was injected with vehicle or THC, and sperm DNAm was
analyzed. Finally, THC-exposed and control adult male rats
were mated with THC-naïve females. DNAm levels of target
genes in brain tissues of the offspring were determined by
pyrosequencing. RRBS identified 2,940 DM CpGs mapping to 627
genes. Significant hypermethylation was confirmed (p < 0.05)
following oral THC administration for cytochrome P450
oxidoreductase (Por), involved in toxin processing and
disorders of sexual development. Por hypermethylation was
not observed after THC injection or in the subsequent
generation. These results support that THC alters DNAm in
sperm and that route of exposure can have differential
effects. Although we did not observe evidence of
intergenerational transmission of the DNAm change, larger
studies are required to definitively exclude this
possibility.},
Doi = {10.1038/s41598-020-69204-7},
Key = {fds358897}
}
@article{fds353023,
Author = {Holloway, Z and Koburov, R and Hawkey, A and Levin,
ED},
Title = {Measuring attention in rats with a visual signal detection
task: Signal intensity vs. signal duration.},
Journal = {Pharmacol Biochem Behav},
Volume = {199},
Pages = {173069},
Year = {2020},
Month = {December},
url = {http://dx.doi.org/10.1016/j.pbb.2020.173069},
Abstract = {Measurement of attentional performance in animal behavioral
research allows us to investigate neural mechanisms
underlying attentional processes and translate results to
better understand human attentional function, dysfunction
and drug treatments to reverse dysfunction. One useful
method to measure attention in experimental animal studies
is to use an operant visual signal detection paradigm,
consisting of two levers and the rapid flashing of a cue
lamp to signal a reward. In this study, we tested the
relative sensitivity of this task when using different
variants of the stimulus signal, varying brightness or
duration of the light cue. To investigate roles of different
neural systems underlying attentional processes, we assessed
the sensitivity of attentional performance with these two
different cue variations with blockade of muscarinic
acetylcholine and NMDA glutamate receptors with scopolamine
and MK-801 (dizocilpine). Operant signal detection was
tested using a signal light that varied in intensity (0.027,
0.269, 1.22 lx) of the signal light or in a paradigm which
varied the duration (0.5 s, 1 s, 2 s) of the signal
light. Both methods of assessing attention showed construct
validity for producing gradients of accuracy for signal
detection; the dimmest cue led to less accurate responding
compared to the brighter cues, and the shortest duration led
to less accuracy compared to the longer durations. However,
the tests differed in their sensitivity to pharmacological
disruption. With the duration test, the high dose of MK-801
along with co-exposure of scopolamine and MK-801 caused a
significant reduction of hit and rejection accuracy.
Conversely, the intensity variation test did not show
significant differences as a function of drug exposures.
These data suggest that changes in signal duration, rather
than signal intensity, during operant signal detection may
have higher sensitivity to detecting drug effects and be a
more useful technique for examining pharmacological
interventions on attentional behavior and
performance.},
Doi = {10.1016/j.pbb.2020.173069},
Key = {fds353023}
}
@article{fds350136,
Author = {Oliveri, AN and Knuth, M and Glazer, L and Bailey, J and Kullman, SW and Levin, ED},
Title = {Zebrafish show long-term behavioral impairments resulting
from developmental vitamin D deficiency.},
Journal = {Physiol Behav},
Volume = {224},
Pages = {113016},
Year = {2020},
Month = {October},
url = {http://dx.doi.org/10.1016/j.physbeh.2020.113016},
Abstract = {Vitamin D has been shown in a wide variety of species to
play critical roles in neurodevelopment. Vitamin D
deficiency disrupts development of the brain and can cause
lasting behavioral dysfunction. Zebrafish have become an
important model for the study of development in general and
neurodevelopment in particular. Zebrafish were used in the
current study to characterize the effects of developmental
vitamin D deficiency on behavioral function. Adult zebrafish
that had been chronically fed a vitamin D deficient or
replete diets were bred and the offspring were continued on
those diets. The offspring were behaviorally tested as
adults. In the novel tank diving test the vitamin D
deficient diet significantly lowered the vertical position
of fish indicative of more anxiety-like behavior. In the
novel tank diving test swimming activity was also
significantly decreased by vitamin D deficiency. Startle
response was increased by developmental vitamin D deficiency
during the early part of the test. No significant effects of
vitamin D deficiency were seen with social affiliation and
predatory stimulus avoidance tests. These results indicate a
phenotype of vitamin D deficiency characterized by more
anxiety-like behavior. This result was relatively specific
inasmuch as few or no behavioral effects were seen in other
behavioral tests.},
Doi = {10.1016/j.physbeh.2020.113016},
Key = {fds350136}
}
@article{fds358898,
Author = {Schrott, R and Rajavel, M and Acharya, K and Huang, Z and Acharya, C and Hawkey, A and Pippen, E and Lyerly, HK and Levin, ED and Murphy,
SK},
Title = {Sperm DNA methylation altered by THC and nicotine:
Vulnerability of neurodevelopmental genes with bivalent
chromatin.},
Journal = {Sci Rep},
Volume = {10},
Number = {1},
Pages = {16022},
Year = {2020},
Month = {September},
url = {http://dx.doi.org/10.1038/s41598-020-72783-0},
Abstract = {Men consume the most nicotine and cannabis products but
impacts on sperm epigenetics are poorly characterized.
Evidence suggests that preconception exposure to these drugs
alters offspring neurodevelopment. Epigenetics may in part
facilitate heritability. We therefore compared effects of
exposure to tetrahydrocannabinol (THC) and nicotine on DNA
methylation in rat sperm at genes involved in
neurodevelopment. Reduced representation bisulfite
sequencing data from sperm of rats exposed to THC via oral
gavage showed that seven neurodevelopmentally active genes
were significantly differentially methylated versus
controls. Pyrosequencing data revealed majority overlap in
differential methylation in sperm from rats exposed to THC
via injection as well as those exposed to nicotine.
Neurodevelopmental genes including autism candidates are
vulnerable to environmental exposures and common features
may mediate this vulnerability. We discovered that autism
candidate genes are significantly enriched for bivalent
chromatin structure, suggesting this configuration may
increase vulnerability of genes in sperm to disrupted
methylation.},
Doi = {10.1038/s41598-020-72783-0},
Key = {fds358898}
}
@article{fds366324,
Author = {Brenner, RG and Oliveri, AN and Sinnott-Armstrong, W and Levin,
ED},
Title = {Effects of sub-chronic methylphenidate on risk-taking and
sociability in zebrafish (Danio rerio).},
Journal = {Naunyn Schmiedebergs Arch Pharmacol},
Volume = {393},
Number = {8},
Pages = {1373-1381},
Year = {2020},
Month = {August},
url = {http://dx.doi.org/10.1007/s00210-020-01835-z},
Abstract = {Attention deficit hyperactive disorder (ADHD) is the most
common psychiatric disorder in children affecting around 11%
of children 4-17 years of age (CDC 2019). Children with
ADHD are widely treated with stimulant medications such as
methylphenidate (Ritalin®). However, there has been little
research on the developmental effects of methylphenidate on
risk-taking and sociability. We investigated in zebrafish
the potential developmental neurobehavioral toxicity of
methylphenidate on these behavioral functions. We chose
zebrafish because they provide a model with extensive
genetic tools for future mechanistic studies. We studied
whether sub-chronic methylphenidate exposure during juvenile
development causes neurobehavioral impairments in zebrafish.
Methylphenidate diminished responses to environmental
stimuli after both acute and sub-chronic dosing. In adult
zebrafish, acute methylphenidate impaired avoidance of an
approaching visual stimulus modeling a predator and
decreased locomotor response to the social visual stimulus
of conspecifics. Adult zebrafish dosed acutely with
methylphenidate demonstrated behaviors of less retreat from
threatening visual stimuli and less approach to conspecifics
compared with controls. In a sub-chronic dosing paradigm
during development, methylphenidate caused less robust
exploration of a novel tank. In the predator avoidance
paradigm, sub-chronic dosing that began at an older
age (28 dpf) decreased activity levels more than
sub-chronic dosing that began at earlier ages (14 dpf and
21 dpf). In the social shoaling task, sub-chronic
methylphenidate attenuated reaction to the social stimulus.
Acute and developmental methylphenidate exposure decreased
response to environmental cues. Additional research is
needed to determine critical mechanisms for these effects
and to see how these results may be translatable to
neurobehavioral toxicity of prescribing Ritalin® to
children and adolescents.},
Doi = {10.1007/s00210-020-01835-z},
Key = {fds366324}
}
@article{fds358901,
Author = {Acharya, KS and Schrott, R and Grenier, C and Huang, Z and Holloway, Z and Hawkey, A and Levin, ED and Murphy, SK},
Title = {Epigenetic alterations in cytochrome P450 oxidoreductase
(Por) in sperm of rats exposed to tetrahydrocannabinol
(THC).},
Journal = {Sci Rep},
Volume = {10},
Number = {1},
Pages = {12251},
Year = {2020},
Month = {July},
url = {http://dx.doi.org/10.1038/s41598-020-69204-7},
Abstract = {As marijuana legalization is increasing, research regarding
possible long-term risks for users and their offspring is
needed. Little data exists on effects of paternal
tetrahydrocannabinol (THC) exposure prior to reproduction.
This study determined if chronic THC exposure alters sperm
DNA methylation (DNAm) and if such effects are
intergenerationally transmitted. Adult male rats underwent
oral gavage with THC or vehicle control. Differentially
methylated (DM) loci in motile sperm were identified using
reduced representation bisulfite sequencing (RRBS). Another
cohort was injected with vehicle or THC, and sperm DNAm was
analyzed. Finally, THC-exposed and control adult male rats
were mated with THC-naïve females. DNAm levels of target
genes in brain tissues of the offspring were determined by
pyrosequencing. RRBS identified 2,940 DM CpGs mapping to 627
genes. Significant hypermethylation was confirmed
(p < 0.05) following oral THC administration for
cytochrome P450 oxidoreductase (Por), involved in toxin
processing and disorders of sexual development. Por
hypermethylation was not observed after THC injection or in
the subsequent generation. These results support that THC
alters DNAm in sperm and that route of exposure can have
differential effects. Although we did not observe evidence
of intergenerational transmission of the DNAm change, larger
studies are required to definitively exclude this
possibility.},
Doi = {10.1038/s41598-020-69204-7},
Key = {fds358901}
}
@article{fds358902,
Author = {Hollander, JA and Cory-Slechta, DA and Jacka, FN and Szabo, ST and Guilarte, TR and Bilbo, SD and Mattingly, CJ and Moy, SS and Haroon, E and Hornig, M and Levin, ED and Pletnikov, MV and Zehr, JL and McAllister,
KA and Dzierlenga, AL and Garton, AE and Lawler, CP and Ladd-Acosta,
C},
Title = {Beyond the looking glass: recent advances in understanding
the impact of environmental exposures on neuropsychiatric
disease.},
Journal = {Neuropsychopharmacology},
Volume = {45},
Number = {7},
Pages = {1086-1096},
Year = {2020},
Month = {June},
url = {http://dx.doi.org/10.1038/s41386-020-0648-5},
Abstract = {The etiologic pathways leading to neuropsychiatric diseases
remain poorly defined. As genomic technologies have advanced
over the past several decades, considerable progress has
been made linking neuropsychiatric disorders to genetic
underpinnings. Interest and consideration of nongenetic risk
factors (e.g., lead exposure and schizophrenia) have, in
contrast, lagged behind heritable frameworks of explanation.
Thus, the association of neuropsychiatric illness to
environmental chemical exposure, and their potential
interactions with genetic susceptibility, are largely
unexplored. In this review, we describe emerging approaches
for considering the impact of chemical risk factors acting
alone and in concert with genetic risk, and point to the
potential role of epigenetics in mediating exposure effects
on transcription of genes implicated in mental disorders. We
highlight recent examples of research in nongenetic risk
factors in psychiatric disorders that point to potential
shared biological mechanisms-synaptic dysfunction, immune
alterations, and gut-brain interactions. We outline new
tools and resources that can be harnessed for the study of
environmental factors in psychiatric disorders. These tools,
combined with emerging experimental evidence, suggest that
there is a need to broadly incorporate environmental
exposures in psychiatric research, with the ultimate goal of
identifying modifiable risk factors and informing new
treatment strategies for neuropsychiatric
disease.},
Doi = {10.1038/s41386-020-0648-5},
Key = {fds358902}
}
@article{fds348740,
Author = {Levin, ED and Wells, C and Hawkey, A and Holloway, Z and Blair, G and Vierling, A and Ko, A and Pace, C and Modarres, J and McKinney, A and Rezvani, AH and Rose, JE},
Title = {Amitifadine, a triple reuptake inhibitor, reduces
self-administration of the opiate remifentanil in
rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {237},
Number = {6},
Pages = {1681-1689},
Year = {2020},
Month = {June},
url = {http://dx.doi.org/10.1007/s00213-020-05489-w},
Abstract = {RATIONALE: A variety of neural systems are involved in drug
addiction, and some of these systems are shared across
different addictive drugs. We have found several different
types of drug treatments that successfully reduce nicotine
self-administration. OBJECTIVES: The current set of studies
is the first in a series to determine if drug treatments
that have been found to significantly reduce nicotine
self-administration would reduce opiate self-administration.
METHODS: Amitifadine, a triple reuptake inhibitor of
dopamine, norepinephrine, and serotonin, was assessed in
female Sprague-Dawley rats to determine whether it
significantly reduces remifentanil self-administration with
either acute or chronic treatment. RESULTS: Acutely,
amitifadine doses of 5, 10, and 20 mg/kg each significantly
reduced remifentanil self-administration. In a chronic
study, repeated treatment with 10 mg/kg of amitifadine
continued to reduce remifentanil self-administration, even
after the cessation of treatment. However, amitifadine was
not found to attenuate the rise in remifentanil
self-administration with continued access. This study and
our earlier one showed that the 10 mg/kg amitifadine dose
did not significantly affect food motivated responding.
Amitifadine did not attenuate remifentanil-induced
antinociception as measured on the hot plate test but
extended and maintained antinociceptive effects.
CONCLUSIONS: These studies show the promise of amitifadine
as a treatment for countering opiate self-administration for
adjunctive use with opioids for analgesia. Further studies
are needed to determine the possible efficacy of amitifadine
for combating opiate addiction or preventing it in humans
during adjunctive use with opioids for chronic
pain.},
Doi = {10.1007/s00213-020-05489-w},
Key = {fds348740}
}
@article{fds349140,
Author = {Blair, G and Wells, C and Ko, A and Modarres, J and Pace, C and Davis, JM and Rezvani, AH and Rose, JE and Levin, ED},
Title = {Dextromethorphan and bupropion reduces high level
remifentanil self-administration in rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {193},
Pages = {172919},
Year = {2020},
Month = {June},
url = {http://dx.doi.org/10.1016/j.pbb.2020.172919},
Abstract = {Opiate addiction has risen substantially during the past
decade. New treatments to combat opiate addiction are sorely
needed. The current study was conducted to determine the
acute individual and interactive effects of bupropion and
dextromethorphan in a rat model of opiate
self-administration using the short-acting synthetic opioid
remifentanil. Both of these drugs have been found to reduce
self-administration of nicotine. Bupropion and
dextromethorphan and their combination had differential
effects depending on whether the rats showed higher or lower
baseline remifentanil self-administration. The rats with
higher initial remifentanil self-administration showed a
significant decrease in remifentanil self-administration
with bupropion or dextromethorphan treatment, compared to
the vehicle control condition. This decrease in
self-remifentanil administration was most pronounced when
combination of the higher doses of bupropion and
dextromethorphan were administered. In contrast, the rats
with lower baseline remifentanil self-administration showed
the opposite effect of drug treatment with an increase in
remifentanil self-administration with bupropion treatment
compared to the vehicle control condition. Dextromethorphan
had no significant effect inthis group. This study shows
that combination bupropion and dextromethorphan affects
remifentanil self-administration in a complex fashion with
differential effects on low and high baseline responders. In
subjects with high baseline remifentanil
self-administration, bupropion and dextromethorphan
treatment significantly reduced self-administration, whereas
in subjects with low baseline remifentanil
self-administration, bupropion increased remifentanil
self-administration and dextromethorphan had no discernible
effect. This finding suggests that combination
bupropion-dextromethorphan should be tested in humans, with
a focus on treating people with high-level opiate
use.},
Doi = {10.1016/j.pbb.2020.172919},
Key = {fds349140}
}
@article{fds366325,
Author = {Holloway, ZR and Hawkey, AB and Pippin, E and White, H and Wells, C and Kenou, B and Rezvani, AH and Murphy, SK and Levin,
ED},
Title = {Paternal factors in neurodevelopmental toxicology: THC
exposure of male rats causes long-lasting neurobehavioral
effects in their offspring.},
Journal = {Neurotoxicology},
Volume = {78},
Pages = {57-63},
Year = {2020},
Month = {May},
url = {http://dx.doi.org/10.1016/j.neuro.2020.01.009},
Abstract = {The potential health risks of cannabis are of growing
concern, including effects on reproduction and development.
Extensive research has investigated risks associated with
maternal exposure to THC during gestation and its impacts on
the development of offspring, but little research has been
done regarding paternal THC exposure effects prior to
conception. We have previously found that paternal THC
exposure in rats causes changes in sperm methylation. In an
initial study we also showed that a 12-day paternal THC
exposure prior to conception alters locomotor activity and
impairs cognitive function of their offspring. This study
investigated the cross-generational effects of chronic
paternal THC exposure in rats (0, 2, or 4 mg/kg/day SC for
28 days) prior to mating with drug naïve females. The
offspring of THC-exposed male rats had significant
alterations in locomotor activity and cognitive function.
Specifically, during adolescence there was significant
locomotor hyperactivity in the offspring of males exposed to
2 mg/kg/day of THC. During the novel object recognition
task, the controls maintained their relative preference for
the novel object across the duration of the ten-min session
while the rats whose fathers received THC (2 mg/kg/day)
showed a significantly greater drop-off in interest in the
novel object during the second half of the session. Learning
in the radial-arm maze was significantly delayed in the
offspring of males exposed to 4 mg/kg/day of THC. This study
shows that premating chronic paternal THC exposure at
multiple dose regimens can cause long-lasting detrimental
behavioral effects in their offspring, including abnormal
locomotor activity and impaired cognitive function. Future
studies should investigate the underlying mechanisms driving
these aberrant developmental outcomes and seek to identify
possible treatments of alleviation in the presence of
paternal THC exposure.},
Doi = {10.1016/j.neuro.2020.01.009},
Key = {fds366325}
}
@article{fds358903,
Author = {Slotkin, TA and Skavicus, S and Levin, ED and Seidler,
FJ},
Title = {Paternal Δ9-Tetrahydrocannabinol Exposure Prior to Mating
Elicits Deficits in Cholinergic Synaptic Function in the
Offspring.},
Journal = {Toxicol Sci},
Volume = {174},
Number = {2},
Pages = {210-217},
Year = {2020},
Month = {April},
url = {http://dx.doi.org/10.1093/toxsci/kfaa004},
Abstract = {Little attention has been paid to the potential impact of
paternal marijuana use on offspring brain development. We
administered Δ9-tetrahydrocannabinol (THC, 0, 2, or
4 mg/kg/day) to male rats for 28 days. Two days after
the last THC treatment, the males were mated to drug-naïve
females. We then assessed the impact on development of
acetylcholine (ACh) systems in the offspring, encompassing
the period from the onset of adolescence (postnatal day 30)
through middle age (postnatal day 150), and including brain
regions encompassing the majority of ACh terminals and cell
bodies. Δ9-Tetrahydrocannabinol produced a dose-dependent
deficit in hemicholinium-3 binding, an index of presynaptic
ACh activity, superimposed on regionally selective increases
in choline acetyltransferase activity, a biomarker for
numbers of ACh terminals. The combined effects produced a
persistent decrement in the hemicholinium-3/choline
acetyltransferase ratio, an index of impulse activity per
nerve terminal. At the low THC dose, the decreased
presynaptic activity was partially compensated by
upregulation of nicotinic ACh receptors, whereas at the high
dose, receptors were subnormal, an effect that would
exacerbate the presynaptic defect. Superimposed on these
effects, either dose of THC also accelerated the age-related
decline in nicotinic ACh receptors. Our studies provide
evidence for adverse effects of paternal THC administration
on neurodevelopment in the offspring and further demonstrate
that adverse impacts of drug exposure on brain development
are not limited to effects mediated by the embryonic or
fetal chemical environment, but rather that vulnerability is
engendered by exposures occurring prior to conception,
involving the father as well as the mother.},
Doi = {10.1093/toxsci/kfaa004},
Key = {fds358903}
}
@article{fds358904,
Author = {Levin, ED and Wells, C and Slade, S and Lee, M and McKinney, AA and Rose,
JE and Rezvani, AH},
Title = {Prolonging the Reduction of Nicotine Self-Administration in
Rats by Coadministering Chronic Nicotine With Amitifadine, a
Triple Monoamine Reuptake Inhibitor With CYP2B6 Inhibitory
Actions.},
Journal = {Nicotine Tob Res},
Volume = {22},
Number = {2},
Pages = {232-237},
Year = {2020},
Month = {February},
url = {http://dx.doi.org/10.1093/ntr/ntz054},
Abstract = {INTRODUCTION: Existing treatments can aid tobacco smoking
cessation, but they have low efficacy. Because there is a
network of neural systems involved in tobacco addiction,
combination treatments may provide greater efficacy. Chronic
nicotine and amitifadine have each been shown to
significantly reduce nicotine self-administration in rats.
This study was conducted to determine if the combination of
chronic nicotine with amitifadine, a triple monoamine
reuptake inhibitor with CYP2B inhibitory effects, would
reduce nicotine self-administration to a greater extent than
either alone or placebo. METHODS: This study tested the
combination of nicotine plus amitifadine in young adult
female Sprague-Dawley rats self-administering nicotine (0.03
mg/kg/infusion). This combination was compared with each
treatment alone and the vehicle during continuing nicotine
self-administration as well as during resumption of
self-administration after a week of enforced abstinence,
modeling a quit attempt. Finally, we studied the residual
effects of these therapies after discontinuation of
treatment. RESULTS: Treatment with either chronic nicotine
or amitifadine alone significantly reduced nicotine
self-administration relative to controls. The combination of
the treatments significantly enhanced this effect. After
treatment withdrawal, all of the groups showed increases in
nicotine self-administration, but only the combined
treatment group remained significantly below control rates
of nicotine self-administration. CONCLUSIONS: This study
showed the promise of amitifadine as a possible new
treatment for smoking cessation and suggested that
amitifadine is more effective when given with chronic
nicotine. The improved efficacy of the amitifadine and
nicotine combination may be potentiated by amitifadine's
inhibitory effects on CYP2B, which slows nicotine
metabolism. IMPLICATIONS: This study replicated the effects
that chronic nicotine or chronic amitifadine, a triple
reuptake inhibitor, significantly reduces nicotine
self-administration in rats. It extends those findings by
showing that the combination of chronic nicotine plus
amitifadine causes significantly greater reduction in
nicotine self-administration than either drug treatment
alone. The combination of chronic amitifadine and chronic
nicotine also causes a persistent significant reduction in
nicotine self-administration after the end of treatment. The
amitifadine and nicotine treatment should be assessed in
humans to determine whether this combination provides
greater efficacy in smoking cessation than transdermal
nicotine treatment alone.},
Doi = {10.1093/ntr/ntz054},
Key = {fds358904}
}
@article{fds347048,
Author = {Hawkey, A and Pippen, E and White, H and Kim, J and Greengrove, E and Kenou, B and Holloway, Z and Levin, ED},
Title = {Gestational and perinatal exposure to diazinon causes
long-lasting neurobehavioral consequences in the
rat.},
Journal = {Toxicology},
Volume = {429},
Pages = {152327},
Year = {2020},
Month = {January},
url = {http://dx.doi.org/10.1016/j.tox.2019.152327},
Abstract = {Diazinon is a widely-used organophosphate pesticide.
Pulsatile exposure to diazinon during neonatal development
has previously been shown cause long-term neurobehavioral
impairments in rats. However, the effects of chronic low
concentration exposures during perinatal development remain
unclear. This experiment evaluated such effects in
Sprague-Dawley rats by implanting osmotic pumps in breeder
females prior to conception (N = 13-15 litters per
condition) which then delivered chronic, zero order kinetic
low-level infusions of 0, 114 or 228 ug/day of diazinon
throughout pregnancy. One male and one female from each
litter was assessed with a battery of behavioral tests that
continued from four weeks of age into adulthood. Litter was
used as the unit of variance for the analysis of variance
test of significance, with sex as a within litter factor.
Diazinon treatment condition was the between subjects factor
and time or sessions were repeated measures. Chronic
diazinon exposure from pre-mating until the neonatal period
caused a significant (p < 0.05) increase in percent of
time spent on the open arms of the elevated plus maze, an
index of risk-taking behavior. Gestational and lactational
diazinon exposure also caused a significant (p < 0.05)
degree of hyperactivity in the Figure-8 apparatus during
adolescence, specifically affecting the early part of the
hour-long test session. This effect had dissipated by the
time the rats reached adulthood. Diazinon exposure also
caused a significant impairment in novel object recognition,
a test of cognitive function. Offspring exposed to 228
ug/day diazinon (p < 0.05) showed significantly less
preference for the novel vs. familiar object than controls
during the first five minutes of the novel object
recognition test.},
Doi = {10.1016/j.tox.2019.152327},
Key = {fds347048}
}
@article{fds358905,
Author = {Schrott, R and Acharya, K and Itchon-Ramos, N and Hawkey, AB and Pippen,
E and Mitchell, JT and Kollins, SH and Levin, ED and Murphy,
SK},
Title = {Cannabis use is associated with potentially heritable
widespread changes in autism candidate gene DLGAP2 DNA
methylation in sperm.},
Journal = {Epigenetics},
Volume = {15},
Number = {1-2},
Pages = {161-173},
Year = {2020},
url = {http://dx.doi.org/10.1080/15592294.2019.1656158},
Abstract = {Parental cannabis use has been associated with adverse
neurodevelopmental outcomes in offspring, but how such
phenotypes are transmitted is largely unknown. Using reduced
representation bisulphite sequencing (RRBS), we recently
demonstrated that cannabis use is associated with widespread
DNA methylation changes in human and rat sperm. Discs-Large
Associated Protein 2 (DLGAP2), involved in synapse
organization, neuronal signaling, and strongly implicated in
autism, exhibited significant hypomethylation (p < 0.05)
at 17 CpG sites in human sperm. We successfully validated
the differential methylation present in DLGAP2 for nine CpG
sites located in intron seven (p < 0.05) using
quantitative bisulphite pyrosequencing. Intron 7 DNA
methylation and DLGAP2 expression in human conceptal brain
tissue were inversely correlated (p < 0.01). Adult male
rats exposed to delta-9-tetrahydrocannabinol (THC) showed
differential DNA methylation at Dlgap2 in sperm
(p < 0.03), as did the nucleus accumbens of rats whose
fathers were exposed to THC prior to conception
(p < 0.05). Altogether, these results warrant further
investigation into the effects of preconception cannabis use
in males and the potential effects on subsequent
generations.},
Doi = {10.1080/15592294.2019.1656158},
Key = {fds358905}
}
@article{fds358899,
Author = {Kwan, LY and Eaton, DL and Andersen, SL and Dow-Edwards, D and Levin,
ED and Talpos, J and Vorhees, CV and Li, AA},
Title = {This is your teen brain on drugs: In search of biological
factors unique to dependence toxicity in
adolescence.},
Journal = {Neurotoxicol Teratol},
Volume = {81},
Pages = {106916},
Year = {2020},
url = {http://dx.doi.org/10.1016/j.ntt.2020.106916},
Abstract = {Response variability across the lifespan is an important
consideration in toxicology and risk assessment, and the
toxic effects of drugs and chemicals during adolescence need
more research. This paper summarizes a workshop presented in
March 2019, at the Society of Toxicology Annual Meeting in
Baltimore, Maryland, that brought together experts in
research on drug dependence and toxicity related to
nicotine, cannabis, cocaine, and other illicit drugs during
adolescence. The goal of the workshop was to address the
following issues: (1) Do the effects of adolescent exposure
differ from the same exposure in adults? (2) Are there
unique biological markers of adolescent brain development?
If so, what are they and how reliable are they? (3) Since
multiple factors influence substance use disorder, can we
disentangle risk factors for abuse and/or toxicity? What are
the underlying biological susceptibilities that lead to
dependence and neurotoxicity? What are the social,
psychosocial and environmental factors that contribute to
abuse susceptibilities? This paper reviews drug policy and
national trends in adolescent substance use; the public
health consequences of e-cigarettes; rat models of
adolescent-onset nicotine self-administration and persisting
effects of gestational nicotine; sex-dependent effects of
delta-9-tetrahydrocannabinol on adolescent brain-behavior
relationships; and translational approaches for identifying
adolescent risk factors for transition to drug dependence.
There is strong evidence that drug exposure prior to
adulthood has longer lasting effects on behavior and the
underlying neural circuitry. These effects, which are
sex-dependent and influenced by stress, may be candidates as
predictors of adolescent vulnerability. A major challenge to
determining if adolescents have a unique susceptibility to
dependence is whether and to what extent the human data
allow distinction between the increased risk due to
biological immaturity, an underlying biological
susceptibility to dependence, or psychosocial and
environmental factors for substance dependence. Factors
important to consider for development of animal models
include the timing and pattern of exposure as it relates to
adolescence; age of assessment, and direct comparison with
similar effects following exposures to adults to demonstrate
that these effects are unique to adolescence. Here we
provide a roadmap for further research into what makes
adolescent brain development unique.},
Doi = {10.1016/j.ntt.2020.106916},
Key = {fds358899}
}
@article{fds348088,
Author = {Hawkey, AB and Glazer, L and Dean, C and Wells, CN and Odamah, K-A and Slotkin, TA and Seidler, FJ and Levin, ED},
Title = {Adult exposure to insecticides causes persistent behavioral
and neurochemical alterations in zebrafish.},
Journal = {Neurotoxicol Teratol},
Volume = {78},
Pages = {106853},
Year = {2020},
url = {http://dx.doi.org/10.1016/j.ntt.2019.106853},
Abstract = {Farmers are often chronically exposed to insecticides, which
may present health risks including increased risk of
neurobehavioral impairment during adulthood and across
aging. Experimental animal studies complement
epidemiological studies to help determine the
cause-and-effect relationship between chronic adult
insecticide exposure and behavioral dysfunction. With the
zebrafish model, we examined short and long-term
neurobehavioral effects of exposure to either an
organochlorine insecticide, dichlorodiphenyltrichloroethane
(DDT) or an organophosphate insecticide chlorpyrifos (CPF).
Adult fish were exposed continuously for either two or
5 weeks (10-30 nM DDT, 0.3-3 μM CPF), with short- and
long-term effects assessed at 1-week post-exposure and at
14 months of age respectively. The behavioral test battery
included tests of locomotor activity, tap startle, social
behavior, anxiety, predator avoidance and learning.
Long-term effects on neurochemical indices of cholinergic
function were also assessed. Two weeks of DDT exposure had
only slight effects on locomotor activity, while a longer
five-week exposure led to hypoactivity and increased
anxiety-like diving responses and predator avoidance at
1-week post-exposure. When tested at 14 months of age,
these fish showed hypoactivity and increased startle
responses. Cholinergic function was not found to be
significantly altered by DDT. The two-week CPF exposure led
to reductions in anxiety-like diving and increases in
shoaling responses at the 1-week time point, but these
effects did not persist through 14 months of age.
Nevertheless, there were persistent decrements in
cholinergic presynaptic activity. A five-week CPF exposure
led to long-term effects including locomotor hyperactivity
and impaired predator avoidance at 14 months of age,
although no effects were apparent at the 1-week time point.
These studies documented neurobehavioral effects of adult
exposure to chronic doses of either organochlorine or
organophosphate pesticides that can be characterized in
zebrafish. Zebrafish provide a low-cost model that has a
variety of advantages for mechanistic studies and may be
used to expand our understanding of neurobehavioral toxicity
in adulthood, including the potential for such toxicity to
influence behavior and development during
aging.},
Doi = {10.1016/j.ntt.2019.106853},
Key = {fds348088}
}
@article{fds350004,
Author = {Oliveri, AN and Glazer, L and Mahapatra, D and Kullman, SW and Levin,
ED},
Title = {Developmental exposure of zebrafish to vitamin D receptor
acting drugs and environmental toxicants disrupts behavioral
function.},
Journal = {Neurotoxicol Teratol},
Volume = {81},
Pages = {106902},
Year = {2020},
url = {http://dx.doi.org/10.1016/j.ntt.2020.106902},
Abstract = {Vitamin D receptor (VDR) signaling is important for optimal
neurobehavioral development. Disruption of VDR signaling by
environmental toxicants during early development might
contribute to the etiology of behavioral dysfunction. In the
current set of studies, we examined ten compounds known to
affect VDR function in vitro for neurobehavioral effects in
vivo in zebrafish. Zebrafish embryos were exposed to
concentrations of the compounds in their water during the
first 5 days post-fertilization. On day 5, the embryos were
tested in an alternating light-dark locomotor assay using a
computerized video tracking system. We found that most of
the compounds produced significant changes in locomotor
behavior in exposed zebrafish larvae, although the direction
of the effect (i.e., hypo- or hyperactivity) and the
sensitivity of the effect to changes in illumination
condition varied across the compounds. The nature of the
behavioral effects generally corresponded to the effects
these compounds have been shown to exert on VDR. These
studies lay a foundation for further investigation to
determine whether behavioral dysfunction persists into
adulthood and if so which behavioral functions are affected.
Zebrafish can be useful for screening compounds identified
in high throughput in vitro assays to provide an initial
test for how those compounds would affect construction and
behavioral function of a complex nervous system, helping to
bridge the gap between in vitro neurotoxicity assays and
mammalian models for risk assessment in humans.},
Doi = {10.1016/j.ntt.2020.106902},
Key = {fds350004}
}
@article{fds345840,
Author = {Willette, BKA and Nangia, A and Howard, S and DiPalma, D and McMillan,
C and Tharwani, S and Evans, J and Wells, C and Slade, S and Hall, BJ and Rezvani, AH and Levin, ED},
Title = {Acute and chronic interactive treatments of serotonin 5HT2C
and dopamine D1 receptor systems for decreasing nicotine
self-administration in female rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {186},
Pages = {172766},
Year = {2019},
Month = {November},
url = {http://dx.doi.org/10.1016/j.pbb.2019.172766},
Abstract = {A variety of neural systems are involved in the brain bases
of tobacco addiction. Animal models of nicotine addiction
have helped identify a variety of interacting neural systems
involved in the pathophysiology of tobacco addiction. We and
others have found that drug treatments affecting many of
those neurotransmitter systems significantly decrease
nicotine self-administration. These treatments include
dopamine D1 receptor antagonist, histamine H1 antagonist,
serotonin 5HT2C agonist, glutamate NMDA antagonist,
nicotinic cholinergic α4β2 partial agonist and nicotinic
cholinergic α3β4 antagonist acting drugs. It may be the
case that combining treatments that affect different neural
systems underlying addiction may be more efficacious than
single drug treatment. In the current study, we tested the
interactions of the D1 antagonist SCH-23390 and the
serotonin 5HT2c agonist lorcaserin, both of which we have
previously shown to significantly reduce nicotine
self-administration. In the acute interactions study, both
SCH-23390 and lorcaserin significantly reduced nicotine
self-administration when given alone and had additive
effects when given in combination. In the chronic study,
each drug alone caused a significant decrease in nicotine
self-administration. No additive effect was seen in
combination because SCH-23390 given alone chronically was
already highly effective. Chronic administration of the
combination was not seen to significantly prolong reduced
nicotine self-administration into the post-treatment period.
This research shows that unlike lorcaserin and SCH-23390
interactions when given acutely, when given chronically in
combination they do not potentiate or prolong each other's
effects in reducing nicotine self-administration.},
Doi = {10.1016/j.pbb.2019.172766},
Key = {fds345840}
}
@article{fds358906,
Author = {Hawkey, A and Junaid, S and Yao, L and Spiera, Z and White, H and Cauley,
M and Levin, ED},
Title = {Gestational exposure to nicotine and/or benzo[a]pyrene
causes long-lasting neurobehavioral consequences.},
Journal = {Birth Defects Res},
Volume = {111},
Number = {17},
Pages = {1248-1258},
Year = {2019},
Month = {October},
url = {http://dx.doi.org/10.1002/bdr2.1568},
Abstract = {Tobacco smoke is a complex mixture that includes thousands
of compounds. Previously, we have found that gestational
exposure to the complex mixture of tobacco smoke extract
caused long-term neurobehavioral impairments. In this study,
we examined the interaction of two of the most biologically
active, nicotine and benzo[a]pyrene (BaP). Developmental
effects were determined in Sprague-Dawley rats prenatally
exposed to low doses of BaP and nicotine (0.03 mg/kg/day
of BaP and 2 mg/kg/day of nicotine) via maternal osmotic
minipumps throughout gestation. Behavioral function was
assessed in the offspring via a battery of tests through
adolescence into adulthood. There were sex-selective effects
in four of the behavioral tests. In the elevated plus maze,
there was a significant interaction of BaP and sex, where
BaP-treated males showed a trend for increased activity. In
the novelty suppressed feeding test, there were significant
sex selective effects in males such that the normal sex
difference in the behavior in this test was eliminated. Male
offspring with prenatal exposure to either nicotine or BaP
showed significant reductions in fear response. In the
Figure-8 locomotor activity test, BAP-exposed male offspring
were significantly hyperactive. This also eliminated the sex
difference typically seen in this test. This effect
persisted into adulthood. In the attention task, males
exposed to nicotine during gestation showed a significant
percent hit impairment. BaP reversed this effect. No
significant effects were seen with percent correct
rejection. These data show that both nicotine and BaP cause
persisting sex-selective behavioral effects that persist
into adulthood.},
Doi = {10.1002/bdr2.1568},
Key = {fds358906}
}
@article{fds345740,
Author = {Levin, ED and Wells, C and Yao, L and Guo, W and Nangia, A and Howard, S and Pippen, E and Hawkey, AB and Rose, JE and Rezvani,
AH},
Title = {Chronic memantine decreases nicotine self-administration in
rats.},
Journal = {Eur J Pharmacol},
Volume = {861},
Pages = {172592},
Year = {2019},
Month = {October},
url = {http://dx.doi.org/10.1016/j.ejphar.2019.172592},
Abstract = {Neurobehavioral bases of tobacco addiction and nicotine
reinforcement are complex, involving more than only
nicotinic cholinergic or dopaminergic systems. Memantine is
an NMDA glutamate antagonist used to improve cognitive
function in people with Alzheimer's disease. Glutamate may
be an important component of the reinforcing effects of
nicotine, so memantine was evaluated as a potential smoking
cessation aid. Two studies were conducted with adult female
rats, one testing acute effects of memantine over a range of
doses for changing nicotine self-administration and the
other testing the chronic effects of memantine to reduce
nicotine self-administration. Acute memantine injections
slightly, but significantly, increased nicotine
self-administration in a dose-related manner. In contrast,
chronic memantine treatment significantly reduced nicotine
self-administration. During the first day of memantine
administration in the chronic study, nicotine
self-administration was significantly elevated replicating
the acute study. Starting in the second week of treatment
there was a significant reduction of nicotine
self-administration relative to controls. This was seen
because memantine treatment prevented the increase in
nicotine self-administration shown by controls. There even
continued to be a memantine-induced lowered nicotine
self-administration during the week after the cessation of
memantine treatment. Memantine or other drugs affecting NMDA
glutamate receptors may be useful aids to smoking cessation.
Full efficacy for reducing nicotine self-administration was
seen as the NMDA drug treatment is given chronically.
Importantly, the effect persisted even after treatment is
ended, indicating the high potential for NMDA glutamate
receptors to impact nicotine addiction.},
Doi = {10.1016/j.ejphar.2019.172592},
Key = {fds345740}
}
@article{fds358907,
Author = {Slotkin, TA and Skavicus, S and Ko, A and Levin, ED and Seidler,
FJ},
Title = {Perinatal diazinon exposure compromises the development of
acetylcholine and serotonin systems.},
Journal = {Toxicology},
Volume = {424},
Pages = {152240},
Year = {2019},
Month = {August},
url = {http://dx.doi.org/10.1016/j.tox.2019.152240},
Abstract = {Organophosphate pesticides are developmental neurotoxicants.
We gave diazinon via osmotic minipumps implanted into dams
prior to conception, with exposure continued into the second
postnatal week, at doses (0.5 or 1 mg/kg/day) that did not
produce detectable brain cholinesterase inhibition. We
evaluated the impact on acetylcholine (ACh) and serotonin
(5-hydroxytryptamine, 5HT) systems in brain regions from
adolescence through full adulthood. Diazinon produced
deficits in presynaptic ACh activity with regional and sex
selectivity: cerebrocortical regions and the hippocampus
were affected to a greater extent than were the striatum,
midbrain or brainstem, and females were more sensitive than
males. Diazinon also reduced nicotinic ACh receptors and
5HT1A receptors, with the same regional and sex preferences.
These patterns were similar to those of diazinon given in a
much more restricted period (postnatal day 1-4) but were of
greater magnitude and consistency; this suggests that the
brain is vulnerable to diazinon over a wide developmental
window. Diazinon's effects differed from those of the
related organophosphate, chlorpyrifos, with regard to
regional and sex selectivity, and more importantly, to the
effects on receptors: chlorpyrifos upregulates nicotinic ACh
receptors and 5HT receptors, effects that compensate for the
presynaptic ACh deficits. Diazinon can thus be expected to
have worse neurodevelopmental outcomes than chlorpyrifos.
Further, the disparities between diazinon and chlorpyrifos
indicate the problems of predicting the developmental
neurotoxicity of organophosphates based on a single
compound, and emphasize the inadequacy of cholinesterase
inhibition as an index of safety.},
Doi = {10.1016/j.tox.2019.152240},
Key = {fds358907}
}
@article{fds358909,
Author = {Westerink, RHS and van Thriel, C and Levin, ED and Shafer,
TJ},
Title = {From molecular mechanisms to functional impact: Developing
integrated analyses in neurotoxicology - The 16th biennial
meeting International Neurotoxicology Association and 8th
meeting of the NeuroToxicity Society.},
Journal = {Neurotoxicology},
Volume = {72},
Pages = {125-126},
Year = {2019},
Month = {May},
url = {http://dx.doi.org/10.1016/j.neuro.2018.11.002},
Doi = {10.1016/j.neuro.2018.11.002},
Key = {fds358909}
}
@article{fds341563,
Author = {Rezvani, AH and Wells, C and Slade, S and Xiao, Y and Kellar, KJ and Levin,
ED},
Title = {Oral sazetidine-A, a selective α4β2* nicotinic receptor
desensitizing agent, reduces nicotine self-administration in
rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {179},
Pages = {109-112},
Year = {2019},
Month = {April},
url = {http://dx.doi.org/10.1016/j.pbb.2019.02.007},
Abstract = {Sazetidine-A selectively desensitizes α4β2 nicotinic
receptors and also has partial agonist effects. We have
shown that subcutaneous acute and repeated injections as
well as chronic infusions of sazetidine-A significantly
reduce intravenous (IV) nicotine self-administration in
rats. To further investigate the promise of sazetidine-A as
a smoking cessation aid, it is important to determine
sazetidine-A effects with oral administration and the
time-effect function for its action on nicotine
self-administration. Young adult female Sprague-Dawley rats
were trained to self-administer IV nicotine at the benchmark
dose of 0.03 mg/kg/infusion dose in an operant FR1
schedule in 45-min sessions. After five sessions of
training, they were tested for the effects of acute oral
doses of sazetidine-A (0, 0.3, 1 and 3 mg/kg) given
30 min before testing. To determine the time-effect
function, these rats were administered 0 or 3 mg/kg of
sazetidine-A 1, 2, 4 or 23 h before the onset of testing.
Our previous study showed that with subcutaneous injections,
only 3 mg/kg of sazetidine-A significantly reduced
nicotine self-administration, however, with oral
administration of sazetidine-A lower dose of 1 mg/kg was
also effective in reducing nicotine intake. A similar effect
was seen in the time-effect study with 3 mg/kg of oral
sazetidine-A causing a significant reduction in nicotine
self-administration across all the time points of 1, 2, 4 or
23 h after oral administration. These results advance the
development of sazetidine-A as a possible aid for smoking
cessation by showing effectiveness with oral administration
and persistence of the effect over the course of a
day.},
Doi = {10.1016/j.pbb.2019.02.007},
Key = {fds341563}
}
@article{fds342294,
Author = {Slotkin, TA and Skavicus, S and Ko, A and Levin, ED and Seidler,
FJ},
Title = {Corrigendum to "The Developmental Neurotoxicity of Tobacco
Smoke Can Be Mimicked by a Combination of Nicotine and
Benzo[a]pyrene: Effects on Cholinergic and Serotonergic
Systems".},
Journal = {Toxicol Sci},
Volume = {168},
Number = {1},
Pages = {280},
Year = {2019},
Month = {March},
url = {http://dx.doi.org/10.1093/toxsci/kfy304},
Doi = {10.1093/toxsci/kfy304},
Key = {fds342294}
}
@article{fds342295,
Author = {Ideraabdullah, FY and Belenchia, AM and Rosenfeld, CS and Kullman,
SW and Knuth, M and Mahapatra, D and Bereman, M and Levin, ED and Peterson,
CA},
Title = {Maternal vitamin D deficiency and developmental origins of
health and disease (DOHaD).},
Journal = {J Endocrinol},
Year = {2019},
Month = {March},
url = {http://dx.doi.org/10.1530/JOE-18-0541},
Abstract = {Vitamin D is an essential nutrient that is metabolized in
the body to generate an active metabolite (1,25(OH)2D) with
hormone-like activity and highly diverse roles in cellular
function. Vitamin D deficiency (VDD) is a prevalent but
easily preventable nutritional disturbance. Emerging
evidence demonstrates the importance of sufficient vitamin D
concentrations during fetal life with deficiencies leading
to long-term effects into adulthood. Here, we provide a
detailed review and perspective of evidence for the role of
maternal VDD in offspring long term health, particularly as
it relates to Developmental Origins of Health and Disease
(DOHaD). We focus on roles in neurobehavioral and
cardiometabolic disorders in humans and highlight recent
findings from zebrafish and rodent models that probe
potential mechanisms linking early life VDD to later life
health outcomes. Moreover, we explore evidence implicating
epigenetic mechanisms as a mediator of this link. Gaps in
our current understanding of how maternal VDD might result
in deleterious offspring outcomes later in life are also
addressed.},
Doi = {10.1530/JOE-18-0541},
Key = {fds342295}
}
@article{fds340154,
Author = {Levin, ED and Rezvani, AH and Wells, C and Slade, S and Yenugonda, VM and Liu, Y and Brown, ML and Xiao, Y and Kellar, KJ},
Title = {α4β2 Nicotinic receptor desensitizing compounds can
decrease self-administration of cocaine and methamphetamine
in rats.},
Journal = {Eur J Pharmacol},
Volume = {845},
Pages = {1-7},
Year = {2019},
Month = {February},
url = {http://dx.doi.org/10.1016/j.ejphar.2018.12.010},
Abstract = {Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol]
is a selective α4β2 nicotinic receptor desensitizing agent
and partial agonist. Sazetidine-A has been shown in our
previous studies to significantly reduce nicotine and
alcohol self-administration in rats. The question arises
whether sazetidine-A would reduce self-administration of
other addictive drugs as well. Nicotinic receptors on the
dopaminergic neurons in the ventral tegmental area play an
important role in controlling the activity of these neurons
and release of dopamine in the nucleus accumbens, which is
critical mechanism for reinforcing value of drugs of abuse.
Previously, we showed that the nonspecific nicotinic
antagonist mecamylamine significantly reduces cocaine
self-administration in rats. In this study, we acutely
administered systemically sazetidine-A and two other
selective α4β2 nicotinic receptor-desensitizing agents,
VMY-2-95 and YL-2-203, to young adult female Sprague-Dawley
rats and determined their effects on IV self-administration
of cocaine and methamphetamine. Cocaine self-administration
was significantly reduced by 0.3 mg/kg of sazetidine-A. In
another set of rats, sazetidine-A (3 mg/kg) significantly
reduced methamphetamine self-administration. VMY-2-95
significantly reduced both cocaine and methamphetamine
self-administration with threshold effective doses of 3 and
0.3 mg/kg, respectively. In contrast, YL-2-203 did not
significantly reduce cocaine self-administration at the same
dose range and actually significantly increased cocaine
self-administration at the 1 mg/kg dose. YL-2-203
(3 mg/kg) did significantly decrease methamphetamine
self-administration. Sazetidine-A and VMY-2-95 are promising
candidates to develop as new treatments to help addicts
successfully overcome a variety of addictions including
tobacco, alcohol as well as the stimulant drugs cocaine and
methamphetamine.},
Doi = {10.1016/j.ejphar.2018.12.010},
Key = {fds340154}
}
@article{fds358910,
Author = {Slotkin, TA and Skavicus, S and Ko, A and Levin, ED and Seidler,
FJ},
Title = {The Developmental Neurotoxicity of Tobacco Smoke Can Be
Mimicked by a Combination of Nicotine and Benzo[a]Pyrene:
Effects on Cholinergic and Serotonergic Systems.},
Journal = {Toxicol Sci},
Volume = {167},
Number = {1},
Pages = {293-304},
Year = {2019},
Month = {January},
url = {http://dx.doi.org/10.1093/toxsci/kfy241},
Abstract = {Tobacco smoke contains polycyclic aromatic hydrocarbons
(PAHs) in addition to nicotine. We compared the
developmental neurotoxicity of nicotine to that of the PAH
archetype, benzo[a]pyrene (BaP), and also evaluated the
effects of combined exposure to assess whether PAHs might
exacerbate the adverse effects of nicotine. Pregnant rats
were treated preconception through the first postnatal week,
modeling nicotine concentrations in smokers and a low BaP
dose devoid of systemic effects. We conducted evaluations of
acetylcholine (ACh) and serotonin (5-hydroxytryptamine, 5HT)
systems in brain regions from adolescence through full
adulthood. Nicotine or BaP alone impaired indices of ACh
presynaptic activity, accompanied by upregulation of
nicotinic ACh receptors and 5HT receptors. Combined
treatment elicited a greater deficit in ACh presynaptic
activity than that seen with either agent alone, and
upregulation of nAChRs and 5HT receptors was impaired or
absent. The individual effects of nicotine and BaP accounted
for only 60% of the combination effects, which thus
displayed unique properties. Importantly, the combined
nicotine + BaP exposure recapitulated the effects of tobacco
smoke, distinct from nicotine. Our results show that the
effects of nicotine on development of ACh and 5HT systems
are worsened by BaP coexposure, and that combination of the
two agents contributes to the greater impact of tobacco
smoke on the developing brain. These results have important
implications for the relative safety in pregnancy of
nicotine-containing products compared with combusted
tobacco, both for active maternal smoking and secondhand
exposure, and for the effects of such agents in "dirty"
environments with high PAH coexposure.},
Doi = {10.1093/toxsci/kfy241},
Key = {fds358910}
}
@article{fds358911,
Author = {Rezvani, AH and Wells, C and Strumph, P and Diamond, I and Blackburn,
BK and Levin, ED},
Title = {Risk for opioid abuse is diminished by inhibiting aldehyde
dehydrogenase-2 (ALDH-2) in rats},
Journal = {Journal of Drug and Alcohol Research},
Volume = {8},
Year = {2019},
Month = {January},
url = {http://dx.doi.org/10.4303/jdar/236076},
Abstract = {Significant opiate addiction is known to follow prescribed
opiate use for pain. There is a serious unmet need for
non-addicting medications to prevent subsequent opiate
addiction after a short period of opioid treatment for
temporary pain. Recent evidence indicates that selective
inhibition of aldehyde dehydrogenase-2 (ALDH-2) reduces
drug-seeking and trained self-administration of alcohol,
cocaine and nicotine, apparently by preventing a concomitant
surge of dopamine in the ventral tegmental area (VTA) and
nucleus accumbens (NAc). Activation of the same dopaminergic
pathway is also implicated in opioid-induced reinforcement.
Therefore, we asked whether the selective ALDH-2 inhibitor,
ANS-6637, would attenuate opioid self-administration in
drug-naïve rats for opioid self-administration. Rats
received oral doses of ANS-6637 (9, 18, 36 or 72 mg/kg) or
an equal volume of control vehicle 2 h before exposure to
remifentanil and a light cue to accentuate
self-administration over 5 consecutive days.
Self-administration and the numbers of lever presses on both
active and inactive levers were recorded. ANS-6637
significantly reduces remifentanil self-administration over
5 sessions of treatment in rats without prior exposure to
remifentanil. We also confirm that the highest dose of
ANS-6637 (72 mg/kg) used in this study did not prevent
remifentanil-induced analgesia using a classic hot plate
test. Thus, ANS-6637 significantly reduces of initial
exposure to remifentanil self-administration without
affecting desired analgesia. These preliminary observations
suggest that ANS-6637 appears to have potential value as a
non-addictive therapeutic agent to prevent abuse of commonly
used opiates in initiating pain management.},
Doi = {10.4303/jdar/236076},
Key = {fds358911}
}
@article{fds337701,
Author = {Oliveri, AN and Levin, ED},
Title = {Dopamine D1 and D2 receptor antagonism during development
alters later behavior in zebrafish.},
Journal = {Behav Brain Res},
Volume = {356},
Pages = {250-256},
Year = {2019},
Month = {January},
url = {http://dx.doi.org/10.1016/j.bbr.2018.08.028},
Abstract = {This study sought to examine the long-term behavioral
impacts of dopamine D1 and D2 receptor antagonism during
development in zebrafish (Danio rerio). Zebrafish embryos of
both the AB* and 5D strains were exposed via immersion to
either the D1 receptor antagonist SCH-23,390 or the D2
receptor antagonist haloperidol, at either 0.5 or 1.5-μM,
from 5 h post-fertilization to 5 days post-fertilization.
Aquarium water served as a control. Fish were then either
tested as larvae on day 6 post-fertilization on a light/dark
locomotor assay, or were grown to adulthood and tested on a
behavioral battery that included assays for novel
environment exploration, startle habituation, social
affiliation, and predator escape (AB* strain only). Overall,
developmental exposure to dopamine D1 and D2 receptor
antagonists caused clear effects in larval locomotor
behavior, driving hyperactivity in dark phases and
hypoactivity in light phases. Additionally, control fish
from the two strains were significantly different from each
other (p < 0.05) with the AB* fish being more active
than SD during the dark periods of the test. In the adult
behavioral battery, developmental exposure to 1.5-μM of the
D1 antagonist SCH-23390 significantly reduced activity
(p < 0.05) in the predator escape assay. Despite the
fact that embryonic exposure to D1 and D2 receptor
antagonists caused clear behavioral alterations in larval
activity there were much more subtle effects persisting into
adulthood.},
Doi = {10.1016/j.bbr.2018.08.028},
Key = {fds337701}
}
@article{fds339670,
Author = {DiPalma, D and Rezvani, AH and Willette, B and Wells, C and Slade, S and Hall, BJ and Levin, ED},
Title = {Persistent attenuation of nicotine self-administration in
rats by co-administration of chronic nicotine infusion with
the dopamine D1 receptor antagonist SCH-23390 or the
serotonin 5-HT2C agonist lorcaserin.},
Journal = {Pharmacol Biochem Behav},
Volume = {176},
Pages = {16-22},
Year = {2019},
Month = {January},
url = {http://dx.doi.org/10.1016/j.pbb.2018.11.002},
Abstract = {Tobacco addiction each year causes millions of deaths
worldwide. Brain nicotinic acetylcholine receptors have been
shown to be central to tobacco addiction. Nicotine
replacement therapy aids tobacco cessation, but the success
rate is still far too low. This may in part be due to the
fact that neurons with nicotinic receptors are not the only
neural systems involved in tobacco addiction. Interacting
neural systems also play important roles in tobacco
addiction. Nicotine increases the release of a variety of
neurotransmitters, including dopamine and serotonin.
Dopamine, in particular dopamine D1 receptors, has been
shown to be involved in the reinforcing action of nicotine.
Serotonin through its actions on 5-HT2C receptors has been
shown to play a key role in modulating the reinforcement of
addictive drugs, including nicotine and alcohol. Combination
of treatments could provide greater treatment efficacy.
These studies were conducted to evaluate combination
therapies utilizing nicotine replacement therapy in
conjunction with either a dopamine D1 receptor antagonist
SCH-23390 or a serotonin 5-HT2C receptor agonist,
lorcaserin. Female Sprague-Dawley rats were given access to
self-administer nicotine via IV infusions. Osmotic pumps
were implanted to reproduce the kinetic of chronic nicotine
patch therapy. SCH-23390 (0.02 mg/kg) or lorcaserin
(0.6 mg/kg) were administered prior to nicotine
self-administration sessions. Reproducing earlier findings
SCH-23390, lorcaserin and nicotine replacement therapy were
effective at reducing IV nicotine self-administration. 5HT2C
agonist treatment had additive effects with chronic nicotine
infusion for significantly lowering nicotine
self-administration. This study demonstrates the feasibility
of combination of chronic nicotine with therapies targeting
non-nicotinic receptors as treatment options for tobacco
addiction.},
Doi = {10.1016/j.pbb.2018.11.002},
Key = {fds339670}
}
@article{fds343374,
Author = {Hawkey, AB and White, H and Pippen, E and Greengrove, E and Rezvani, AH and Murphy, SK and Levin, ED},
Title = {Paternal nicotine exposure in rats produces long-lasting
neurobehavioral effects in the offspring.},
Journal = {Neurotoxicol Teratol},
Volume = {74},
Pages = {106808},
Year = {2019},
url = {http://dx.doi.org/10.1016/j.ntt.2019.05.001},
Abstract = {Studies of intergenerational effects of parental chemical
exposure have principally focused on maternal exposure,
particularly for studies of adverse neurobehavioral
consequences on the offspring. Maternal nicotine exposure
has long been known to cause adverse neurobehavioral effects
on the offspring. However, paternal toxicant exposure has
also been found to cause neurobehavioral toxicity in their
offspring. Recent work suggests that paternal nicotine
exposure can have epigenetic effects, although it remains
unclear whether such changes lead to neurobehavioral
effects. In the current study, we investigated the effects
of paternal nicotine exposure on neurobehavioral development
of their offspring. Male Sprague-Dawley rats were exposed to
0 or 2 mg/kg/day nicotine (sc) for 56 consecutive days
with two consecutive 2ML4 osmotic minipumps. Following
treatment, these males were mated with drug-naïve female
rats. Offspring of both sexes were tested in a behavioral
battery to assess locomotion, emotional function and
cognition. Paternal nicotine exposure did not impact
offspring viability, health or growth. However, behavioral
function of the offspring was significantly altered by
paternal nicotine exposure. Male offspring with paternal
nicotine exposure exhibited locomotor hyperactivity in the
Figure-8 apparatus when tested during adolescence. When
retested in adulthood and regardless of sex, offspring of
the nicotine exposed father showed significantly reduced
habituation of locomotor activity over the course of the
session. Compared to controls, female offspring of
nicotine-exposed fathers showed significantly reduced
response latency in the radial arm maze test. In addition to
locomotor hyperactivity, the offspring of nicotine-exposed
fathers also showed significantly diminished habituation in
the novel object recognition test. These results indicate
that chronic paternal nicotine exposure can impact the
behavior of offspring, producing locomotor hyperactivity and
impaired habituation.},
Doi = {10.1016/j.ntt.2019.05.001},
Key = {fds343374}
}
@article{fds342565,
Author = {Levin, ED and Hawkey, AB and Hall, BJ and Cauley, M and Slade, S and Yazdani, E and Kenou, B and White, H and Wells, C and Rezvani, AH and Murphy, SK},
Title = {Paternal THC exposure in rats causes long-lasting
neurobehavioral effects in the offspring.},
Journal = {Neurotoxicol Teratol},
Volume = {74},
Pages = {106806},
Year = {2019},
url = {http://dx.doi.org/10.1016/j.ntt.2019.04.003},
Abstract = {Developmental neurotoxicity of a wide variety of toxicants
mediated via maternal exposure during gestation is very well
established. In contrast, the impacts of paternal toxicant
exposure on offspring neurobehavioral function are much less
well studied. A vector for paternal toxicant exposure on
development of his offspring has been identified. Sperm DNA
can be imprinted by chemical exposures of the father. Most
but not all of the epigenetic marks in sperm are
reprogrammed after fertilization. The persisting epigenetic
marks can lead to abnormal genetic expression in the
offspring. We have found that paternal delta-9-tetrohydrocannabinol
(THC) exposure in rats causes changes in methylation of
sperm (Murphy et al., 2018). This is similar to
cannabis-associated changes in sperm DNA methylation we
found in human males who smoke cannabis (Murphy et al.,
2018). In the current study we investigated the
intergeneration effects of THC exposure of young adult male
rats (0 or 2 mg/kg/day orally for 12 days) to the
neurobehavioral development of their offspring. This
paternal THC exposure was not found to significantly impact
the clinical health of the offspring, including litter size,
sex ratio, pup birth weight, survival and growth. However,
it did cause a long-lasting significant impairment in
attentional performance in the offspring relative to
controls when they were tested in adulthood. There was also
a significant increase in habituation of locomotor activity
in the adult offspring of the males exposed to THC prior to
mating. This study shows that premating paternal THC
exposure even at a modest dose for a brief period can cause
deleterious long-term behavioral effects in the offspring,
notably significant impairment in an operant attention task.
Further research should be conducted to determine the degree
to which this type of risk is seen in humans and to
investigate the mechanisms underlying these effects and
possible treatments to ameliorate these long-term adverse
behavioral consequences of paternal THC exposure.},
Doi = {10.1016/j.ntt.2019.04.003},
Key = {fds342565}
}
@article{fds336089,
Author = {Pitt, JA and Trevisan, R and Massarsky, A and Kozal, JS and Levin, ED and Di Giulio and RT},
Title = {Maternal transfer of nanoplastics to offspring in zebrafish
(Danio rerio): A case study with nanopolystyrene.},
Journal = {Sci Total Environ},
Volume = {643},
Pages = {324-334},
Year = {2018},
Month = {December},
url = {http://dx.doi.org/10.1016/j.scitotenv.2018.06.186},
Abstract = {Plastics are ubiquitous anthropogenic contaminants that are
a growing concern in aquatic environments. The ecological
implications of macroplastics pollution are well documented,
but less is known about nanoplastics. The current study
investigates the potential adverse effects of nanoplastics,
which likely contribute to the ecological burden of plastic
pollution. To this end, we examined whether a dietary
exposure of adult zebrafish (Danio rerio) to polystyrene
nanoparticles (PS NPs) could lead to the transfer of
nanoplastics to the offspring, and whether nanoplastics
exposure affects zebrafish physiology. Specifically, adult
female and male zebrafish (F0 generation) were exposed to PS
NPs via diet for one week and bred to produce the F1
generation. Four F1 groups were generated: control
(unexposed females and males), maternal (exposed females),
paternal (exposed males), and co-parental (exposed males and
females). Co-parental PS NP exposure did not significantly
affect reproductive success. Assessment of tissues from F0
fish revealed that exposure to PS NPs significantly reduced
glutathione reductase activity in brain, muscle, and testes,
but did not affect mitochondrial function parameters in
heart or gonads. Assessment of F1 embryos and larvae
revealed that PS NPs were present in the yolk sac,
gastrointestinal tract, liver, and pancreas of the
maternally and co-parentally exposed F1 embryos/larvae.
Bradycardia was also observed in embryos from maternal and
co-parental exposure groups. In addition, the activity of
glutathione reductase and the levels of thiols were reduced
in F1 embryos/larvae from maternal and/or co-parental
exposure groups. Mitochondrial function and locomotor
activity were not affected in F1 larvae. This study
demonstrates that (i) PS NPs are transferred from mothers to
offspring, and (ii) exposure to PS NPs modifies the
antioxidant system in adult tissues and F1 larvae. We
conclude that PS NPs could bioaccumulate and be passed on to
the offspring, but this does not lead to major physiological
disturbances.},
Doi = {10.1016/j.scitotenv.2018.06.186},
Key = {fds336089}
}
@article{fds358913,
Author = {Glazer, L and Hawkey, AB and Wells, CN and Drastal, M and Odamah, K-A and Behl, M and Levin, ED},
Title = {Developmental Exposure to Low Concentrations of
Organophosphate Flame Retardants Causes Life-Long Behavioral
Alterations in Zebrafish.},
Journal = {Toxicol Sci},
Volume = {165},
Number = {2},
Pages = {487-498},
Year = {2018},
Month = {October},
url = {http://dx.doi.org/10.1093/toxsci/kfy173},
Abstract = {As the older class of brominated flame retardants (BFRs) are
phased out of commercial use because of findings of
neurotoxicity with developmental exposure, a newer class of
flame retardants have been introduced, the organophosphate
flame retardants (OPFRs). Presently, little is known about
the potential for developmental neurotoxicity or the
behavioral consequences of OPFR exposure. Our aim was to
characterize the life-long neurobehavioral effects of 4
widely used OPFRs using the zebrafish model. Zebrafish
embryos were exposed to 0.1% DMSO (vehicle control); or one
of the following treatments; isopropylated phenyl phosphate
(IPP) (0.01, 0.03, 0.1, 0.3 µM); butylphenyl diphenyl
phosphate (BPDP) (0.003, 0.03, 0.3, 3 µM); 2-ethylhexyl
diphenyl phosphate (EHDP) (0.03, 0.3, 1 µM); isodecyl
diphenyl phosphate (IDDP) (0.1, 0.3, 1, 10 µM) from 0- to
5-days postfertilization. On Day 6, the larvae were tested
for motility under alternating dark and light conditions.
Finally, at 5-7 months of age the exposed fish and
controls were tested on a battery of behavioral tests to
assess emotional function, sensorimotor response, social
interaction and predator evasion. These tests showed
chemical-specific short-term effects of altered motility in
larvae in all of the tested compounds, and long-term
impairment of anxiety-related behavior in adults following
IPP, BPDP, or EHDP exposures. Our results show that OPFRs
may not be a safe alternative to the phased-out BFRs and may
cause behavioral impacts throughout the lifespan. Further
research should evaluate the risk to mammalian experimental
models and humans.},
Doi = {10.1093/toxsci/kfy173},
Key = {fds358913}
}
@article{fds336088,
Author = {Cauley, M and Hall, BJ and Abreu-Villaça, Y and Junaid, S and White, H and Kiany, A and Slotkin, TA and Levin, ED},
Title = {Critical developmental periods for effects of low-level
tobacco smoke exposure on behavioral performance.},
Journal = {Neurotoxicology},
Volume = {68},
Pages = {81-87},
Year = {2018},
Month = {September},
url = {http://dx.doi.org/10.1016/j.neuro.2018.07.012},
Abstract = {Tobacco exposure during development leads to neurobehavioral
dysfunction in children, even when exposure is limited to
secondhand smoke. We have previously shown in rats that
developmental exposure to tobacco smoke extract (TSE), at
levels mimicking secondhand smoke, starting preconception
and extending throughout gestation, evoked subsequent
locomotor hyperactivity and cognitive impairment. These
effects were greater than those caused by equivalent
exposures to nicotine alone, implying that other agents in
tobacco smoke contributed to the adverse behavioral effects.
In the present study, we examined the critical developmental
windows of vulnerability for these effects, restricting TSE
administration (0.2 mg/kg/day nicotine equivalent, or DMSO
vehicle, delivered by subcutaneously-implanted pumps) to
three distinct 10 day periods: the 10 days preceding mating,
the first 10 days of gestation (early gestation), or the
second 10 days of gestation (late gestation). The principal
behavioral effects revealed a critical developmental window
of vulnerability, as well as sex selectivity. Late
gestational TSE exposure significantly increased errors in
the initial training on the radial-arm maze in female
offspring, whereas no effects were seen in males exposed
during late gestation, or with either sex in the other
exposure windows. In attentional testing with the visual
signal detection test, male offspring exposed to TSE during
early or late gestation showed hypervigilance during
low-motivating conditions. These results demonstrate that
gestational TSE exposure causes persistent behavioral
effects that are dependent on the developmental window in
which exposure occurs. The fact that effects were seen at
TSE levels modeling secondhand smoke, emphasizes the need
for decreasing involuntary tobacco smoke exposure,
particularly during pregnancy.},
Doi = {10.1016/j.neuro.2018.07.012},
Key = {fds336088}
}
@article{fds358914,
Author = {Massarsky, A and Jayasundara, N and Glazer, L and Levin, ED and Prasad,
GL and Di Giulio and RT},
Title = {Outcomes of developmental exposure to total particulate
matter from cigarette smoke in zebrafish (Danio
rerio).},
Journal = {Neurotoxicology},
Volume = {68},
Pages = {101-114},
Year = {2018},
Month = {September},
url = {http://dx.doi.org/10.1016/j.neuro.2018.07.003},
Abstract = {The effects of prenatal exposure to cigarette smoke remain a
subject of major interest, especially as it relates to
neural development and adverse behavioral outcomes. Several
studies have investigated the developmental toxicity of
cigarette smoke components in a zebrafish model, showing
that developmental exposure to total particulate matter
(TPM; particulate phase of cigarette smoke) leads to adverse
physiological aberrations and locomotor hyperactivity. Thus,
the current study examines whether developmental TPM
exposure of zebrafish embryos/larvae (F0) leads to
physiological and behavioral alterations, and whether
adverse effects are observed in adult fish and the next
generation (F1; i.e. F0 offspring). We also examine whether
behavioral effects are associated with changes in neural
development, stress response, neurotransmitters, and
bioenergetics. We demonstrate that TPM exposure during F0
development increased the incidence of deformities in F0
larvae, but F1 larvae did not exhibit any deformities. TPM
exposure also resulted in swimming hyperactivity in F0
larvae and several behavioral changes were noted in F0 fish
when they grew into adulthood. These behavioral changes were
generally not associated with changes in markers of neural
development in larvae, stress response in F0 adults, and
concentration of neurotransmitters (acetylcholine, dopamine,
and serotonin) in F0 adult brain. There were also no changes
in F0 or F1 embryonic oxygen consumption rate (OCR; marker
of bioenergetics and mitochondrial health); however, the OCR
in the brain of F0 males was reduced with TPM. We conclude
that developmental exposure to TPM affects larval physiology
and induces hyperactive swimming behavior, but these effects
do not persist in F1 larvae. Moreover, developmental TPM
exposure leads to long-lasting sex-specific behavioral
outcomes in the F0 adult fish.},
Doi = {10.1016/j.neuro.2018.07.003},
Key = {fds358914}
}
@article{fds358915,
Title = {Obituary—Philip J. Bushnell, Ph.D. (1947–2018)},
Journal = {Neurotoxicology and Teratology},
Volume = {69},
Pages = {73-74},
Publisher = {Elsevier BV},
Year = {2018},
Month = {September},
url = {http://dx.doi.org/10.1016/j.ntt.2018.08.002},
Doi = {10.1016/j.ntt.2018.08.002},
Key = {fds358915}
}
@article{fds329144,
Author = {Glazer, L and Wells, CN and Drastal, M and Odamah, K-A and Galat, RE and Behl, M and Levin, ED},
Title = {Developmental exposure to low concentrations of two
brominated flame retardants, BDE-47 and BDE-99, causes
life-long behavioral alterations in zebrafish.},
Journal = {Neurotoxicology},
Volume = {66},
Pages = {221-232},
Year = {2018},
Month = {May},
url = {http://dx.doi.org/10.1016/j.neuro.2017.09.007},
Abstract = {BACKGROUND: Polybrominated diphenyl ethers (PBDEs) were
widely used as flame retardants until the early 2000s,
mainly in home furnishings and electronics. The persistence
of PBDEs in the environment leads to continued ubiquitous
exposure to low levels, with infants and children
experiencing higher exposures than adults. Accumulating
evidence suggest that low-level exposures during early life
stages can affect brain development and lead to long-term
behavioral impairments. We investigated the effects of
zebrafish exposure to low doses of the two prominent PBDEs;
2,2',4,4',5,-Pentabromodiphenyl ether (BDE-99) and
2,2',4,4',-Tetrabromodiphenyl ether (BDE-47), during
embryo-development on short- and long-term behavioral
endpoints. We included the organophosphate pesticide
chlorpyrifos (CPF) due to its well documented neurotoxicity
across species from zebrafish to humans. METHODS: Zebrafish
embryos were exposed to the following individual treatments;
0.1% DMSO (vehicle control); 0.3μM CPF; 0.01, 0.03, 0.1,
0.3μM BDE-47; 0.003, 0.03, 0.3, 1, 3, 10, 20μM BDE-99 from
5 until 120h post fertilization (hpf). Low exposure levels
were determined as those not causing immediate overt
toxicity, and behavior assays were conducted in the
low-level range. At 144 hpf the larvae were tested for
locomotor activity. At approximately 6 months of age adult
zebrafish were tested in a behavioral battery including
assays for anxiety-related behavior, sensorimotor response
and habituation, social interaction, and predator avoidance.
RESULTS: In the short-term, larval locomotor activity was
reduced in larvae treated with 0.3μM CPF and 0.1μM BDE-47.
BDE-99 treatment caused non-monotonic dose effects, with
0.3μM causing hyperactivity and 1μM or higher causing
hypoactivity. In the long-term, adult anxiety-related
behavior was reduced in all treatments as measured in both
the novel tank dive test and tap test. DISCUSSION: We show
that exposure of zebrafish embryos to low concentrations of
the brominated flame retardants BDE-47 and BDE-99, and the
organophosphate pesticide CPF, caused both short- and
long-term behavioral impairments. Interestingly, we also
found that at very low exposure concentrations, where there
were no visible effects on larval activity, adult behavior
was still strongly affected.},
Doi = {10.1016/j.neuro.2017.09.007},
Key = {fds329144}
}
@article{fds332068,
Author = {Rezvani, AH and Tizabi, Y and Slade, S and Getachew, B and Levin,
ED},
Title = {Sub-anesthetic doses of ketamine attenuate nicotine
self-administration in rats.},
Journal = {Neurosci Lett},
Volume = {668},
Pages = {98-102},
Year = {2018},
Month = {March},
url = {http://dx.doi.org/10.1016/j.neulet.2018.01.022},
Abstract = {Smoking cessation strategies are of prime medical
importance. Despite availability of various pharmacological
agents in combating addiction to nicotine, more effective
medications are needed. Based on recent findings, the
glutamatergic system in the brain may provide novel targets.
Here, we evaluated the effects of acute administration of
sub-anesthetic doses of ketamine, an NMDA receptor
antagonist, in both male and female Sprague-Dawley rats
trained to self-administer nicotine. Animals were injected
subcutaneously with 5, 7.5 and 10 mg/kg ketamine or saline
and the effects on the number of intravenous nicotine
infusions during a 45 min session was measured. Ketamine
treatment significantly reduced nicotine self-administration
in a dose-dependent manner. Moreover, a differential
sensitivity between the sexes was observed as male rats
responded to a lower dose of ketamine and with higher
magnitude of effect than female rats. It is concluded that
glutamatergic receptor manipulations may offer a novel and
potentially sex-dependent intervention in nicotine
addiction.},
Doi = {10.1016/j.neulet.2018.01.022},
Key = {fds332068}
}
@article{fds332218,
Author = {Levin, ED and Wells, C and Slade, S and Rezvani, AH},
Title = {Mutually augmenting interactions of dextromethorphan and
sazetidine-A for reducing nicotine self-administration in
rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {166},
Pages = {42-47},
Year = {2018},
Month = {March},
url = {http://dx.doi.org/10.1016/j.pbb.2018.01.005},
Abstract = {A variety of nicotinic drug treatments have been found to
decrease nicotine self-administration. However, interactions
of drugs affecting different nicotinic receptor subtypes
have not been much investigated. This study investigated the
interactions between dextromethorphan, which blocks
nicotinic α3β2 receptors as well as a variety of other
receptors with sazetidine-A which is a potent and selective
α4β2 nicotinic receptor partial agonist with desensitizing
properties. This interaction was compared with
dextromethorphan combination treatment with mecamylamine,
which is a nonspecific nicotinic channel blocker.
Co-administration of dextromethorphan (either 0.5 or
5 mg/kg) and lower dose of sazetidine-A (0.3 mg/kg)
caused a significant reduction in nicotine SA. With regard
to food-motivated responding, 3 mg/kg of sazetidine-A
given alone caused a significant decrease in food intake.
However, the lower 0.3 mg/kg sazetidine-A dose did not
significantly affect food-motivated responding even when
given in combination with the higher 5 mg/kg
dextromethorphan dose which itself caused a significant
decrease in food motivated responding. Interestingly, this
higher dextromethorphan dose significantly attenuated the
decrease in food motivated responding caused by 3 mg/kg of
sazetidine-A. Locomotor activity was increased by the lower
0.3 mg/kg sazetidine-A dose and decreased by the 5 mg/kg
dextromethorphan dose. Mecamylamine at the doses (0.1 and
1 mg/kg) did not affect nicotine SA, but at 1 mg/kg
significantly decreased food-motivated responding. None of
the mecamylamine doses augmented the effect of
dextromethorphan in reducing nicotine self-administration.
These studies showed that the combination of
dextromethorphan and sazetidine-A had mutually potentiating
effects, which could provide a better efficacy for promoting
smoking cessation, however the strength of the interactions
was fairly modest.},
Doi = {10.1016/j.pbb.2018.01.005},
Key = {fds332218}
}
@article{fds333002,
Author = {Massarsky, A and Abdel, A and Glazer, L and Levin, ED and Di Giulio,
RT},
Title = {Neurobehavioral effects of 1,2-propanediol in zebrafish
(Danio rerio).},
Journal = {Neurotoxicology},
Volume = {65},
Pages = {111-124},
Year = {2018},
Month = {March},
url = {http://dx.doi.org/10.1016/j.neuro.2018.02.007},
Abstract = {The use of electronic cigarettes (e-cigarettes) is
increasing despite insufficient information concerning their
long-term effects, including the effects of maternal
e-cigarette use on pre- and postnatal development. Our
previous study demonstrated that developmental exposure to
1,2-propanediol (a principal component of e-cigarette
liquid) affected early development of zebrafish, causing
reduced growth, deformities, and hyperactive swimming
behavior in larvae. The current study extends assessment of
the developmental toxicity of 1,2-propanediol by examining
additional long-term behavioral effects. We demonstrate that
embryonic/larval exposure of zebrafish to 1,2-propanediol
(0.625% or 1.25%) not only affected behavioral parameters in
the larvae, but also caused persisting behavioral effects in
adults after early developmental exposure. Additional
parameters, including neural and vascular development in
larvae, stress response in adults, and concentration of
neurotransmitters dopamine and serotonin in adult brain were
examined, in order to explain the behavioral differences.
These additional assessments did not find 1,2-propanediol
exposure to significantly affect Tg(Neurog1:GFP) or the
transcript abundance of neural genes (Neurog1, Ascl1a,
Elavl3, and Lef1). Vascular development was not found to be
affected by 1,2-propanediol exposure, as inferred from
experiments with Tg(Flk1:eGFP) zebrafish; however,
transcript abundance of vascular genes (Flk1, Vegf, Tie-2,
and Angpt1) was decreased. No statistically significant
changes were noted for plasma cortisol or brain
neurotransmitters in adult fish. Lastly, analysis of gene
transcripts involved with 1,2-propanediol metabolism (Adh5,
Aldh2.1, and Ldha) showed an increase in Adh5 transcript.
This is the first study to demonstrate that developmental
exposure to 1,2-propanediol has long-term neurobehavioral
consequences in adult zebrafish, showing that e-cigarettes
contain substances potentially harmful to
neurodevelopment.},
Doi = {10.1016/j.neuro.2018.02.007},
Key = {fds333002}
}
@article{fds332917,
Author = {Pitt, JA and Kozal, JS and Jayasundara, N and Massarsky, A and Trevisan,
R and Geitner, N and Wiesner, M and Levin, ED and Di Giulio,
RT},
Title = {Uptake, tissue distribution, and toxicity of polystyrene
nanoparticles in developing zebrafish (Danio
rerio).},
Journal = {Aquat Toxicol},
Volume = {194},
Pages = {185-194},
Year = {2018},
Month = {January},
url = {http://dx.doi.org/10.1016/j.aquatox.2017.11.017},
Abstract = {Plastic pollution is a critical environmental concern and
comprises the majority of anthropogenic debris in the ocean,
including macro, micro, and likely nanoscale (less than
100nm in at least one dimension) plastic particles. While
the toxicity of macroplastics and microplastics is
relatively well studied, the toxicity of nanoplastics is
largely uncharacterized. Here, fluorescent polystyrene
nanoparticles (PS NPs) were used to investigate the
potential toxicity of nanoplastics in developing zebrafish
(Danio rerio), as well as to characterize the uptake and
distribution of the particles within embryos and larvae.
Zebrafish embryos at 6h post-fertilization (hpf) were
exposed to PS NPs (0.1, 1, or 10ppm) until 120 hpf. Our
results demonstrate that PS NPs accumulated in the yolk sac
as early as 24 hpf and migrated to the gastrointestinal
tract, gallbladder, liver, pancreas, heart, and brain
throughout development (48-120 hpf). Accumulation of PS NPs
decreased during the depuration phase (120-168 hpf) in all
organs, but at a slower rate in the pancreas and
gastrointestinal tract. Notably, exposure to PS NPs did not
induce significant mortality, deformities, or changes to
mitochondrial bioenergetics, but did decrease the heart
rate. Lastly, exposure to PS NPs altered larval behavior as
evidenced by swimming hypoactivity in exposed larvae. Taken
together, these data suggest that at least some nanoplastics
can penetrate the chorion of developing zebrafish,
accumulate in the tissues, and affect physiology and
behavior, potentially affecting organismal fitness in
contaminated aquatic ecosystems.},
Doi = {10.1016/j.aquatox.2017.11.017},
Key = {fds332917}
}
@article{fds333553,
Author = {Oliveri, AN and Ortiz, E and Levin, ED},
Title = {Developmental exposure to an organophosphate flame retardant
alters later behavioral responses to dopamine antagonism in
zebrafish larvae.},
Journal = {Neurotoxicol Teratol},
Volume = {67},
Pages = {25-30},
Year = {2018},
url = {http://dx.doi.org/10.1016/j.ntt.2018.03.002},
Abstract = {Human exposure to organophosphate flame retardants (OPFRs)
is widespread, including pregnant women and young children
with whom developmental neurotoxic risk is a concern. Given
similarities of OPFRs to organophosphate (OP) pesticides,
research into the possible neurotoxic impacts of
developmental OPFR exposure has been growing. Building upon
research implicating exposure to OP pesticides in
dopaminergic (DA) dysfunction, we exposed developing
zebrafish to the OPFR tris(1,3-dichloroisopropyl) phosphate
(TDCIPP), during the first 5 days following fertilization.
On day 6, larvae were challenged with acute administration
of dopamine D1 and D2 receptor antagonists and then tested
in a light-dark locomotor assay. We found that both
developmental TDCIPP exposure and acute dopamine D1 and D2
antagonism decreased locomotor activity separately. The OPFR
and DA effects were not additive; rather, TDCIPP blunted
further D1 and D2 antagonist-induced decreases in activity.
Our results suggest that TDCIPP exposure may be disrupting
dopamine signaling. These findings support further research
on the effects of OPFR exposure on the normal
neurodevelopment of DA systems, whether these results might
persist into adulthood, and whether they interact with OPFR
effects on other neurotransmitter systems in producing the
developmental neurobehavioral toxicity.},
Doi = {10.1016/j.ntt.2018.03.002},
Key = {fds333553}
}
@article{fds358918,
Author = {Murphy, SK and Itchon-Ramos, N and Visco, Z and Huang, Z and Grenier, C and Schrott, R and Acharya, K and Boudreau, M-H and Price, TM and Raburn,
DJ and Corcoran, DL and Lucas, JE and Mitchell, JT and McClernon, FJ and Cauley, M and Hall, BJ and Levin, ED and Kollins,
SH},
Title = {Cannabinoid exposure and altered DNA methylation in rat and
human sperm.},
Journal = {Epigenetics},
Volume = {13},
Number = {12},
Pages = {1208-1221},
Year = {2018},
url = {http://dx.doi.org/10.1080/15592294.2018.1554521},
Abstract = {Little is known about the reproductive effects of paternal
cannabis exposure. We evaluated associations between
cannabis or tetrahydrocannabinol (THC) exposure and altered
DNA methylation in sperm from humans and rats, respectively.
DNA methylation, measured by reduced representation
bisulfite sequencing, differed in the sperm of human users
from non-users by at least 10% at 3,979 CpG sites. Pathway
analyses indicated Hippo Signaling and Pathways in Cancer as
enriched with altered genes (Bonferroni p < 0.02). These
same two pathways were also enriched with genes having
altered methylation in sperm from THC-exposed versus
vehicle-exposed rats (p < 0.01). Data validity is
supported by significant correlations between THC exposure
levels in humans and methylation for 177 genes, and
substantial overlap in THC target genes in rat sperm (this
study) and genes previously reported as having altered
methylation in the brain of rat offspring born to parents
both exposed to THC during adolescence. In humans, cannabis
use was also associated with significantly lower sperm
concentration. Findings point to possible pre-conception
paternal reproductive risks associated with cannabis
use.},
Doi = {10.1080/15592294.2018.1554521},
Key = {fds358918}
}
@article{fds330580,
Author = {Lacagnina, MJ and Kopec, AM and Cox, SS and Hanamsagar, R and Wells, C and Slade, S and Grace, PM and Watkins, LR and Levin, ED and Bilbo,
SD},
Title = {Opioid Self-Administration is Attenuated by Early-Life
Experience and Gene Therapy for Anti-Inflammatory IL-10 in
the Nucleus Accumbens of Male Rats.},
Journal = {Neuropsychopharmacology},
Volume = {42},
Number = {11},
Pages = {2128-2140},
Year = {2017},
Month = {October},
url = {http://dx.doi.org/10.1038/npp.2017.82},
Abstract = {Early-life conditions can contribute to the propensity for
developing neuropsychiatric disease, including substance
abuse disorders. However, the long-lasting mechanisms that
shape risk or resilience for drug addiction remain unclear.
Previous work has shown that a neonatal handling procedure
in rats (which promotes enriched maternal care) attenuates
morphine conditioning, reduces morphine-induced glial
activation, and increases microglial expression of the
anti-inflammatory cytokine interleukin-10 (IL-10). We thus
hypothesized that anti-inflammatory signaling may underlie
the effects of early-life experience on later-life opioid
drug-taking. Here we demonstrate that neonatal handling
attenuates intravenous self-administration of the opioid
remifentanil in a drug-concentration-dependent manner.
Transcriptional profiling of the nucleus accumbens (NAc)
from handled rats following repeated exposure to
remifentanil reveals a suppression of pro-inflammatory
cytokine and chemokine gene expression, consistent with an
anti-inflammatory phenotype. To determine if
anti-inflammatory signaling alters drug-taking behavior, we
administered intracranial injections of plasmid DNA encoding
IL-10 (pDNA-IL-10) into the NAc of non-handled rats. We
discovered that pDNA-IL-10 treatment reduces remifentanil
self-administration in a drug-concentration-dependent
manner, similar to the effect of handling. In contrast,
neither handling nor pDNA-IL-10 treatment alters
self-administration of food or sucrose rewards. These
collective observations suggest that neuroimmune signaling
mechanisms in the NAc are shaped by early-life experience
and may modify motivated behaviors for opioid drugs.
Moreover, manipulation of the IL-10 signaling pathway
represents a novel approach for influencing opioid
reinforcement.},
Doi = {10.1038/npp.2017.82},
Key = {fds330580}
}
@article{fds327308,
Author = {Rezvani, AH and Slade, S and Wells, C and Yenugonda, VM and Liu, Y and Brown, ML and Xiao, Y and Kellar, KJ and Levin, ED},
Title = {Differential efficacies of the nicotinic α4β2
desensitizing agents in reducing nicotine
self-administration in female rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {234},
Number = {17},
Pages = {2517-2523},
Year = {2017},
Month = {September},
url = {http://dx.doi.org/10.1007/s00213-017-4641-6},
Abstract = {RATIONALE AND OBJECTIVES: Desensitization of neuronal
nicotinic acetylcholine receptors holds promise as an
effective treatment of tobacco addiction. Previously, we
found that sazetidine-A (Saz-A), which selectively
desensitizes α4β2 nicotinic receptors, significantly
decreased intravenous (IV) nicotine self-administration (SA)
in rats with an effective dose of 3 mg/kg in acute and
repeated injection studies. We also found that chronic
infusions of Saz-A at doses of 2 and 6 mg/kg/day
significantly reduced nicotine SA in rats. In continuing
studies, we have characterized other Saz-A analogs, YL-2-203
and VMY-2-95, to determine their efficacies in reducing
nicotine SA in rats. METHODS: Young adult female
Sprague-Dawley rats were fitted with IV catheters and were
trained for nicotine SA (0.03 mg/kg/infusion) on a fixed
ratio 1 schedule for ten sessions. The same rats were also
implanted subcutaneously with osmotic minipumps to
continually deliver 2 or 6 mg/kg body weight YL-2-203,
VMY-2-95, or saline for four consecutive weeks. RESULTS:
Chronic administration of VMY-2-95 at doses of 2 and
6 mg/kg/day caused significant (p < 0.01) decreases in
nicotine SA over the 2 weeks of continued nicotine SA and
for the 1-week period of resumed access after a week of
enforced abstinence, whereas chronic administration of
YL-2-203 at the same doses was not found to be effective.
CONCLUSIONS: These studies, together with our previous
studies of Saz-A, revealed a spectrum of efficacies for
these α4β2 nicotinic receptor desensitizing agents and
provide a path forward for the most effective compounds to
be further developed as possible aids to smoking
cessation.},
Doi = {10.1007/s00213-017-4641-6},
Key = {fds327308}
}
@article{fds330581,
Author = {Massarsky, A and Abdel, A and Glazer, L and Levin, ED and Di Giulio,
RT},
Title = {Exposure to 1,2-Propanediol Impacts Early Development of
Zebrafish (Danio rerio) and Induces Hyperactivity.},
Journal = {Zebrafish},
Volume = {14},
Number = {3},
Pages = {216-222},
Year = {2017},
Month = {June},
url = {http://dx.doi.org/10.1089/zeb.2016.1400},
Abstract = {The use of electronic cigarettes (e-cigarettes) is
increasing as an alternative to tobacco burning cigarettes;
however, their safety remains to be fully determined. The
long-term effects of e-cigarettes are unknown, including the
effects of maternal e-cigarette use on pre- and postnatal
development. Additional research on the safety of
e-cigarettes is needed. Especially useful would be
information from high- and moderate-throughput economic
model systems. This study investigates the effects of
1,2-propanediol, which was identified as the main component
of e-cigarette liquid, on early development of zebrafish (an
in vivo high-throughput model system that was recently
proposed for the study of tobacco cigarette and e-cigarette
toxicity). Zebrafish embryos were exposed to 1.25% or 2.5%
1,2-propanediol from 6 to 72 h post-fertilization (hpf).
We show that exposure to 1,2-propanediol did not
significantly affect mortality. Hatching success was
significantly lower in 2.5% 1,2-propanediol-exposed embryos
at 48 hpf, but at 72 hpf no significant differences were
noted. Moreover, exposure to 1,2-propanediol reduced growth
and increased the incidence of string heart, pericardial
edema, and yolk sac edema. Most importantly, developmental
exposure to 1.25% 1,2-propanediol caused hyperactive
swimming behavior in larvae. This study demonstrates that
1,2-propanediol has adverse impacts on early development in
zebrafish.},
Doi = {10.1089/zeb.2016.1400},
Key = {fds330581}
}
@article{fds324065,
Author = {Hall, BJ and Abreu-Villaça, Y and Cauley, M and Junaid, S and White, H and Kiany, A and Levin, ED},
Title = {The ventral hippocampal muscarinic cholinergic system plays
a key role in sexual dimorphisms of spatial working memory
in rats.},
Journal = {Neuropharmacology},
Volume = {117},
Pages = {106-113},
Year = {2017},
Month = {May},
url = {http://dx.doi.org/10.1016/j.neuropharm.2017.01.019},
Abstract = {Sex differences in cognitive processing and function have
been documented in human and animal studies. Females have
been found to perform better than males on non-spatial
memory tasks, while males tend to outperform females on
spatial memory tasks. The neural mechanisms underlying these
sexual dimorphisms are unclear. However, it is known that
the cholinergic system is critically involved in memory
processes, and there are notable differences between males
and females in cholinergic system function and receptor
expression. In particular, there are sex differences in the
processing of information in the frontal cortex and
hippocampus. In this study, we examined the roles of
muscarinic and nicotinic acetylcholine receptors in the
medial frontal cortex (MfC) and ventral hippocampus (VH) on
spatial working memory in male and female rats. Local
infusions of scopolamine (SCOP) and mecamylamine (MEC) (10,
20, 50 μg/side) were used to antagonize these receptors in
each respective brain region during performance in the
16-arm radial arm maze. Infusions of SCOP into the VH caused
a significant increase in memory errors in female rats, but
had no significant effect on males, while infusions of MEC
into the VH had no effect on either sex. Infusions of both
SCOP (50 μg/side) and MEC (20 μg/side) into the MfC caused
working memory impairments in both sexes. These results show
that muscarinic acetylcholine receptors in the VH are
differentially vulnerable to spatial memory impairments in
females. Ventral hippocampal muscarinic acetylcholine
receptors may play a key role in male-female differences in
spatial memory.},
Doi = {10.1016/j.neuropharm.2017.01.019},
Key = {fds324065}
}
@article{fds330582,
Author = {van Thriel, C and Levin, E and Lein, P and Costa, LG and Westerink,
RHS},
Title = {Neural mechanisms of functional impairment across the
lifespan: The 15th Biennial Meeting of the International
Neurotoxicology Association and 39th Annual Meeting of the
Neurobehavioral Teratology Society.},
Journal = {Neurotoxicology},
Volume = {59},
Pages = {131-132},
Year = {2017},
Month = {March},
url = {http://dx.doi.org/10.1016/j.neuro.2017.03.003},
Doi = {10.1016/j.neuro.2017.03.003},
Key = {fds330582}
}
@article{fds324066,
Author = {Abreu-Villaça, Y and Levin, ED},
Title = {Developmental neurotoxicity of succeeding generations of
insecticides.},
Journal = {Environ Int},
Volume = {99},
Pages = {55-77},
Year = {2017},
Month = {February},
url = {http://dx.doi.org/10.1016/j.envint.2016.11.019},
Abstract = {Insecticides are by design toxic. They must be toxic to
effectively kill target species of insects. Unfortunately,
they also have off-target toxic effects that can harm other
species, including humans. Developmental neurotoxicity is
one of the most prominent off-target toxic risks of
insecticides. Over the past seven decades several classes of
insecticides have been developed, each with their own
mechanisms of effect and toxic side effects. This review
covers the developmental neurotoxicity of the succeeding
generations of insecticides including organochlorines,
organophosphates, pyrethroids, carbamates and
neonicotinoids. The goal of new insecticide development is
to more effectively kill target species with fewer toxic
side effects on non-target species. From the experience with
the developmental neurotoxicity caused by the generations of
insecticides developed in the past advice is offered how to
proceed with future insecticide development to decrease
neurotoxic risk.},
Doi = {10.1016/j.envint.2016.11.019},
Key = {fds324066}
}
@article{fds330184,
Author = {Macaulay, LJ and Chernick, M and Chen, A and Hinton, DE and Bailey, JM and Kullman, SW and Levin, ED and Stapleton, HM},
Title = {Exposure to a PBDE/OH-BDE mixture alters juvenile zebrafish
(Danio rerio) development.},
Journal = {Environ Toxicol Chem},
Volume = {36},
Number = {1},
Pages = {36-48},
Year = {2017},
Month = {January},
url = {http://dx.doi.org/10.1002/etc.3535},
Abstract = {Polybrominated diphenyl ethers (PBDEs) and their metabolites
(e.g., hydroxylated BDEs [OH-BDEs]) are contaminants
frequently detected together in human tissues and are
structurally similar to thyroid hormones. Thyroid hormones
partially mediate metamorphic transitions between life
stages in zebrafish, making this a critical developmental
window that may be vulnerable to chemicals disrupting
thyroid signaling. In the present study, zebrafish were
exposed to 6-OH-BDE-47 (30 nM; 15 μg/L) alone, or to a
low-dose (30 μg/L) or high-dose (600 μg/L) mixture of
PentaBDEs, 6-OH-BDE-47 (0.5-6 μg/L), and
2,4,6-tribromophenol (5-100 μg/L) during juvenile
development (9-23 d postfertilization) and evaluated for
developmental endpoints mediated by thyroid hormone
signaling. Fish were sampled at 3 time points and examined
for developmental and skeletal morphology, apical thyroid
and skeletal gene markers, and modifications in swimming
behavior (as adults). Exposure to the high-dose mixture
resulted in >85% mortality within 1 wk of exposure,
despite being below reported acute toxicity thresholds for
individual congeners. The low-dose mixture and 6-OH-BDE-47
groups exhibited reductions in body length and delayed
maturation, specifically relating to swim bladder, fin, and
pigmentation development. Reduced skeletal ossification was
also observed in 6-OH-BDE-47-treated fish. Assessment of
thyroid and osteochondral gene regulatory networks
demonstrated significantly increased expression of genes
that regulate skeletal development and thyroid hormones.
Overall, these results indicate that exposures to
PBDE/OH-BDE mixtures adversely impact zebrafish maturation
during metamorphosis. Environ Toxicol Chem 2017;36:36-48. ©
2016 SETAC.},
Doi = {10.1002/etc.3535},
Key = {fds330184}
}
@article{fds330275,
Author = {Slotkin, TA and Stadler, A and Skavicus, S and Card, J and Ruff, J and Levin, ED and Seidler, FJ},
Title = {Is There a Critical Period for the Developmental
Neurotoxicity of Low-Level Tobacco Smoke
Exposure?},
Journal = {Toxicol Sci},
Volume = {155},
Number = {1},
Pages = {75-84},
Year = {2017},
Month = {January},
url = {http://dx.doi.org/10.1093/toxsci/kfw180},
Abstract = {Secondhand tobacco smoke exposure in pregnancy increases the
risk of neurodevelopmental disorders. We evaluated in rats
whether there is a critical period during which tobacco
smoke extract (TSE) affects the development of acetylcholine
and serotonin systems, prominent targets for adverse effects
of nicotine and tobacco smoke. We simulated secondhand smoke
exposure by administering TSE so as to produce nicotine
concentrations one-tenth those in active smoking, with 3
distinct, 10-day windows: premating, early gestation or late
gestation. We conducted longitudinal evaluations in multiple
brain regions, starting in early adolescence (postnatal day
30) and continued to full adulthood (day 150). TSE exposure
in any of the 3 windows impaired presynaptic cholinergic
activity, exacerbated by a decrement in nicotinic
cholinergic receptor concentrations. Although the adverse
effects were seen for all 3 treatment windows, there was a
distinct progression, with lowest sensitivity for premating
exposure and higher sensitivity for gestational exposures.
Serotonin receptors were also reduced by TSE exposure with
the same profile: little effect with premating exposure,
intermediate effect with early gestational exposure and
large effect with late gestational exposure. As serotonergic
circuits can offset the neurobehavioral impact of
cholinergic deficits, these receptor changes were
maladaptive. Thus, there is no single 'critical period' for
effects of low-level tobacco smoke but there is differential
sensitivity dependent upon the developmental stage at the
time of exposure. Our findings reinforce the need to avoid
secondhand smoke exposure not only during pregnancy, but
also in the period prior to conception, or generally for
women of childbearing age.},
Doi = {10.1093/toxsci/kfw180},
Key = {fds330275}
}
@article{fds330161,
Author = {Rezvani, AH and Levin, ED and Cauley, M and Getachew, B and Tizabi,
Y},
Title = {Ketamine Differentially Attenuates Alcohol Intake in Male
Versus Female Alcohol Preferring (P) Rats.},
Journal = {J Drug Alcohol Res},
Volume = {6},
Pages = {236030},
Year = {2017},
url = {http://dx.doi.org/10.4303/jdar/236030},
Abstract = {BACKGROUND: Although various pharmacological tools in
combating addiction to alcohol are available, their efficacy
is limited. Hence, there is a critical need for development
of more effective medications. Recent advances in the field
have identified the glutamatergic system as a potential
novel target for intervention in addictive behaviors.
PURPOSE: Hence, we evaluated the effects of acute
administration of low (subanesthetic) doses of ketamine, an
NMDA receptor antagonist, on alcohol intake and alcohol
preference in both male and female rats. STUDY DESIGN: Adult
alcohol preferring (P) rats were exposed to two-bottle
choice (ethanol 10% and water) for at least three weeks
following a nine-day training period and the effects of
various doses of ketamine (5 mg/kg, 7.5 mg/kg, and 10 mg/kg,
injected subcutaneously, SC) on consumption of alcohol over
various time periods during a 24 h interval were measured.
RESULTS: Our results indicate that ketamine treatment
significantly reduced both alcohol intake and preference in
a time- and dose-dependent manner in both sexes. Moreover, a
differential sensitivity between the sexes was observed.
Thus, although alcohol intake was higher in males, female
rats responded much more strongly to the highest dose of
ketamine than males in the initial time periods. CONCLUSION:
It is concluded that glutamatergic receptor manipulations
may be of therapeutic potential in addiction to alcohol and
that different sexes may respond differentially to such
treatments.},
Doi = {10.4303/jdar/236030},
Key = {fds330161}
}
@article{fds320364,
Author = {Slotkin, TA and Skavicus, S and Card, J and Levin, ED and Seidler,
FJ},
Title = {Diverse neurotoxicants target the differentiation of
embryonic neural stem cells into neuronal and glial
phenotypes.},
Journal = {Toxicology},
Volume = {372},
Pages = {42-51},
Year = {2016},
Month = {November},
url = {http://dx.doi.org/10.1016/j.tox.2016.10.015},
Abstract = {The large number of compounds that needs to be tested for
developmental neurotoxicity drives the need to establish in
vitro models to evaluate specific neurotoxic endpoints. We
used neural stem cells derived from rat neuroepithelium on
embryonic day 14 to evaluate the impact of diverse toxicants
on their ability to differentiate into glia and neurons: a
glucocorticoid (dexamethasone), organophosphate insecticides
(chlorpyrifos, diazinon, parathion), insecticides targeting
the GABAA receptor (dieldrin, fipronil), heavy metals (Ni2+,
Ag+), nicotine and tobacco smoke extract. We found three
broad groupings of effects. One diverse set of compounds,
dexamethasone, the organophosphate pesticides, Ni2+ and
nicotine, suppressed expression of the glial phenotype while
having little or no effect on the neuronal phenotype. The
second pattern was restricted to the pesticides acting on
GABAA receptors. These compounds promoted the glial
phenotype and suppressed the neuronal phenotype. Notably,
the actions of compounds eliciting either of these
differentiation patterns were clearly unrelated to deficits
in cell numbers: dexamethasone, dieldrin and fipronil all
reduced cell numbers, whereas organophosphates and Ni2+ had
no effect. The third pattern, shared by Ag+ and tobacco
smoke extract, clearly delineated cytotoxicity,
characterized by major cell loss with suppression of
differentiation into both glial and neuronal phenotypes; but
here again, there was some selectivity in that glia were
suppressed more than neurons. Our results, from this survey
with diverse compounds, point to convergence of
neurotoxicant effects on a specific "decision node" that
controls the emergence of neurons and glia from neural stem
cells.},
Doi = {10.1016/j.tox.2016.10.015},
Key = {fds320364}
}
@article{fds320363,
Author = {Petro, A and Sexton, HG and Miranda, C and Rastogi, A and Freedman, JH and Levin, ED},
Title = {Persisting neurobehavioral effects of developmental copper
exposure in wildtype and metallothionein 1 and 2 knockout
mice.},
Journal = {BMC Pharmacol Toxicol},
Volume = {17},
Number = {1},
Pages = {55},
Year = {2016},
Month = {November},
url = {http://dx.doi.org/10.1186/s40360-016-0096-3},
Abstract = {BACKGROUND: Metallothioneins (MT) are small proteins, which
are crucial for the distribution of heavy and transition
metals. Previously, we found in mice that knockout of MT 1
and 2 genes (MTKO) impaired spatial learning and potentiated
the learning impairment caused by developmental mercury
exposure. The current study examined the neurocognitive and
neurochemical effects of MTKO with the developmental copper
(Cu) supplementation. METHODS: Wildtype (WT) and MTKO mice
were given supplemental Cu (0, 10 or 50 mg/l) in their
drinking water during gestation and until weaning. When the
mice were young adults they were trained on the win-shift
8-arm radial maze test of spatial learning and memory. After
cognitive testing, their brains were analyzed for
norepinepherine, dopamine and serotonin levels. RESULTS: In
the spatial learning test, wildtype mice showed the normal
sex difference with males performing more accurately than
the females. This effect was eliminated by MTKO and restored
by moderate Cu supplementation during development. In
neurochemical studies, MTKO caused a significant overall
increase in serotonin in all of the regions studied: the
frontal cortex, posterior cortex, hippocampus, striatum,
midbrain, and brainstem. MTKO also caused a significant
increase in norepinepherine in the brainstem and
hippocampus. In wildtype mice, Cu supplementation during
development caused a significant decline in dopamine and
norepinepherine in the midbrain and dopamine in the frontal
cortex. These effects were blocked by MTKO. CONCLUSIONS: The
normal sex difference in spatial working memory accuracy,
which was eliminated by MTKO, was restored by moderate
copper supplementation. MTKO increased serotonin across all
brain areas studied and increased norepinepherine only in
the hippocampus and brainstem. MTKO blocked copper-induced
decreases in dopamine and norepinepherine in the midbrain
and dopamine in the frontal cortex.},
Doi = {10.1186/s40360-016-0096-3},
Key = {fds320363}
}
@article{fds320365,
Author = {Levin, ED and Hall, BJ and Chattopadhyay, A and Slade, S and Wells, C and Rezvani, AH and Rose, JE},
Title = {Reduction of nicotine self-administration by chronic
nicotine infusion with H1 histamine blockade in female
rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {233},
Number = {15-16},
Pages = {3009-3015},
Year = {2016},
Month = {August},
url = {http://dx.doi.org/10.1007/s00213-016-4347-1},
Abstract = {RATIONALE: Chronic nicotine infusion via transdermal patches
has been widely shown to assist with smoking cessation. In
particular, transdermal nicotine treatment prior to quitting
smoking helps reduce ad libitum smoking and aids cessation
Rose et al. (Nicotine Tob Res 11:1067-75, 2009). However,
despite this success, the majority of smokers who use
transdermal nicotine fail to permanently quit smoking.
Additional treatments are needed. Tobacco addiction does not
just depend on nicotinic receptor systems; a variety of
neural systems are involved, including dopamine,
norepinepherine, serotonin, and histamine. OBJECTIVES: Given
the involvement of a variety of neural systems in the
circuits of addiction, combination therapy may offer
improved efficacy for successful smoking cessation beyond
single treatments alone. We have found that pyrilamine, an
H1 histamine antagonist, significantly decreases nicotine
self-administration in rats. METHODS: The current study was
conducted to confirm the effect of chronic nicotine infusion
on ongoing nicotine self-administration and resumed access
after enforced abstinence and to determine the interaction
of chronic nicotine with an H1 antagonist treatment.
RESULTS: Chronic nicotine infusion via osmotic minipump (2.5
and 5 mg/kg/day for 28 days) significantly reduced
nicotine self-administration in a dose-dependent manner.
Chronic nicotine infusion also reduced the resumption of
nicotine self-administration after enforced abstinence.
Chronic pyrilamine infusion (25 mg/kg/day for 14 days)
also significantly reduced nicotine self-administration.
CONCLUSION: The combination of chronic nicotine and
pyrilamine reduced nicotine self-administration to a greater
extent than treatment with either drug alone.},
Doi = {10.1007/s00213-016-4347-1},
Key = {fds320365}
}
@article{fds316072,
Author = {Hall, BJ and Cauley, M and Burke, DA and Kiany, A and Slotkin, TA and Levin, ED},
Title = {Cognitive and Behavioral Impairments Evoked by Low-Level
Exposure to Tobacco Smoke Components: Comparison with
Nicotine Alone.},
Journal = {Toxicol Sci},
Volume = {151},
Number = {2},
Pages = {236-244},
Year = {2016},
Month = {June},
ISSN = {1096-6080},
url = {http://dx.doi.org/10.1093/toxsci/kfw042},
Abstract = {Active maternal smoking has adverse effects on
neurobehavioral development of the offspring, with nicotine
(Nic) providing much of the underlying causative mechanism.
To determine whether the lower exposures caused by
second-hand smoke are deleterious, we administered tobacco
smoke extract (TSE) to pregnant rats starting preconception
and continued through the second postnatal week,
corresponding to all 3 trimesters of fetal brain
development. Dosing was adjusted to produce maternal plasma
Nic concentrations encountered with second-hand smoke, an
order of magnitude below those seen in active smokers. We
then compared TSE effects to those of an equivalent dose of
Nic alone, and to a 10-fold higher Nic dose. Gestational
exposure to TSE and Nic significantly disrupted cognitive
and behavioral function in behavioral tests given during
adolescence and adulthood (postnatal weeks 4-40), producing
hyperactivity, working memory deficits, and impairments in
emotional processing, even at the low exposure levels
corresponding to second-hand smoke. Although TSE effects
were highly correlated with those of Nic, the effects of TSE
were much larger than could be attributed to just the Nic in
the mixture. Indeed, TSE effects more closely resembled
those of the 10-fold higher Nic levels, but still exceeded
their magnitude. In combination with our earlier findings,
this study thus completes the chain of causation to prove
that second-hand smoke exposure causes neurodevelopmental
deficits, originating in disruption of neurodifferentiation,
leading to miswiring of neuronal circuits, and as shown
here, culminating in behavioral dysfunction. As low level
exposure to Nic alone produced neurobehavioral teratology,
'harm reduction' Nic products do not abolish the potential
for neurodevelopmental damage.},
Doi = {10.1093/toxsci/kfw042},
Key = {fds316072}
}
@article{fds316071,
Author = {Levin, ED},
Title = {Crumbling Infrastructure and Learning Impairment: A Call for
Responsibility.},
Journal = {Environ Health Perspect},
Volume = {124},
Number = {5},
Pages = {A79},
Year = {2016},
Month = {May},
ISSN = {0091-6765},
url = {http://dx.doi.org/10.1289/EHP69},
Doi = {10.1289/EHP69},
Key = {fds316071}
}
@article{fds316073,
Author = {Bao, X and Chandramohan, V and Reynolds, RP and Norton, JN and Wetsel,
WC and Rodriguiz, RM and Aryal, DK and McLendon, RE and Levin, ED and Petry, NA and Zalutsky, MR and Burnett, BK and Kuan, C-T and Pastan, IH and Bigner, DD},
Title = {Preclinical toxicity evaluation of a novel immunotoxin,
D2C7-(scdsFv)-PE38KDEL, administered via intracerebral
convection-enhanced delivery in rats.},
Journal = {Invest New Drugs},
Volume = {34},
Number = {2},
Pages = {149-158},
Year = {2016},
Month = {April},
ISSN = {0167-6997},
url = {http://dx.doi.org/10.1007/s10637-015-0318-3},
Abstract = {D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that
reacts with wild-type epidermal growth factor receptor
(EGFRwt) and mutant EGFRvIII proteins overexpressed in
glioblastomas. This study assessed the toxicity of
intracerebral administration of D2C7-IT to support an
initial Food and Drug Administration Investigational New
Drug application. After the optimization of the formulation
and administration, two cohorts (an acute and chronic cohort
necropsied on study days 5 and 34) of Sprague-Dawley (SD)
rats (four groups of 5 males and 5 females) were infused
with the D2C7-IT formulation at total doses of 0, 0.05, 0.1,
0.4 μg (the acute cohort) and 0, 0.05, 0.1, 0.35 μg (the
chronic cohort) for approximately 72 h by intracerebral
convection-enhanced delivery using osmotic pumps. Mortality
was observed in the 0.40 μg (5/10 rats) and 0.35 μg
(4/10 rats) high-dose groups of each cohort. Body weight
loss and abnormal behavior were only revealed in the rats
treated with high doses of D2C7-IT. No dose-related effects
were observed in clinical laboratory tests in either cohort.
A gross pathologic examination of systemic tissues from the
high-dose and control groups in both cohorts exhibited no
dose-related or drug-related pathologic findings. Brain
histopathology revealed the frequent occurrence of
dose-related encephalomalacia, edema, and demyelination in
the high-dose groups of both cohorts. In this study, the
maximum tolerated dose of D2C7-IT was determined to be
between 0.10 and 0.35 μg, and the no-observed-adverse-effect-level
was 0.05 μg in SD rats. Both parameters were utilized to
design the Phase I/II D2C7-IT clinical trial.},
Doi = {10.1007/s10637-015-0318-3},
Key = {fds316073}
}
@article{fds313800,
Author = {Briggs, SA and Hall, BJ and Wells, C and Slade, S and Jaskowski, P and Morrison, M and Rezvani, AH and Rose, JE and Levin,
ED},
Title = {Dextromethorphan interactions with histaminergic and
serotonergic treatments to reduce nicotine
self-administration in rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {142},
Pages = {1-7},
Year = {2016},
Month = {March},
ISSN = {0091-3057},
url = {http://dx.doi.org/10.1016/j.pbb.2015.12.004},
Abstract = {Combining effective treatments with diverse mechanisms of
action for smoking cessation may provide better therapy by
targeting multiple points of control in the neural circuits
underlying addiction. Previous research in a rat model has
shown that dextromethorphan, which has α3β4 nicotinic and
NMDA glutamatergic antagonist actions, significantly
decreases nicotine self-administration. We have found in the
rat model that the H1 histamine antagonist pyrilamine and
the serotonin 5HT2C agonist lorcaserin also significantly
reduce nicotine self-administration. The current studies
were conducted to determine the interactive effects of
dextromethorphan with pyrilamine and lorcaserin on nicotine
self-administration in rats. Young adult female rats were
fitted with jugular IV catheters and trained to
self-administer a nicotine infusion dose of
0.03-mg/kg/infusion. In an initial dose-effect function
study of dextromethorphan, we found a monotonic decrease in
nicotine self-administration over a dose range of 1 to
30-mg/kg with the lowest effective dose of 3-mg/kg. Then,
with two separate cohorts of rats, dextromethorphan (0, 3.3,
and 10-mg/kg) interactions with pyrilamine (0, 4.43, and
13.3-mg/kg) were investigated as well as interactions with
lorcaserin (0, 0.3125 and 0.625-mg/kg). In the
pyrilamine-dextromethorphan interaction study, an acute dose
of pyrilamine (13.3-mg/kg) as well as an acute dose of
dextromethorphan caused a significant decrease in nicotine
self-administration. There were mutually augmenting effects
of these two drugs. The combination of dextromethorphan
(10-mg/kg) and pyrilamine (13.3-mg/kg) significantly lowered
nicotine self-administration relative to either 10-mg/kg of
dextromethorphan alone (p<0.05) or 13.3-mg/kg of pyrilamine
alone (p<0.0005). In the lorcaserin-dextromethorphan study,
an acute dose of lorcaserin (0.312-mg/kg) as well as an
acute dose of dextromethorphan (10-mg/kg) caused a
significant decrease in nicotine self-administration
replicating previous findings. Augmenting interactions were
observed with dextromethorphan and pyrilamine as well as
lorcaserin. These findings suggest that combination therapy
may be more effective smoking cessation treatments than
monotherapy.},
Doi = {10.1016/j.pbb.2015.12.004},
Key = {fds313800}
}
@article{fds313802,
Author = {Bailey, JM and Oliveri, AN and Karbhari, N and Brooks, RAJ and De La
Rocha and AJ and Janardhan, S and Levin, ED},
Title = {Persistent behavioral effects following early life exposure
to retinoic acid or valproic acid in zebrafish.},
Journal = {Neurotoxicology},
Volume = {52},
Pages = {23-33},
Year = {2016},
Month = {January},
ISSN = {0161-813X},
url = {http://dx.doi.org/10.1016/j.neuro.2015.10.001},
Abstract = {BACKGROUND: Moderate to severe dysregulation in retinoid
signaling during early development is associated with a
constellation of physical malformations and/or neural tube
defects, including spina bifida. It is thought that more
subtle dysregulation of this system, which might be
achievable via dietary (i.e. hypervitaminosis A) or
pharmacological (i.e. valproic acid) exposure in humans,
will manifest on behavioral domains including sociability,
without overt physical abnormalities. METHODS: During early
life, zebrafish were exposed to low doses of two chemicals
that disrupt retinoid signaling. From 0 to 5dpf, larvae were
reared in aqueous solutions containing retinoic acid (0,
0.02, 0.2 or 2nM) or valproic acid (0, 0.5, 5.0 or 50μM).
One cohort of zebrafish was assessed using a locomotor
activity screen at 6-dpf; another was reared to adulthood
and assessed using a neurobehavioral test battery (startle
habituation, novel tank exploration, shoaling, and predator
escape/avoidance). RESULTS: There was no significant
increase in the incidence of physical malformation among
exposed fish compared to controls. Both retinoic acid and
valproic acid exposures during development disrupted larval
activity with persisting behavioral alterations later in
life, primarily manifesting as decreased social affiliation.
CONCLUSIONS: Social behavior and some aspects of motor
function were altered in exposed fish; the importance of
examining emotional or psychological consequences of early
life exposure to retinoid acting chemicals is
discussed.},
Doi = {10.1016/j.neuro.2015.10.001},
Key = {fds313802}
}
@article{fds320366,
Author = {Rezvani, AH and Levin, ED and Wells, C and Slade, S and Morrison, M and Marshall, L and Morris, M and Confino, J and Allenby, C and Lumeng,
L},
Title = {Different lines of rats selectively-bred for high
alcohol-drinking demonstrate disparate preferences for
nicotine self-administration},
Journal = {Journal of Drug and Alcohol Research},
Volume = {2016},
Number = {5},
Pages = {1-9},
Publisher = {Ashdin Publishing},
Year = {2016},
Month = {January},
url = {http://dx.doi.org/10.4303/jdar/235972},
Abstract = {Background. Alcohol and nicotine are commonly coabused. The
search for a common core of neural, behavioral, and genetic
factors underlying addiction has been the goal of addiction
research. Purpose. Genetic predisposition to high alcohol
intake has been studied in rats by selectively breeding rats
that have high preference for alcohol. The current
experiments were conducted to determine if the level of
intravenous nicotine administration for the various lines of
alcohol-preferring rats differs from that for
nonalcohol-preferring controls. Study design. Adult
alcohol-naïve selectively-bred alcohol-preferring male rats
from four lines (P, AA, HAD-1, sP) and their control
nonalcohol-preferring rats (NP, ANA, LAD-1, sNP) were
trained and given access to self-administer nicotine
(0.03mg/kg/infusion). Results. The results show that the P
rats selfadministered significantly more nicotine than NP
rats. In contrast, there were no significant differences in
nicotine self-administration between the sP and sNP or the
AA and ANA rats. Unexpectedly, high alcohol-drinking HAD-1
rats self-administered significantly less nicotine than low
alcohol-drinking LAD-1 rats. Conclusion. This suggests that
some genetic factors that underlie high-alcohol intake have
more general effects in promoting high nicotine intake
tendencies, while other genetic factors are more specific to
only heavy drinking.},
Doi = {10.4303/jdar/235972},
Key = {fds320366}
}
@article{fds330162,
Author = {Rezvani, AH and Cauley, MC and Slade, S and Wells, C and Glick, S and Rose,
JE and Levin, ED},
Title = {Acute oral 18-methoxycoronaridine (18-MC) decreases both
alcohol intake and IV nicotine self-administration in
rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {150-151},
Pages = {153-157},
Year = {2016},
url = {http://dx.doi.org/10.1016/j.pbb.2016.10.010},
Abstract = {The ibogaine derivative 18-methoxycoronaridine (18-MC) has
been found to decrease self-administration of morphine,
nicotine and alcohol in rats after systemic injection.
However oral dosing is the preferred route clinically. The
current study evaluated the effect of oral 18-MC dosing in
rats on alcohol and nicotine self-administration. For the
nicotine study, young adult female Sprague-Dawley rats were
fitted with IV jugular infusion catheters and trained for
nicotine self-administration in 45min. sessions. At weekly
intervals they were administered by oral gavage doses of
18-MC (0, 10, 20 and 40mg/kg) following a repeated measures
counterbalanced design twice. Acute oral 18-MC, at the
40mg/kg dosage, significantly reduced nicotine
self-administration. There was a differential effect of
18-MC with rats above or below the median level of nicotine
self-administration during the pretreatment baseline
performance. Rats with lower baseline performance showed a
significant reduction in nicotine self-administration with
the 40mg/kg dosage, while those in the higher baseline group
did not show a significant effect of 18-MC. In alcohol
studies, the effects of the same doses of 18-MC were tested
in both male and female alcohol preferring (P) rats that had
free access to water and alcohol (10% v/v) 6h/day. The
results show that 18-MC dose-dependently reduced alcohol
intake in both male and female rats. All doses caused
significant reductions in alcohol self-administration. These
data reinforce previous findings that 18-MC is significantly
effective in reducing alcohol intake and nicotine
self-administration. The finding that 18-MC is also
effective orally makes it advantageous for further
development as a possible new therapy for treating
alcoholism as well as smoking addiction.},
Doi = {10.1016/j.pbb.2016.10.010},
Key = {fds330162}
}
@article{fds313801,
Author = {Brown, DR and Bailey, JM and Oliveri, AN and Levin, ED and Di Giulio,
RT},
Title = {Developmental exposure to a complex PAH mixture causes
persistent behavioral effects in naive Fundulus heteroclitus
(killifish) but not in a population of PAH-adapted
killifish.},
Journal = {Neurotoxicol Teratol},
Volume = {53},
Pages = {55-63},
Year = {2016},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2015.10.007},
Abstract = {Acute exposures to some individual polycyclic aromatic
hydrocarbons (PAHs) and complex PAH mixtures are known to
cause cardiac malformations and edema in the developing fish
embryo. However, the heart is not the only organ impacted by
developmental PAH exposure. The developing brain is also
affected, resulting in lasting behavioral dysfunction. While
acute exposures to some PAHs are teratogenically lethal in
fish, little is known about the later life consequences of
early life, lower dose subteratogenic PAH exposures. We
sought to determine and characterize the long-term
behavioral consequences of subteratogenic developmental PAH
mixture exposure in both naive killifish and PAH-adapted
killifish using sediment pore water derived from the
Atlantic Wood Industries Superfund Site. Killifish offspring
were embryonically treated with two low-level PAH mixture
dilutions of Elizabeth River sediment extract (ERSE) (TPAH
5.04 μg/L and 50.4 μg/L) at 24h post fertilization.
Following exposure, killifish were raised to larval,
juvenile, and adult life stages and subjected to a series of
behavioral tests including: a locomotor activity test (4
days post-hatch), a sensorimotor response tap/habituation
test (3 months post hatch), and a novel tank diving and
exploration test (3months post hatch). Killifish were also
monitored for survival at 1, 2, and 5 months over 5-month
rearing period. Developmental PAH exposure caused short-term
as well as persistent behavioral impairments in naive
killifish. In contrast, the PAH-adapted killifish did not
show behavioral alterations following PAH exposure. PAH
mixture exposure caused increased mortality in reference
killifish over time; yet, the PAH-adapted killifish, while
demonstrating long-term rearing mortality, had no
significant changes in mortality associated with ERSE
exposure. This study demonstrated that early embryonic
exposure to PAH-contaminated sediment pore water caused
long-term locomotor and behavioral alterations in killifish,
and that locomotor alterations could be observed in early
larval stages. Additionally, our study highlights the
resistance to behavioral alterations caused by low-level PAH
mixture exposure in the adapted killifish population.
Furthermore, this is the first longitudinal behavioral study
to use killifish, an environmentally important estuarine
teleost fish, and this testing framework can be used for
future contaminant assessment.},
Doi = {10.1016/j.ntt.2015.10.007},
Key = {fds313801}
}
@article{fds274169,
Author = {Bailey, JM and Oliveri, AN and Levin, ED},
Title = {Pharmacological analyses of learning and memory in zebrafish
(Danio rerio).},
Journal = {Pharmacol Biochem Behav},
Volume = {139 Pt B},
Number = {0 0},
Pages = {103-111},
Year = {2015},
Month = {December},
ISSN = {0091-3057},
url = {http://dx.doi.org/10.1016/j.pbb.2015.03.006},
Abstract = {Over the last decade, zebrafish (Danio rerio) have become
valuable as a complementary model in behavioral
pharmacology, opening a new avenue for understanding the
relationships between drug action and behavior. This species
offers a useful intermediate approach bridging the gap
between in vitro studies and traditional mammalian models.
Zebrafish offer great advantages of economy compared to
their rodent counterparts, their complex brains and
behavioral repertoire offer great translational potential
relative to in vitro models. The development and validation
of a variety of tests to measure behavior, including
cognition, in zebrafish have set the stage for the use of
this animal for behavioral pharmacology studies. This has
led to research into the basic mechanisms of cognitive
function as well as screening for potential
cognition-improving drug therapies, among other lines of
research. As with all models, zebrafish have limitations,
which span pharmacokinetic challenges to difficulties
quantifying behavior. The use, efficacy and limitations
associated with a zebrafish model of cognitive function are
discussed in this review, within the context of behavioral
pharmacology.},
Doi = {10.1016/j.pbb.2015.03.006},
Key = {fds274169}
}
@article{fds274170,
Author = {Hall, BJ and Slade, S and Allenby, C and Kutlu, MG and Levin,
ED},
Title = {Neuro-anatomic mapping of dopamine D1 receptor involvement
in nicotine self-administration in rats.},
Journal = {Neuropharmacology},
Volume = {99},
Pages = {689-695},
Year = {2015},
Month = {December},
ISSN = {0028-3908},
url = {http://dx.doi.org/10.1016/j.neuropharm.2015.03.005},
Abstract = {Dopaminergic signaling has long been known to be a critical
factor in nicotine addiction, as well as other drugs of
abuse. Dopaminergic projections from the VTA to the nucleus
accumbens and prefrontal cortex have been well established
to be critical to the reinforcing effects of these drugs.
However, other projections of dopamine neurons are likely to
have significant roles in this process. Also, the relative
contributions of D1 and D2 dopamine receptors in drug
addiction and its treatment remain to be fully understood.
In this study, we examined the effects of blocking D1 and D2
receptors in the nucleus accumbens shell (AcS), anterior
cingulate cortex (ACC), and parietal association cortex
(PtA) on nicotine self-administration in rats. Female
Sprague-Dawley rats were fitted with jugular catheters and
allowed to self-administer nicotine (0.03 mg/kg/infusion)
on an FR1 schedule. Rats were fitted with bilateral infusion
cannulae to allow infusion of D1 or D2 antagonists
(SCH-23390 or haloperidol) into each targeted brain area.
Acute local infusions of SCH-23390 (1-4 μg/side) into the
AcS and PtA significantly reduced nicotine
self-administration by up to 75%. SCH-23390 infusion into
the ACC was less effective with only suggestive
non-significant reductions of nicotine self-administration.
Acute, local infusions of haloperidol (0.5-2 μg/side) in
any of the brain regions targeted did not have significant
effects on nicotine self-administration. These results
demonstrate a more significant role for D1 receptor
mechanisms in the process of nicotine reinforcement and help
provide a more detailed neuroanatomic map of nicotine
dependence in the brain.},
Doi = {10.1016/j.neuropharm.2015.03.005},
Key = {fds274170}
}
@article{fds316074,
Author = {Levin, ED and Kalueff, AV and Gerlai, RT},
Title = {Perspectives on zebrafish neurobehavioral
pharmacology.},
Journal = {Pharmacol Biochem Behav},
Volume = {139 Pt B},
Pages = {93},
Year = {2015},
Month = {December},
ISSN = {0091-3057},
url = {http://dx.doi.org/10.1016/j.pbb.2015.11.007},
Doi = {10.1016/j.pbb.2015.11.007},
Key = {fds316074}
}
@article{fds274177,
Author = {Levin, ED and Wells, C and Johnson, JE and Rezvani, AH and Bymaster, FP and Rose, JE},
Title = {Amitifadine, a triple monoamine re-uptake inhibitor, reduces
nicotine self-administration in female rats.},
Journal = {Eur J Pharmacol},
Volume = {764},
Pages = {30-37},
Year = {2015},
Month = {October},
ISSN = {0014-2999},
url = {http://dx.doi.org/10.1016/j.ejphar.2015.06.041},
Abstract = {A wider diversity of drug treatments to aid smoking
cessation is needed to help tailor the most efficacious
treatment for different types of smokers. This study was
conducted to determine whether amitifadine, which inhibits
re-uptake of dopamine, norepinephrine and serotonin, would
decrease nicotine self-administration at doses that do not
cause adverse side effects. Adult female Sprague-Dawley rats
were trained to self-administer nicotine intravenous (IV)
and were given acute doses of amitifadine in a repeated
measures counterbalanced design. Effects of amitifadine on
locomotor activity and food motivated responding were also
evaluated. Chronic amitifadine effects were also examined.
The 30 mg/kg amitifadine dose significantly reduced nicotine
self-administration. The 5 and 10 mg/kg doses reduced
nicotine self-administration during the first 15 min of the
session when the greatest amount of nicotine was
self-administered. The 30 mg/kg amitifadine dose, but not
the lower doses caused a significant reduction in locomotor
activity averaged over the one-hour session and reduced food
motivated responding. The 10 mg/kg dose caused hypoactivity
at the beginning of the session, but 5 mg/kg did not cause
any hypoactivity. The effects of chronic amitifadine
treatment (10 mg/kg) over the course of 15 sessions was also
determined. Amitifadine caused a significant reduction in
nicotine self-administration, which was not seen to diminish
over two consecutive weeks of treatment and a week after
enforced abstinence. Amitifadine significantly reduced
nicotine self-administration. This prompts further research
to determine if amitifadine might be an effective treatment
for smoking cessation.},
Doi = {10.1016/j.ejphar.2015.06.041},
Key = {fds274177}
}
@article{fds274176,
Author = {Slotkin, TA and Skavicus, S and Card, J and Stadler, A and Levin, ED and Seidler, FJ},
Title = {Developmental Neurotoxicity of Tobacco Smoke Directed Toward
Cholinergic and Serotonergic Systems: More Than Just
Nicotine.},
Journal = {Toxicol Sci},
Volume = {147},
Number = {1},
Pages = {178-189},
Year = {2015},
Month = {September},
ISSN = {1096-6080},
url = {http://dx.doi.org/10.1093/toxsci/kfv123},
Abstract = {Tobacco smoke contains thousands of compounds in addition to
nicotine, a known neuroteratogen. We evaluated the
developmental neurotoxicity of tobacco smoke extract (TSE)
administered to pregnant rats starting preconception and
continued through the second postnatal week. We simulated
nicotine concentrations encountered with second-hand smoke,
an order of magnitude below those seen in active smokers,
and compared TSE with an equivalent dose of nicotine alone,
and to a 10-fold higher nicotine dose. We conducted
longitudinal evaluations in multiple brain regions, starting
in adolescence (postnatal day 30) and continued to full
adulthood (day 150). TSE exposure impaired presynaptic
cholinergic activity, exacerbated by a decrement in
nicotinic cholinergic receptor concentrations. Although both
nicotine doses produced presynaptic cholinergic deficits,
these were partially compensated by hyperinnervation and
receptor upregulation, effects that were absent with TSE.
TSE also produced deficits in serotonin receptors in females
that were not seen with nicotine. Regression analysis showed
a profound sex difference in the degree to which nicotine
could account for overall TSE effects: whereas the 2
nicotine doses accounted for 36%-46% of TSE effects in
males, it accounted for only 7%-13% in females. Our results
show that the adverse effects of TSE on neurodevelopment
exceed those that can be attributed to just the nicotine
present in the mixture, and further, that the sensitivity
extends down to levels commensurate with second-hand smoke
exposure. Because nicotine itself evoked deficits at low
exposures, "harm reduction" nicotine products do not
eliminate the potential for neurodevelopmental
damage.},
Doi = {10.1093/toxsci/kfv123},
Key = {fds274176}
}
@article{fds274172,
Author = {Larrauri, JA and Burke, DA and Hall, BJ and Levin,
ED},
Title = {Role of nicotinic receptors in the lateral habenula in the
attenuation of amphetamine-induced prepulse inhibition
deficits of the acoustic startle response in
rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {232},
Number = {16},
Pages = {3009-3017},
Year = {2015},
Month = {August},
ISSN = {0033-3158},
url = {http://dx.doi.org/10.1007/s00213-015-3940-z},
Abstract = {RATIONALE: Prepulse inhibition (PPI) refers to the reduction
of the startle response magnitude when a startling stimulus
is closely preceded by a weak stimulus. PPI is commonly used
to measure sensorimotor gating. In rats, the PPI reduction
induced by the dopamine agonist apomorphine can be reversed
by systemic administration of nicotine. A high concentration
of nicotinic receptors is found in the lateral habenula
(LHb), an epithalamic structure with efferent projections to
brain regions involved in the modulation of PPI, which has
been shown to regulate the activity of midbrain dopamine
neurons. OBJECTIVES: The prospective role of nicotinic
receptors in the LHb in the regulation of PPI was assessed
in this study, using different pharmacological models of
sensorimotor gating deficits. METHODS: Interactions between
systemic amphetamine and haloperidol and intra-LHb infusions
of mecamylamine (10 μg/side) or nicotine (30 μg/side) on
PPI were analyzed in Experiments 1 and 2. Intra-LHb
infusions of different nicotine doses (25, and 50 μg/side)
and their interactions with systemic administration of
amphetamine or dizocilpine on PPI were examined in
Experiments 3 and 4. RESULTS: Infusions of nicotine into the
LHb dose-dependently attenuated amphetamine-induced PPI
deficits but had no effect on PPI disruptions caused by
dizocilpine. Intra-LHb mecamylamine infusions did not affect
PPI nor interact with dopaminergic manipulations.
CONCLUSIONS: These results are congruent with previous
reports of systemic nicotine effects on PPI, suggesting a
role of the LHb in the attenuation of sensorimotor gating
deficits caused by the hyperactivity of dopamine
systems.},
Doi = {10.1007/s00213-015-3940-z},
Key = {fds274172}
}
@article{fds274171,
Author = {Slotkin, TA and Skavicus, S and Card, J and Levin, ED and Seidler,
FJ},
Title = {Amelioration strategies fail to prevent tobacco smoke
effects on neurodifferentiation: Nicotinic receptor
blockade, antioxidants, methyl donors.},
Journal = {Toxicology},
Volume = {333},
Pages = {63-75},
Year = {2015},
Month = {July},
ISSN = {0300-483X},
url = {http://dx.doi.org/10.1016/j.tox.2015.04.005},
Abstract = {Tobacco smoke exposure is associated with neurodevelopmental
disorders. We used neuronotypic PC12 cells to evaluate the
mechanisms by which tobacco smoke extract (TSE) affects
neurodifferentiation. In undifferentiated cells, TSE
impaired DNA synthesis and cell numbers to a much greater
extent than nicotine alone; TSE also impaired cell viability
to a small extent. In differentiating cells, TSE enhanced
cell growth at the expense of cell numbers and promoted
emergence of the dopaminergic phenotype. Nicotinic receptor
blockade with mecamylamine was ineffective in preventing the
adverse effects of TSE and actually enhanced the effect of
TSE on the dopamine phenotype. A mixture of antioxidants
(vitamin C, vitamin E, N-acetyl-l-cysteine) provided partial
protection against cell loss but also promoted loss of the
cholinergic phenotype in response to TSE. Notably, the
antioxidants themselves altered neurodifferentiation,
reducing cell numbers and promoting the cholinergic
phenotype at the expense of the dopaminergic phenotype, an
effect that was most prominent for N-acetyl-l-cysteine.
Treatment with methyl donors (vitamin B12, folic acid,
choline) had no protectant effect and actually enhanced the
cell loss evoked by TSE; they did have a minor, synergistic
interaction with antioxidants protecting against TSE effects
on growth. Thus, components of tobacco smoke perturb
neurodifferentiation through mechanisms that cannot be
attributed to the individual effects of nicotine, oxidative
stress or interference with one-carbon metabolism.
Consequently, attempted amelioration strategies may be
partially effective at best, or, as seen here, can actually
aggravate injury by interfering with normal developmental
signals and/or by sensitizing cells to TSE effects on
neurodifferentiation.},
Doi = {10.1016/j.tox.2015.04.005},
Key = {fds274171}
}
@article{fds274167,
Author = {Hall, BJ and Slade, S and Wells, C and Rose, JE and Levin,
ED},
Title = {Bupropion-varenicline interactions and nicotine
self-administration behavior in rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {130},
Pages = {84-89},
Year = {2015},
Month = {March},
ISSN = {0091-3057},
url = {http://dx.doi.org/10.1016/j.pbb.2015.01.009},
Abstract = {Varenicline and bupropion each have been shown to
significantly improve cessation of tobacco addiction in
humans. They act through different mechanisms and the
question about the potential added efficacy with their
combined used has arisen. Preclinical animal models of
nicotine addiction can help with the evaluation of this
combined approach and what dose combinations of varenicline
and bupropion may be useful for enhancing tobacco cessation.
In this study, we investigated the interacting dose-effect
functions of varenicline and bupropion in a rat model of
nicotine self-administration. Young adult female
Sprague-Dawley rats were allowed to self-administer nicotine
in 1-h sessions under an FR1 reinforcement schedule.
Varenicline (0.3, 1. 3 mg/kg) and bupropion (8.33, 25, 75
mg/kg) were administered alone or together 15 min before
each session. The vehicle saline was the control. Higher
doses of each drug alone reduced nicotine
self-administration compared to control with reductions of
62% and 75% with 3 mg/kg varenicline and 75 mg/kg bupropion
respectively. Lower dose varenicline which does not by
itself reduce nicotine self-administration, significantly
augmented bupropion effects. The 0.3 mg/kg varenicline dose
combined with the 25 and 75 mg/kg bupropion doses caused
greater reductions of nicotine self-administration than
either dose of bupropion given alone. However, higher dose
varenicline did not have this effect. Lower dose bupropion
did not augment varenicline effects. Only the high bupropion
dose significantly enhanced the varenicline effect.
Likewise, combining 1 mg/kg varenicline with 75 mg/kg
bupropion reduced self-administration to a greater extent
than either dose alone. These results demonstrate that
combination therapy with varenicline and bupropion may be
more beneficial than monotherapy with either drug
alone.},
Doi = {10.1016/j.pbb.2015.01.009},
Key = {fds274167}
}
@article{fds274165,
Author = {Slotkin, TA and Skavicus, S and Levin, ED and Seidler,
FJ},
Title = {Prenatal nicotine changes the response to postnatal
chlorpyrifos: Interactions targeting serotonergic synaptic
function and cognition.},
Journal = {Brain Res Bull},
Volume = {111},
Pages = {84-96},
Year = {2015},
Month = {February},
ISSN = {0361-9230},
url = {http://dx.doi.org/10.1016/j.brainresbull.2015.01.003},
Abstract = {Nicotine and chlorpyrifos are developmental neurotoxicants
that target serotonin systems. We examined whether prenatal
nicotine exposure alters the subsequent response to
chlorpyrifos given postnatally. Pregnant rats received
nicotine throughout gestation at 3mg/kg/day, a regimen
designed to achieve plasma levels seen in smokers;
chlorpyrifos was given to pups on postnatal days (PN) 1-4 at
1mg/kg, just above the detection threshold for brain
cholinesterase inhibition. We assessed long-term effects
from adolescence (PN30) through full adulthood (PN150),
measuring the expression of serotonin receptors and
serotonin turnover (index of presynaptic impulse activity)
in cerebrocortical brain regions encompassing the
projections that are known targets for nicotine and
chlorpyrifos. Nicotine or chlorpyrifos individually
increased the expression of serotonin receptors, with
greater effects on males than on females and with distinct
temporal and regional patterns indicative of adaptive
synaptic changes rather than simply an extension of initial
injury. This interpretation was confirmed by our finding an
increase in serotonin turnover, connoting presynaptic
serotonergic hyperactivity. Animals receiving the combined
treatment showed a reduction in these adaptive effects on
receptor binding and turnover relative to the individual
agents, or even an effect in the opposite direction;
further, normal sex differences in serotonin receptor
concentrations were dissipated or reversed, an effect that
was confirmed by behavioral evaluations in the Novel
Objection Recognition Test. In addition to the known
liabilities associated with maternal smoking during
pregnancy, our results point to additional costs in the form
of heightened vulnerability to neurotoxic chemicals
encountered later in life.},
Doi = {10.1016/j.brainresbull.2015.01.003},
Key = {fds274165}
}
@article{fds330185,
Author = {Rezvani, AH and Levin, ED and Arolfo, MP and Wells, C and Graupe, M and Diamond, I},
Title = {Inhibition of aldehyde dehydrogenase-2 (ALDH-2) suppresses
nicotine self-administration in rats},
Journal = {Journal of Drug and Alcohol Research},
Volume = {4},
Pages = {1-6},
Publisher = {Ashdin Publishing},
Year = {2015},
Month = {January},
url = {http://dx.doi.org/10.4303/jdar/235940},
Abstract = {Introduction. Aldehyde dehydrogenase-2 (ALDH-2) inhibitors
have been shown to reduce cocaine and alcohol intake in
rats. The mechanism of action appears to be due to
inhibition of drug-induced dopamine (DA) production in the
ventral tegmental area (VTA) and DA release in the nucleus
accumbens. The purpose of this study was to explore the
potential of a selective ALDH-2 inhibitor to reduce
self-administration of nicotine. Materials and methods.
Adult male rats were trained to self-administer nicotine
intravenously. After acquiring a stable baseline for
nicotine intake, rats were given one of the three oral
gavage doses (5, 10 or 30mg eq/kg, calculated based on
parent drug) of the prodrug GS-6637 of an ALDH-2 inhibitor
or vehicle one hour before a nicotine self-administration
session. Results. Our data showed that acute administration
of GS-6637 at 10 mg eq/kg and 30mg eq/kg significantly
reduced nicotine self-administration. Similarly, subchronic
administration of GS-6637 for seven days significantly
reduced nicotine self-administration at 10mg eq/kg and 30 mg
eq/kg without inducing tolerance. In order to compare
GS-6637 with varenicline, rats were given single doses of
varenicline at 1.6, 3.2, and 6.4 mg/kg. Consistent with
previous reports, significant inhibitions of nicotine
self-administration was observed at the 3.2mg/kg and
6.4mg/kg doses but less than observed with GS-6637.
Discussion and conclusions. Our data suggest that selective
ALDH-2 inhibition appears to have therapeutic potentials as
novel therapy for smoking cessation.},
Doi = {10.4303/jdar/235940},
Key = {fds330185}
}
@article{fds274163,
Author = {Massarsky, A and Jayasundara, N and Bailey, JM and Oliveri, AN and Levin, ED and Prasad, GL and Di Giulio and RT},
Title = {Teratogenic, bioenergetic, and behavioral effects of
exposure to total particulate matter on early development of
zebrafish (Danio rerio) are not mimicked by
nicotine.},
Journal = {Neurotoxicol Teratol},
Volume = {51},
Pages = {77-88},
Year = {2015},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2015.09.006},
Abstract = {Cigarette smoke has been associated with a number of
pathologies; however, the mechanisms leading to
developmental effects are yet to be fully understood. The
zebrafish embryo is regarded as a 'bridge model'; however,
not many studies examined its applicability to cigarette
smoke toxicity. This study examined the effects of total
particulate matter (TPM) from 3R4F reference cigarettes on
the early development of zebrafish (Danio rerio). Zebrafish
embryos were exposed to two concentrations of TPM (0.4 and
1.4 μg/mL equi-nicotine units) or nicotine at equivalent
doses. The exposures began at 2h post-fertilization (hpf)
and lasted until 96 hpf. Several physiological parameters
were assessed during or after the exposure. We show that TPM
increased mortality, delayed hatching, and increased the
incidence of deformities in zebrafish. TPM exposure also
increased the incidence of hemorrhage and disrupted the
angiogenesis of the major vessels in the brain. Moreover,
TPM exposure reduced the larval body length, decreased the
heart rate, and reduced the metabolic rate. Biomarkers of
xenobiotic metabolism and oxidative stress were also
affected. TPM-exposed zebrafish also differed behaviorally:
at 24 hpf the embryos had a higher frequency of spontaneous
contractions and at 144 hpf the larvae displayed swimming
hyperactivity. This study demonstrates that TPM disrupts
several aspects of early development in zebrafish. The
effects reported for TPM were not attributable to nicotine,
since embryos treated with nicotine alone did not differ
significantly from the control group. Collectively, our work
illustrates the utility of zebrafish as an alternative model
to evaluate the toxic effects of cigarette smoke
constituents.},
Doi = {10.1016/j.ntt.2015.09.006},
Key = {fds274163}
}
@article{fds274164,
Author = {Oliveri, AN and Bailey, JM and Levin, ED},
Title = {Developmental exposure to organophosphate flame retardants
causes behavioral effects in larval and adult
zebrafish.},
Journal = {Neurotoxicol Teratol},
Volume = {52},
Number = {Pt B},
Pages = {220-227},
Year = {2015},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2015.08.008},
Abstract = {BACKGROUND: Organophosphate flame retardants (OPFRs) have
grown in usage since concerns about the health effects of
the previously used polybrominated flame retardants led to
their being phased out. The potential for OPFRs to cause
adverse health effects of their own is still unexamined.
Because of their structural similarities to organophosphate
pesticides, which have themselves been heavily researched
and shown to be neurobehavioral teratogens, we investigated
the possibility that developmental exposure to two OPFRs,
triphenyl phosphate (TPHP), and tris(1,3-dichloroisopropyl)phosphate
(TDCIPP) might lead to behavioral impairment across the
lifespan, as has been observed with the organophosphate
pesticide chlorpyrifos. METHODS: Zebrafish were exposed to
0.03 or 0.3 μM of TPHP, TDCIPP, or chlorpyrifos from 0 to 5
days post fertilization. Vehicle control consisted of 0.03%
solution of DMSO. At 6 days post fertilization, larvae were
tested on a locomotor assay. Separate cohorts of 6 day old
larvae that were not tested on the larval assay were allowed
to grow to adulthood. At 12 weeks post fertilization, these
adult zebrafish were tested on a battery of behavioral
assays that included tests of novel environment exploration,
startle habituation, social affiliation, and predator
escape. RESULTS: Developmental exposure altered zebrafish
behavior across the lifespan. Larval zebrafish exposed to
the 0.03 μM doses of chlorpyrifos or TDCIPP exhibited
significant (p<0.05) hyperactivity in the locomotor assay.
Organophosphate exposure significantly (p<0.05) altered the
time course of adult zebrafish behavior in the novel
environment, startle habituation, and social affiliation
assays. Predator escape behavior was significantly (p<0.05)
reduced in fish exposed to the 0.3 μM dose of TDCIPP.
Exposure also caused hyperactivity in adult fish, with fish
exposed to the 0.3 μM dose of TDCIPP exhibiting
significantly (p<0.05) elevated locomotor behavior in the
novel environment assay. DISCUSSION: Early developmental
exposure to OPFRs produced behavioral impairment that
persisted into adulthood. These findings support broader
research investigating the role of organophosphate
compounds, including the OPFRs used here, in developmental
neurotoxicity.},
Doi = {10.1016/j.ntt.2015.08.008},
Key = {fds274164}
}
@article{fds274166,
Author = {Bailey, JM and Oliveri, AN and Zhang, C and Frazier, JM and Mackinnon,
S and Cole, GJ and Levin, ED},
Title = {Long-term behavioral impairment following acute embryonic
ethanol exposure in zebrafish.},
Journal = {Neurotoxicol Teratol},
Volume = {48},
Pages = {1-8},
Year = {2015},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2015.01.005},
Abstract = {BACKGROUND: Developmental exposure to ethanol has long been
known to cause persisting neurobehavioral impairment.
However, the neural and behavioral mechanisms underlying
these deficits and the importance of exposure timing are not
well-characterized. Given the importance of timing and
sequence in neurodevelopment it would be expected that
alcohol intoxication at different developmental periods
would result in distinct neurobehavioral consequences.
METHODS: Zebrafish embryos were exposed to ethanol (0%, 1%,
3%) at either 8-10 or 24-27 h post-fertilization (hpf) then
reared to adolescence and evaluated on several behavioral
endpoints. Habituation to a repeated environmental stimulus
and overall sensorimotor function were assessed using a tap
startle test; measurements of anxiety and exploration
behavior were made following introduction to a novel tank;
and spatial discrimination learning was assessed using
aversive control in a three-chambered apparatus. Overt signs
of dysmorphogenesis were also scored (i.e. craniofacial
malformations, including eye diameter and midbrain-hindbrain
boundary morphology). RESULTS: Ethanol treated fish were
more active both at baseline and following a tap stimulus
compared to the control fish and were hyperactive when
placed in a novel tank. These effects were more prominent
following exposure at 24-27 hpf than with the earlier
exposure window, for both dose groups. Increases in physical
malformation were only present in the 3% ethanol group; all
malformed fish were excluded from behavioral testing.
DISCUSSION: These results suggest specific domains of
behavior are affected following ethanol exposure, with some
but not all of the tests revealing significant impairment.
The behavioral phenotypes following distinct exposure
windows described here can be used to help link cellular and
molecular mechanisms of developmental ethanol exposure to
functional neurobehavioral effects.},
Doi = {10.1016/j.ntt.2015.01.005},
Key = {fds274166}
}
@article{fds274168,
Author = {Levin, ED and Hall, BJ and Rezvani, AH},
Title = {Heterogeneity across brain regions and neurotransmitter
interactions with nicotinic effects on memory
function.},
Journal = {Curr Top Behav Neurosci},
Volume = {23},
Pages = {87-101},
Year = {2015},
ISSN = {1866-3370},
url = {http://dx.doi.org/10.1007/978-3-319-13665-3_4},
Abstract = {Nicotinic acetylcholine receptors have been shown in many
studies to be critically involved in memory function. The
precise roles these receptors play depend on the receptor
subtype, their anatomic localization, their interactions
with other parts of the neural systems underlying cognition
and the particular domain of cognitive function. Nicotinic
agonists can significantly improve learning, memory, and
attention. Nicotinic receptors in the hippocampus are
innervated by cholinergic projections from the medial septum
and diagonal band. Local infusions of either α7 or α4β2
nicotinic antagonists into either the dorsal or ventral
hippocampus produce amnestic effects in rats navigating
about a radial arm maze. There is cholinergic innervation of
nicotinic receptors in other components of the limbic system
as well. In the basolateral amygdala and the anterior
thalamus, similar amnestic effects of nicotinic α7 and
α4β2 antagonists are seen. Interestingly, there are no
additive amnestic effects observed in these limbic areas
when α7 and α4β2 receptor antagonists are combined. The
particular expression patterns of α7 and α4β2 nicotinic
receptors in these limbic and cortical areas may explain
this nonadditivity, but further research is needed to
determine the specific cause of this phenomenon. Nicotinic
receptor mechanisms in the limbic system play an important
role in cognitive impairment for a variety of neurological
disorders, including Alzheimer's disease and schizophrenia.
Alzheimer's disease results in a dramatic decrease in
hippocampal nicotinic receptor density, affecting α4β2
receptor expression most prominently. In schizophrenia,
there are anomalies in α7 nicotinic receptor expression,
which seem to be crucial for the cognitive impairment of the
disorder. Chronic nicotine exposure, such as seen with
tobacco use, results in an increase in nicotinic receptor
density in the limbic system. This effect appears to be
related to the desensitization of nicotinic receptors seen
after agonist application. Open questions remain concerning
the role of desensitization versus activation of nicotinic
receptors in cognitive improvement.},
Doi = {10.1007/978-3-319-13665-3_4},
Key = {fds274168}
}
@article{fds274173,
Author = {Crosby, EB and Bailey, JM and Oliveri, AN and Levin,
ED},
Title = {Neurobehavioral impairments caused by developmental
imidacloprid exposure in zebrafish.},
Journal = {Neurotoxicol Teratol},
Volume = {49},
Pages = {81-90},
Year = {2015},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2015.04.006},
Abstract = {BACKGROUND: Neonicotinoid insecticides are becoming more
widely applied as organophosphate (OP) insecticides are
decreasing in use. Because of their relative specificity to
insect nicotinic receptors, they are thought to have reduced
risk of neurotoxicity in vertebrates. However, there is
scant published literature concerning the neurobehavioral
effects of developmental exposure of vertebrates to
neonicotinoids. METHODS: Using zebrafish, we investigated
the neurobehavioral effects of developmental exposure to
imidacloprid, a prototypic neonicotinoid pesticide. Nicotine
was also administered for comparison. Zebrafish were exposed
via immersion in aqueous solutions containing 45 μM or 60
μM of imidacloprid or nicotine (or vehicle control) from 4h
to 5d post fertilization. The functional effects of
developmental exposure to both imidacloprid and nicotine
were assessed in larvae using an activity assay and during
adolescence and adulthood using a battery of neurobehavioral
assays, including assessment of sensorimotor response and
habituation in a tactile startle test, novel tank swimming,
and shoaling behavior. RESULTS: In larvae, developmental
imidacloprid exposure at both doses significantly decreased
swimming activity. The 5D strains of zebrafish were more
sensitive to both nicotine and imidacloprid than the AB*
strain. In adolescent and adult fish, developmental exposure
to imidacloprid significantly decreased novel tank
exploration and increased sensorimotor response to startle
stimuli. While nicotine did not affect novel tank swimming,
it increased sensorimotor response to startle stimuli at the
low dose. No effects of either compound were found on
shoaling behavior or habituation to a startling stimulus.
DISCUSSION: Early developmental exposure to imidacloprid has
both early-life and persisting effects on neurobehavioral
function in zebrafish. Its developmental neurotoxicity
should be further investigated.},
Doi = {10.1016/j.ntt.2015.04.006},
Key = {fds274173}
}
@article{fds274174,
Author = {Macaulay, LJ and Bailey, JM and Levin, ED and Stapleton,
HM},
Title = {Persisting effects of a PBDE metabolite, 6-OH-BDE-47, on
larval and juvenile zebrafish swimming behavior.},
Journal = {Neurotoxicol Teratol},
Volume = {52},
Number = {Pt B},
Pages = {119-126},
Publisher = {PERGAMON-ELSEVIER SCIENCE LTD},
Year = {2015},
ISSN = {0892-0362},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000367108400003&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Abstract = {Polybrominated diphenyl ethers (PBDEs) are persistent
organic pollutants that are widely detected in the
environment, biota, and humans. In mammals, PBDEs can be
oxidatively metabolized to form hydroxylated polybrominated
diphenyl ethers (OH-BDEs). While studies have examined
behavioral deficits or alterations induced by exposure to
PBDEs in both rodents and fish, no study to date has
explored behavioral effects from exposure to OH-BDEs, which
have been shown to have greater endocrine disrupting
potential compared to PBDEs. In the present study, zebrafish
(Danio rerio) were exposed during embryonic and larval
development (0-6 days post fertilization, dpf) to a PBDE
metabolite, 6-hydroxy, 2,2',4,4' tetrabromodiphenyl ether
(10-50 nM) and then examined for short and long-term
behavioral effects. Exposed zebrafish tested as larvae (6
dpf) showed an altered swimming response to light-dark
transitions, exhibiting hypoactivity in light periods
compared to control fish. When fish exposed from 0-6 dpf
were tested as juveniles (45 dpf), they showed an increased
fear response and hyperactivity in response to tests of
novel environment exploration and habituation learning.
These results demonstrate that early life exposure to a PBDE
metabolite can have immediate or later life (more than a
month after exposure) effects on activity levels,
habituation, and fear/anxiety.},
Doi = {10.1016/j.ntt.2015.05.002},
Key = {fds274174}
}
@article{fds274175,
Author = {Levin, ED},
Title = {Learning about cognition risk with the radial-arm maze in
the developmental neurotoxicology battery.},
Journal = {Neurotoxicol Teratol},
Volume = {52},
Number = {Pt A},
Pages = {88-92},
Year = {2015},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2015.05.007},
Abstract = {Cognitive dysfunction has been found in epidemiological
studies to be among the most sensitive impairments
associated with developmental exposure to a variety of
environmental contaminants from heavy metals to
polyhalogenated hydrocarbons and pesticides. These chemicals
have been also shown to impair cognitive function after
developmental exposure in experimental animal models. The
radial-arm maze (RAM) has proven to be a sensitive and
reliable way to assess both learning and memory in a variety
of species, most often in rats and mice. The RAM is a very
adaptable test method that takes advantage of rodents'
instinct to explore new places in the environment to forage.
That is, rodents do not need to be trained to run through
the maze; they will normally do this from the initial
session of testing. Training with differential reinforcement
for arm choices provides a more rigorous test of learning
and memory. The RAM is quite adaptable for assessing various
aspects of cognition. Although the RAM has been mostly used
to assess spatial learning and memory, it can be configured
to assess non-spatial memory as well. Both working and
reference memory can be easily distinguished. The RAM can be
run with both appetitive (food reinforced) and aversive
(water escape) motivators. The RAM has been found to be
sensitive to a wide variety of developmental toxicants
including heavy metals such as mercury and pesticides such
as chlorpyrifos. There is an extremely rich literature
especially with rats showing the effects of many types of
brain lesions and drug effects so that the participation of
a wide variety of neural systems in RAM performance is
known. These systems, notably the hippocampus and frontal
cortex, and acetylcholine and glutamate neurotransmitter
systems, are the same neural systems that have been shown in
humans to be critical for learning and memory. This
considerably aids the interpretation of neurobehavioral
toxicity studies.},
Doi = {10.1016/j.ntt.2015.05.007},
Key = {fds274175}
}
@article{fds274178,
Author = {Bailey, JM and Levin, ED},
Title = {Neurotoxicity of FireMaster 550® in zebrafish (Danio
rerio): Chronic developmental and acute adolescent
exposures.},
Journal = {Neurotoxicol Teratol},
Volume = {52},
Number = {Pt B},
Pages = {210-219},
Year = {2015},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2015.07.001},
Abstract = {BACKGROUND: FireMaster® 550 (FM 550) is the second most
commonly used flame retardant (FR) product in consumer goods
and has been detected in household dust samples. However,
neurobehavioral effects associated with exposure have not
been characterized in detail. We investigated the behavioral
effects of FM 550 in zebrafish to facilitate the integration
of the cellular and molecular effects of FM 550 with its
behavioral consequences. The effects of developmental FM 550
exposure on zebrafish larvae swimming shortly after the end
of exposure as well as the persisting effects of this
exposure on adolescent behavior were studied. In addition,
the acute effects of FM 550 on behavior with exposure during
adolescence in zebrafish were studied. METHODS:
Developmental exposure to 0, 0.01, 0.1 or 1 mg/L of FM 550
via immersion spanned 0-5 days post fertilization, with
larval testing on day 6 and adolescent testing on days
40-45. Acute adolescent (45 dpf) exposure was to 0, 1.0 or
3.0 mg/L of FM 550 via immersion, for 24 h, with testing 2 h
or 1 week later. The vehicle condition was colony tank water
with .0004% (developmental) or .0012% (adolescent) DMSO.
Zebrafish behavior was characterized across several domains
including learning, social affiliation, sensorimotor
function, predator escape, and novel environment
exploration. RESULTS: Persisting effects of developmental FM
550 exposure included a significant (p<0.01) reduction in
social behavior among all dose groups. Acute FM 550 exposure
during adolescence caused hypoactivity and reduced social
behavior (p's<0.05) when the fish were tested 2 h after
exposure. These effects were attenuated at the 1 week post
exposure testing point DISCUSSION: Taken together, these
data indicate that FM 550 may cause persisting
neurobehavioral alterations to social behavior in the
absence of perturbations along other behavioral domains and
that developmental exposure is more costly to the organism
than acute adolescent exposure.},
Doi = {10.1016/j.ntt.2015.07.001},
Key = {fds274178}
}
@article{fds274181,
Author = {Burke, DA and Heshmati, P and Kholdebarin, E and Levin,
ED},
Title = {Decreasing nicotinic receptor activity and the spatial
learning impairment caused by the NMDA glutamate antagonist
dizocilpine in rats.},
Journal = {Eur J Pharmacol},
Volume = {741},
Pages = {132-139},
Year = {2014},
Month = {October},
ISSN = {0014-2999},
url = {http://dx.doi.org/10.1016/j.ejphar.2014.07.030},
Abstract = {Nicotinic systems have been shown by a variety of studies to
be involved in cognitive function. Nicotinic receptors have
an inherent property to become desensitized after
activation. The relative role of nicotinic receptor
activation vs. net receptor inactivation by desensitization
in the cognitive effects of nicotinic drugs remains to be
fully understood. In these studies, we tested the effects of
the α7 nicotinic receptor antagonist methyllycaconitine
(MLA), the α4β2 nicotinic receptor antagonist
dihydro-β-erythroidine (DHβE), the nonspecific nicotinic
channel blocker mecamylamine and the α4β2 nicotinic
receptor desensitizing agent sazetidine-A on learning in a
repeated acquisition test. Adult female Sprague-Dawley rats
were trained on a repeated acquisition learning procedure in
an 8-arm radial maze. MLA (1-4mg/kg), DHβE (1-4mg/kg),
mecamylamine (0.125-0.5mg/kg) or sazetidine-A (1 and 3mg/kg)
were administered in four different studies either alone or
together with the NMDA glutamate antagonist dizocilpine
(0.05 and 0.10mg/kg). MLA significantly counteracted the
learning impairment caused by dizocilpine. The overall
choice accuracy impairment caused by dizocilpine was
significantly attenuated by co-administration of DHβE. Low
doses of the non-specific nicotinic antagonist mecamylamine
also reduced dizocilpine-induced repeated acquisition
impairment. Sazetidine-A reversed the accuracy impairment
caused by dizocilpine. These studies provide evidence that a
net decrease in nicotinic receptor activity can improve
learning by attenuating learning impairment induced by NMDA
glutamate blockade. This adds to evidence in cognitive tests
that nicotinic antagonists can improve cognitive function.
Further research characterizing the efficacy and mechanisms
underlying nicotinic antagonist and desensitization induced
cognitive improvement is warranted.},
Doi = {10.1016/j.ejphar.2014.07.030},
Key = {fds274181}
}
@article{fds274182,
Author = {Cousins, V and Rose, JE and Levin, ED},
Title = {IV nicotine self-administration in rats using a consummatory
operant licking response: sensitivity to serotonergic,
glutaminergic and histaminergic drugs.},
Journal = {Prog Neuropsychopharmacol Biol Psychiatry},
Volume = {54},
Pages = {200-205},
Year = {2014},
Month = {October},
ISSN = {0278-5846},
url = {http://dx.doi.org/10.1016/j.pnpbp.2014.06.004},
Abstract = {Tobacco smoking is characterized by repeated
self-administration of nicotine by placing the cigarette in
the mouth. The repeated hand-to-mouth self-administration is
essentially a consummatory act. We recently developed a
paradigm in which rats lick one of two spouts to trigger
intravenous (IV) delivery of nicotine, which combines a
consummatory act with rapid delivery of nicotine to model
the act of tobacco smoking. We have found that rats will
lick hundreds of times per nicotine infusion. In the current
study, using the operant licking nicotine
self-administration model with young adult Sprague-Dawley
rats (0.03mg/kg/infusion of nicotine), we tested the effect
of antagonists of H1 histamine receptors pyrilamine,
serotonin (5HT) type 2 receptors ketanserin and
N-methyl-d-aspartate (NMDA) glutamate receptors with
d-cycloserine as well as an agonist of 5HT2c receptors
lorcaserin, in dose ranges that we have found in previous
studies to significantly reduce IV nicotine
self-administration with the operant lever press operand.
The H1 antagonist pyrilamine significantly reduced operant
licking for nicotine self-administration. Pyrilamine caused
significant reductions in the operant licking paradigm at
lower doses (10 and 20mg/kg) than those we previously
observed to affect responding in the operant lever press
paradigm. In contrast, the 5HT2A and C antagonist ketanserin
did not show an effect of reducing nicotine
self-administration in the same dose range we had found in a
previous study to significantly reduce operant lever press
nicotine self-administration. The 5HT2C agonist lorcaserin
significantly decreased nicotine self-administration in the
licking paradigm at the same dose threshold as with lever
press responding. The NMDA glutamate partial agonist
d-cycloserine did not produce any change in nicotine
self-administration with the licking operand, in contrast to
its effect on the classic lever-pressing task. The rat model
incorporating consummatory aspects of tobacco addiction can
provide distinct and potentially more relevant information
concerning possible new avenues of treatment to combat
tobacco addiction.},
Doi = {10.1016/j.pnpbp.2014.06.004},
Key = {fds274182}
}
@article{fds274179,
Author = {Rezvani, AH and Cauley, MC and Levin, ED},
Title = {Lorcaserin, a selective 5-HT(2C) receptor agonist, decreases
alcohol intake in female alcohol preferring
rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {125},
Pages = {8-14},
Year = {2014},
Month = {October},
ISSN = {0091-3057},
url = {http://dx.doi.org/10.1016/j.pbb.2014.07.017},
Abstract = {Serotonergic systems in the brain have been found to be
important in the addiction to alcohol. The purpose of this
study was to evaluate the efficacy of a novel 5-HT2c
receptor agonist, lorcaserin for reducing alcohol
consumption in alcohol-preferring (P) rats. Adult female
rats were allowed to drink water or alcohol (12%, v/v) using
a standard two-bottle choice procedure. Once stable
baselines were established, the acute (0, 0.3125, 0.625 and
1.25 mg/kg, s.c.), and chronic (0, 0.625 mg/kg, sc for 10
days) effects of lorcaserin on alcohol intake and preference
were assessed at different time points. In a separate
experiment, the effects of lorcaserin on locomotor activity
were determined. Our results show that both 0.625 and 1.25
mg/kg lorcaserin significantly reduced alcohol intake at 2,
4 and 6 h. after the drug administration. The chronic
administration of 0.625 mg/kg lorcaserin significantly
reduced alcohol intake up to 6h every day after the
injection and there was no sign of diminished efficacy of
the drug during 10-day treatment. To determine the effects
of lorcaserin on sucrose intake, rats were put on a
two-bottle choice of water vs a solution of 7% sucrose. The
high dose of lorcaserin (1.25 mg/kg, s.c.) reduced sucrose
intake only for up to 2 h. When tested for locomotor
activity, lorcaserin injected 20 min before testing
significantly reduced locomotor activity at all doses.
However, when it was injected 5.5h before the start of the
1-h session, neither dose had a significant effect on
locomotor activity. These results show the efficacy of
lorcaserin in reducing alcohol intake without a significant
effect on water intake and locomotion suggesting the
involvement of 5-HT2c receptors in alcohol seeking behavior.
Further research is warranted to determine the possible
efficacy of lorcaserin or similar drugs as treatments for
the treatment of alcoholism.},
Doi = {10.1016/j.pbb.2014.07.017},
Key = {fds274179}
}
@article{fds274180,
Author = {Levin, ED and Hao, I and Burke, DA and Cauley, M and Hall, BJ and Rezvani,
AH},
Title = {Effects of tobacco smoke constituents, anabasine and
anatabine, on memory and attention in female
rats.},
Journal = {J Psychopharmacol},
Volume = {28},
Number = {10},
Pages = {915-922},
Year = {2014},
Month = {October},
ISSN = {0269-8811},
url = {http://dx.doi.org/10.1177/0269881114543721},
Abstract = {Nicotine has been well characterized to improve memory and
attention. Nicotine is the primary, but not only neuroactive
compound in tobacco. Other tobacco constituents such as
anabasine and anatabine also have agonist actions on
nicotinic receptors. The current study investigated the
effects of anabasine and anatabine on memory and attention.
Adult female Sprague-Dawley rats were trained on a win-shift
spatial working and reference memory task in the 16-arm
radial maze or a visual signal detection operant task to
test attention. Acute dose-effect functions of anabasine and
anatabine over two orders of magnitude were evaluated for
both tasks. In the radial-arm maze memory test, anabasine
but not anatabine significantly reduced the memory
impairment caused by the NMDA antagonist dizocilpine
(MK-801). In the signal detection attentional task,
anatabine but not anabasine significantly attenuated the
attentional impairment caused by dizocilpine. These studies
show that non-nicotine nicotinic agonists in tobacco,
similar to nicotine, can significantly improve memory and
attentional function. Both anabasine and anatabine produced
cognitive improvement, but their effectiveness differed with
regard to memory and attention. Follow-up studies with
anabasine and anatabine are called for to determine their
efficacy as therapeutics for memory and attentional
dysfunction.},
Doi = {10.1177/0269881114543721},
Key = {fds274180}
}
@article{fds274184,
Author = {Hall, BJ and Wells, C and Allenby, C and Lin, MY and Hao, I and Marshall,
L and Rose, JE and Levin, ED},
Title = {Differential effects of non-nicotine tobacco constituent
compounds on nicotine self-administration in
rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {120},
Pages = {103-108},
Year = {2014},
Month = {May},
ISSN = {0091-3057},
url = {http://dx.doi.org/10.1016/j.pbb.2014.02.011},
Abstract = {Tobacco smoking has been shown to be quite addictive in
people. However, nicotine itself is a weak reinforcer
compared to other commonly abused drugs, leading speculation
that other factors contribute to the high prevalence of
tobacco addiction in the human population. In addition to
nicotine, there are over 5000 chemical compounds that have
been identified in tobacco smoke, and more work is needed to
ascertain their potential contributions to tobacco's highly
addictive properties, or as potential candidates for smoking
cessation treatment. In this study, we examined seven
non-nicotine tobacco constituent compounds (anabasine,
anatabine, nornicotine, myosmine, harmane, norharmane, and
tyramine) for their effects on nicotine self-administration
behavior in rats. Young adult female Sprague-Dawley rats
were allowed to self-administer nicotine (0.03 mg/kg/50 μl
infusion) under a fixed ratio-1 schedule of reinforcement.
Each self-administration session lasted 45 min. Doses of
each tobacco constituent compound were administered
subcutaneously 10 min prior to the start of each session in
a repeated measures, counterbalanced order two times.
Anabasine displayed a biphasic dose-effect function.
Pretreatment with 0.02 mg/kg anabasine resulted in a 25%
increase in nicotine self-administration, while 2.0mg/kg of
anabasine reduced nicotine infusions per session by over
50%. Pretreatment with 2.0mg/kg anatabine also significantly
reduced nicotine self-administration by nearly half. These
results suggest that some non-nicotine tobacco constituents
may enhance or reduce nicotine's reinforcing properties.
Also, depending upon the appropriate dose, some of these
compounds may also serve as potential smoking cessation
agents.},
Doi = {10.1016/j.pbb.2014.02.011},
Key = {fds274184}
}
@article{fds274186,
Author = {Levin, ED},
Title = {Nicotinic attention-deficit/hyperactivity disorder
treatment.},
Journal = {Biol Psychiatry},
Volume = {75},
Number = {3},
Pages = {174},
Year = {2014},
Month = {February},
url = {http://www.ncbi.nlm.nih.gov/pubmed/24370349},
Doi = {10.1016/j.biopsych.2013.11.024},
Key = {fds274186}
}
@article{fds274193,
Author = {Larrauri, JA and Kelley, LD and Jenkins, MR and Westman, EC and Schmajuk, NA and Rosenthal, MZ and Levin, ED},
Title = {Meclizine enhancement of sensorimotor gating in healthy male
subjects with high startle responses and low prepulse
inhibition.},
Journal = {Neuropsychopharmacology},
Volume = {39},
Number = {3},
Pages = {651-659},
Year = {2014},
Month = {February},
url = {http://www.ncbi.nlm.nih.gov/pubmed/24045586},
Abstract = {Histamine H1 receptor systems have been shown in animal
studies to have important roles in the reversal of
sensorimotor gating deficits, as measured by prepulse
inhibition (PPI). H1-antagonist treatment attenuates the PPI
impairments caused by either blockade of NMDA glutamate
receptors or facilitation of dopamine transmission. The
current experiment brought the investigation of H1 effects
on sensorimotor gating to human studies. The effects of the
histamine H1 antagonist meclizine on the startle response
and PPI were investigated in healthy male subjects with high
baseline startle responses and low PPI levels. Meclizine was
administered to participants (n=24) using a within-subjects
design with each participant receiving 0, 12.5, and 25 mg
of meclizine in a counterbalanced order. Startle response,
PPI, heart rate response, galvanic skin response, and
changes in self-report ratings of alertness levels and
affective states (arousal and valence) were assessed. When
compared with the control (placebo) condition, the two doses
of meclizine analyzed (12.5 and 25 mg) produced
significant increases in PPI without affecting the magnitude
of the startle response or other physiological variables.
Meclizine also caused a significant increase in overall
self-reported arousal levels, which was not correlated with
the observed increase in PPI. These results are in agreement
with previous reports in the animal literature and suggest
that H1 antagonists may have beneficial effects in the
treatment of subjects with compromised sensorimotor gating
and enhanced motor responses to sensory stimuli.},
Doi = {10.1038/npp.2013.248},
Key = {fds274193}
}
@article{fds274183,
Author = {Slotkin, TA and Card, J and Stadler, A and Levin, ED and Seidler,
FJ},
Title = {Effects of tobacco smoke on PC12 cell neurodifferentiation
are distinct from those of nicotine or benzo[a]pyrene.},
Journal = {Neurotoxicol Teratol},
Volume = {43},
Pages = {19-24},
Year = {2014},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2014.03.002},
Abstract = {Although nicotine accounts for a great deal of the
neurodevelopmental damage associated with maternal smoking
or second-hand exposure, tobacco smoke contains thousands of
potentially neurotoxic compounds. We used PC12 cells, a
standard in vitro model of neurodifferentiation, to compare
tobacco smoke extract (TSE) to nicotine, matching TSE
exposure (with its inherent nicotine content) to parallel
concentrations of nicotine, or to benzo[a]pyrene, a tobacco
combustion product. TSE promoted the transition from cell
replication to differentiation, resulting in fewer, but
larger cells with greater neurite extension. TSE also biased
differentiation into the dopaminergic versus the cholinergic
phenotype, evidenced by an increase in tyrosine hydroxylase
activity but not choline acetyltransferase. Nicotine
likewise promoted differentiation at the expense of cell
numbers, but its effect on growth and neurite extension was
smaller than that of TSE; furthermore, nicotine did not
promote the dopaminergic phenotype. Benzo[a]pyrene had
effects opposite to those of TSE, retarding
neurodifferentiation, which resulted in higher cell numbers,
smaller cells, reduced neurite information, and impaired
emergence of both dopaminergic and cholinergic phenotypes.
Our studies show that the complex mixture of compounds in
tobacco smoke exerts direct effects on neural cell
replication and differentiation that resemble those of
nicotine in some ways but not others, and most importantly,
that are greater in magnitude than can be accounted for from
just the nicotine content of TSE. Thus, fetal tobacco smoke
exposure, including lower levels associated with second-hand
smoke, could be more injurious than would be anticipated
from measured levels of nicotine or its metabolites.},
Doi = {10.1016/j.ntt.2014.03.002},
Key = {fds274183}
}
@article{fds274190,
Author = {Levin, ED and Cauley, M and Johnson, JE and Cooper, EM and Stapleton,
HM and Ferguson, PL and Seidler, FJ and Slotkin, TA},
Title = {Prenatal dexamethasone augments the neurobehavioral
teratology of chlorpyrifos: significance for maternal stress
and preterm labor.},
Journal = {Neurotoxicol Teratol},
Volume = {41},
Pages = {35-42},
Year = {2014},
url = {http://www.ncbi.nlm.nih.gov/pubmed/24177596},
Abstract = {Glucocorticoids are the consensus treatment given in preterm
labor and are also elevated by maternal stress;
organophosphate exposures are virtually ubiquitous, so human
developmental coexposures to these two agents are common.
This study explores how prenatal dexamethasone exposure
modifies the neurobehavioral teratology of chlorpyrifos, one
of the most widely used organophosphates. We administered
dexamethasone to pregnant rats on gestational days 17-19 at
a standard therapeutic dose (0.2 mg/kg); offspring were then
given chlorpyrifos on postnatal days 1-4, at a dose (1
mg/kg) that produces barely-detectable (<10%) inhibition of
brain cholinesterase activity. Dexamethasone did not alter
brain chlorpyrifos concentrations, nor did either agent
alone or in combination affect brain thyroxine levels.
Assessments were carried out from adolescence through
adulthood encompassing T-maze alternation, Figure 8 maze
(locomotor activity, habituation), novelty-suppressed
feeding and novel object recognition tests. For behaviors
where chlorpyrifos or dexamethasone individually had small
effects, the dual exposure produced larger, significant
effects that reflected additivity (locomotor activity,
novelty-suppressed feeding, novel object recognition). Where
the individual effects were in opposite directions or were
restricted to only one agent, we found enhancement of
chlorpyrifos' effects by prenatal dexamethasone
(habituation). Finally, for behaviors where controls
displayed a normal sex difference in performance, the
combined treatment either eliminated or reversed the
difference (locomotor activity, novel object recognition).
Combined exposure to dexamethasone and chlorpyrifos results
in a worsened neurobehavioral outcome, providing a
proof-of-principle that prenatal glucocorticoids can create
a subpopulation with enhanced vulnerability to environmental
toxicants.},
Doi = {10.1016/j.ntt.2013.10.004},
Key = {fds274190}
}
@article{fds274189,
Author = {Yenugonda, VM and Xiao, Y and Levin, ED and Rezvani, AH and Tran, T and Al-Muhtasib, N and Sahibzada, N and Xie, T and Wells, C and Slade, S and Johnson, JE and Dakshanamurthy, S and Kong, H-S and Tomita, Y and Liu,
Y and Paige, M and Kellar, KJ and Brown, ML},
Title = {Design, synthesis and discovery of picomolar selective
α4β2 nicotinic acetylcholine receptor ligands.},
Journal = {J Med Chem},
Volume = {56},
Number = {21},
Pages = {8404-8421},
Year = {2013},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/24047231},
Abstract = {Developing novel and selective compounds that desensitize
α4β2 nicotinic acetylcholine receptors (nAChRs) could
provide new effective treatments for nicotine addiction, as
well as other disorders. Here we report a new class of nAChR
ligands that display high selectivity and picomolar binding
affinity for α4β2 nicotinic receptors. The novel compounds
have Ki values in the range of 0.031-0.26 nM and properties
that should make them good candidates as drugs acting in the
CNS. The selected lead compound 1 (VMY-2-95) binds with high
affinity and potently desensitizes α4β2 nAChRs. At a dose
of 3 mg/kg, compound 1 significantly reduced rat nicotine
self-administration. The overall results support further
characterizations of compound 1 and its analogues in
preclinical models of nicotine addiction and perhaps other
disorders involving nAChRs.},
Doi = {10.1021/jm4008455},
Key = {fds274189}
}
@article{fds274195,
Author = {Kutlu, MG and Burke, D and Slade, S and Hall, BJ and Rose, JE and Levin,
ED},
Title = {Role of insular cortex D₁ and D₂ dopamine receptors in
nicotine self-administration in rats.},
Journal = {Behav Brain Res},
Volume = {256},
Pages = {273-278},
Year = {2013},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23948214},
Abstract = {The insular cortex has been associated with the processing
of rewarding stimuli and with the neural bases of drug
addiction. Ischemic damage to the insula has been associated
with decreased desire to smoke cigarettes. Which component
of insular function is involved in the neural basis of
cigarette smoking is not clear. Dopamine systems are crucial
for the reinforcing value of addictive drugs. The DA
projection from the ventral tegmental area to the nucleus
accumbens (NAc) has been shown to be a vital pathway for the
primary reinforcement caused by taking a variety of abused
drugs. In the current set of studies, the roles of D₁ and
D₂ receptors in the insular cortex in the
self-administration of nicotine by rats were assessed. Adult
female Sprague-Dawley rats were fitted with jugular
catheters and given access to self-administer nicotine.
Bilateral local infusion cannulae were implanted into the
agranular insular cortex to locally administer D₁ and D₂
antagonists (SCH-23390 and haloperidol). Acute local
infusions of the D₁ antagonist SCH-23390 into the insula
(1-2 μg/side) significantly decreased nicotine
self-administration by more than 50%. Repeated infusions of
SCH-23390 into the agranular insula caused continuing
decreases in nicotine self-administration without signs of
tolerance. In contrast, local infusions of the D₂
antagonist haloperidol 0.5-2 μg/side did not have any
discernable effect on nicotine self-administration. These
studies show the importance of DA D₁ systems in the insula
for nicotine reward.},
Doi = {10.1016/j.bbr.2013.08.005},
Key = {fds274195}
}
@article{fds274194,
Author = {Levin, ED and Sexton, HG and Gordon, K and Gordon, CJ and Xiao, Y and Kellar, KJ and Yenugonda, VM and Liu, Y and White, MP and Paige, M and Brown, ML and Rezvani, AH},
Title = {Effects of the sazetidine-a family of compounds on the body
temperature in wildtype, nicotinic receptor β2-/- and
α7-/- mice.},
Journal = {Eur J Pharmacol},
Volume = {718},
Number = {1-3},
Pages = {167-172},
Year = {2013},
Month = {October},
url = {http://www.ncbi.nlm.nih.gov/pubmed/24036108},
Abstract = {Nicotine elicits hypothermic responses in rodents. This
effect appears to be related to nicotinic receptor
desensitization because sazetidine-A, an α4β2 nicotinic
receptor desensitizing agent, produces marked hypothermia
and potentiates nicotine-induced hypothermia in mice. To
determine the specificity of sazetidine-A induced
hypothermia to β2 subunit-containing nicotinic receptors,
we tested its efficacy in β2 knockout (β2(-/-)) mice.
These effects were compared with wildtype (WT) and α7
knockout (α7(-/-)) mice. Confirming our earlier results,
sazetidine-A elicited a pronounced and long-lasting
hypothermia in WT mice. In comparison, sazetidine-A induced
a much attenuated and shorter hypothermic response in
β2(-/-) mice. This indicates that the greater proportion of
sazetidine-A induced hypothermia is mediated via actions on
β2-containing nicotinic receptors, while a smaller
component of hypothermia induced by sazetidine-A is mediated
by non-β2 receptors. Similar to WT mice, α7(-/-) mice
showed the full extent of the sazetidine-A effect,
suggesting that the hypothermia produced by sazetidine-A did
not depend on actions on α7 nicotinic receptor subtype.
Three other novel nicotinic receptor desensitizing agents
derived from sazetidine-A, triazetidine-O, VMY-2-95 and
YL-1-127 also produced hypothermia in WT and α7(-/-) mice.
Furthermore, unlike sazetidine-A, triazetidine-O and
YL-1-127 did not show any hint of a hypothermic effect in
β2(-/-) mice. VMY-2-95 like sazetidine-A did show a
residual hypothermic effect in the β2(-/-) mice. These
studies show that the hypothermic effects of sazetidine-A
and the related compound VMY-2-95 are mainly mediated by
nicotinic receptors containing β2 subunit, but that a small
component of the effect is apparently mediated by non-β2
containing receptors.},
Doi = {10.1016/j.ejphar.2013.08.037},
Key = {fds274194}
}
@article{fds274196,
Author = {Levin, ED},
Title = {Complex relationships of nicotinic receptor actions and
cognitive functions.},
Journal = {Biochem Pharmacol},
Volume = {86},
Number = {8},
Pages = {1145-1152},
Year = {2013},
Month = {October},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23928190},
Abstract = {Nicotine has been shown in a variety of studies to improve
cognitive function including learning, memory and attention.
Nicotine both stimulates and desensitizes nicotinic
receptors, thus acting both as an agonist and a net
antagonist. The relative roles of these two actions for
nicotine-induced cognitive improvement have not yet been
fully determined. We and others have found that acute
nicotinic antagonist treatment can improve learning and
attention. Nicotine acts on a variety of nicotinic receptor
subtypes. The relative role and interactions of neuronal
nicotinic receptor subtypes for cognition also needs to be
better characterized. Nicotine acts on nicotinic receptors
in a wide variety of brain areas. The role of some of these
areas such as the hippocampus has been relatively well
studied but other areas like the thalamus, which has the
densest nicotinic receptor concentration are still only
partially characterized. In a series of studies we
characterized nicotinic receptor actions, anatomic
localization and circuit interactions, which are critical to
nicotine effects on the cognitive functions of learning,
memory and attention. The relative role of increases and
decreases in nicotinic receptor activation by nicotine were
determined in regionally specific studies of the
hippocampus, the amygdala, the frontal cortex and the
mediodorsal thalamic nucleus with local infusions of
antagonists of nicotinic receptor subtypes (α7 and α4β2).
The understanding of the functional neural bases of
cognitive function is fundamental to the more effective
development of nicotinic drugs for treating cognitive
dysfunction.},
Doi = {10.1016/j.bcp.2013.07.021},
Key = {fds274196}
}
@article{fds274198,
Author = {Rezvani, AH and Sexton, HG and Johnson, J and Wells, C and Gordon, K and Levin, ED},
Title = {Effects of caffeine on alcohol consumption and nicotine
self-administration in rats.},
Journal = {Alcohol Clin Exp Res},
Volume = {37},
Number = {9},
Pages = {1609-1617},
Year = {2013},
Month = {September},
ISSN = {0145-6008},
url = {http://dx.doi.org/10.1111/acer.12127},
Abstract = {BACKGROUND: Caffeine, alcohol, and nicotine are 3 of the
most widespread self-administered psychoactive substances,
which are known to be extensively co-administered. However,
little is known about the degree to which they may mutually
potentiate each other's consumption. METHODS: In the current
set of studies, we examined in rats the effect of caffeine
administration on alcohol drinking and intravenous (i.v.)
self-administration of nicotine. In male alcohol-preferring
(P) rats, caffeine (5, 10, and 20 mg/kg) or the saline
vehicle was administered acutely either by subcutaneous
(S.C.) injection or orally (PO) by gavage. In a chronic
study, the effect of PO caffeine (5 and 20 mg/kg) on alcohol
intake over a 10-day period was tested. In another
experiment, the effect of acute PO administration of
caffeine (20 mg/kg) or saline on saccharin intake (0.2%
solution) was determined in P rats. Effects of 20 mg/kg
caffeine on motor activity were also determined in P rats.
Finally, the effects of acute PO caffeine administration on
nicotine self-administration in Sprague-Dawley rats were
also determined. RESULTS: Both routes of administration of
caffeine, S.C. and PO, caused a significant dose-related
decrease in alcohol intake and preference during free access
to alcohol and after 4-day deprivation of alcohol. However,
the low dose of 5 mg/kg caffeine increased alcohol intake.
Acute PO caffeine also reduced saccharin intake. Acute
systemic administration of 20 mg/kg caffeine did not exert a
significant effect on motor activity. In Sprague-Dawley rats
trained to self-administer i.v. nicotine, acute PO
administration of caffeine significantly increased
self-administration of nicotine in a dose-related manner.
CONCLUSIONS: These results suggest that adenosine receptor
systems may play a role in both alcohol and nicotine intake
and deserve further study regarding these
addictions.},
Doi = {10.1111/acer.12127},
Key = {fds274198}
}
@article{fds274199,
Author = {Liu, Y and Richardson, J and Tran, T and Al-Muhtasib, N and Xie, T and Yenugonda, VM and Sexton, HG and Rezvani, AH and Levin, ED and Sahibzada, N and Kellar, KJ and Brown, ML and Xiao, Y and Paige,
M},
Title = {Chemistry and pharmacological studies of
3-alkoxy-2,5-disubstituted-pyridinyl compounds as novel
selective α4β2 nicotinic acetylcholine receptor ligands
that reduce alcohol intake in rats.},
Journal = {J Med Chem},
Volume = {56},
Number = {7},
Pages = {3000-3011},
Year = {2013},
Month = {April},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23540678},
Abstract = {Neuronal acetylcholine receptors mediate the addictive
effects of nicotine and may also be involved in alcohol
addiction. Varenicline, an approved smoking cessation
medication, showed clear efficacy in reducing alcohol
consumption in heavy-drinking smokers. More recently,
sazetidine-A, which selectively desensitizes α4β2
nicotinic receptors, was shown to significantly reduce
alcohol intake in a rat model. To develop novel therapeutics
for treating alcohol use disorder, we designed and
synthesized novel sazetidine-A analogues containing a methyl
group at the 2-position of the pyridine ring. In vitro
pharmacological studies revealed that some of the novel
compounds showed overall pharmacological property profiles
similar to that of sazetidine-A but exhibited reduced
agonist activity across all nicotinic receptor subtypes
tested. In rat studies, compound (S)-9 significantly reduced
alcohol uptake. More importantly, preliminary results from
studies in a ferret model indicate that these novel nAChR
ligands have an improved adverse side-effect profile in
comparison with that of varenicline.},
Doi = {10.1021/jm4000374},
Key = {fds274199}
}
@article{fds274200,
Author = {Bailey, J and Oliveri, A and Levin, ED},
Title = {Zebrafish model systems for developmental neurobehavioral
toxicology.},
Journal = {Birth Defects Res C Embryo Today},
Volume = {99},
Number = {1},
Pages = {14-23},
Year = {2013},
Month = {March},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23723169},
Abstract = {Zebrafish offer many advantages that complement classic
mammalian models for the study of normal development as well
as for the teratogenic effects of exposure to hazardous
compounds. The clear chorion and embryo of the zebrafish
allow for continuous visualization of the anatomical changes
associated with development, which, along with short
maturation times and the capability of complex behavior,
makes this model particularly useful for measuring changes
to the developing nervous system. Moreover, the rich array
of developmental, behavioral, and molecular benefits offered
by the zebrafish have contributed to an increasing demand
for the use of zebrafish in behavioral teratology. Essential
for this endeavor has been the development of a battery of
tests to evaluate a spectrum of behavior in zebrafish.
Measures of sensorimotor plasticity, emotional function,
cognition and social interaction have been used to
characterize the persisting adverse effects of developmental
exposure to a variety of chemicals including therapeutic
drugs, drugs of abuse and environmental toxicants. In this
review, we present and discuss such tests and data from a
range of developmental neurobehavioral toxicology studies
using zebrafish as a model. Zebrafish provide a key
intermediate model between high throughput in vitro screens
and the classic mammalian models as they have the
accessibility of in vitro models and the complex functional
capabilities of mammalian models.},
Doi = {10.1002/bdrc.21027},
Key = {fds274200}
}
@article{fds274311,
Author = {Rezvani, AH and Cauley, M and Xiao, Y and Kellar, KJ and Levin,
ED},
Title = {Effects of chronic sazetidine-A, a selective α4β2 neuronal
nicotinic acetylcholine receptors desensitizing agent on
pharmacologically-induced impaired attention in
rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {226},
Number = {1},
Pages = {35-43},
Year = {2013},
Month = {March},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23100170},
Abstract = {RATIONALE: Nicotine and nicotinic agonists have been shown
to improve attentional function. Nicotinic receptors are
easily desensitized, and all nicotinic agonists are also
desensitizing agents. Although both receptor activation and
desensitization are components of the mechanism that
mediates the overall effects of nicotinic agonists, it is
not clear how each of the two opposed actions contributes to
attentional improvements. Sazetidine-A has high binding
affinity at α4β2 nicotinic receptors and causes a
relatively brief activation followed by a long-lasting
desensitization of the receptors. Acute administration of
sazetidine-A has been shown to significantly improve
attention by reversing impairments caused by the muscarinic
cholinergic antagonist scopolamine and the NMDA glutamate
antagonist dizocilpine. METHODS: In the current study, we
tested the effects of chronic subcutaneous infusion of
sazetidine-A (0, 2, or 6 mg/kg/day) on attention in
Sprague-Dawley rats. Furthermore, we investigated the
effects of chronic sazetidine-A treatment on attentional
impairment induced by an acute administration of 0.02 mg/kg
scopolamine. RESULTS: During the first week period, the
6-mg/kg/day sazetidine-A dose significantly reversed the
attentional impairment induced by scopolamine. During
weeks 3 and 4, the scopolamine-induced impairment was no
longer seen, but sazetidine-A (6 mg/kg/day) significantly
improved attentional performance on its own. Chronic
sazetidine-A also reduced response latency and response
omissions. CONCLUSIONS: This study demonstrated that similar
to its acute effects, chronic infusions of sazetidine-A
improve attentional performance. The results indicate that
the desensitization of α4β2 nicotinic receptors with some
activation of these receptors may play an important role in
improving effects of sazetidine-A on attention.},
Doi = {10.1007/s00213-012-2895-6},
Key = {fds274311}
}
@article{fds274203,
Author = {Levin, ED and Cauley, M and Rezvani, AH},
Title = {Improvement of attentional function with antagonism of
nicotinic receptors in female rats.},
Journal = {Eur J Pharmacol},
Volume = {702},
Number = {1-3},
Pages = {269-274},
Year = {2013},
Month = {February},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23399762},
Abstract = {Nicotinic agonists have been shown in a variety of studies
to improve cognitive function. Since nicotinic receptors are
easily desensitized by agonists, it is not completely clear
to what degree receptor desensitization or receptor
activation are responsible for nicotinic agonist-induced
cognitive improvement. In the current study, the effect of
the neuronal nicotinic cholinergic α4β2 receptor
antagonist dihydro-β-erythroidine (DHβE) and the α7
nicotinic receptor antagonist methyllycaconitine (MLA) on
attentional function was determined. Adult female
Sprague-Dawley rats were trained on the visual signal
detection task. They were required to discriminate whether
or not a light signal occurred on a trial and respond with a
lever press on one side after a signal and the opposite side
after the absence of a signal in order to receive a food
pellet reinforcer. Acute administration of the α4β2
antagonist DHβE improved attentional function either alone
or in reversing the attentional impairment caused by the
NMDA glutamate antagonist dizocilpine (MK-801). Acute
administration of MLA also significantly attenuated the
dizocilpine-induced attentional impairment. In previous
research we have shown that the α4β2 nicotinic
desensitizing agent and partial agonist sazetidine-A also
was effective in reversing dizocilpine-induced attentional
impairments on the signal detection task and that low doses
of the general nicotinic antagonist mecamylamine improved
learning and memory. The current studies indicate that
blockade of nicotinic receptors can effectively attenuate
attentional impairments. Development of drugs that provide a
net decrease in nicotinic receptor activity either through
antagonism or desensitization could be worth exploring for
beneficial effects for treating cognitive
impairments.},
Doi = {10.1016/j.ejphar.2013.01.056},
Key = {fds274203}
}
@article{fds274204,
Author = {Coppola, A and Wenner, BR and Ilkayeva, O and Stevens, RD and Maggioni,
M and Slotkin, TA and Levin, ED and Newgard, CB},
Title = {Branched-chain amino acids alter neurobehavioral function in
rats.},
Journal = {Am J Physiol Endocrinol Metab},
Volume = {304},
Number = {4},
Pages = {E405-E413},
Year = {2013},
Month = {February},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23249694},
Abstract = {Recently, we have described a strong association of
branched-chain amino acids (BCAA) and aromatic amino acids
(AAA) with obesity and insulin resistance. In the current
study, we have investigated the potential impact of BCAA on
behavioral functions. We demonstrate that supplementation of
either a high-sucrose or a high-fat diet with BCAA induces
anxiety-like behavior in rats compared with control groups
fed on unsupplemented diets. These behavioral changes are
associated with a significant decrease in the concentration
of tryptophan (Trp) in brain tissues and a consequent
decrease in serotonin but no difference in indices of
serotonin synaptic function. The anxiety-like behaviors and
decreased levels of Trp in the brain of BCAA-fed rats were
reversed by supplementation of Trp in the drinking water but
not by administration of fluoxetine, a selective serotonin
reuptake inhibitor, suggesting that the behavioral changes
are independent of the serotonergic pathway of Trp
metabolism. Instead, BCAA supplementation lowers the brain
levels of another Trp-derived metabolite, kynurenic acid,
and these levels are normalized by Trp supplementation. We
conclude that supplementation of high-energy diets with BCAA
causes neurobehavioral impairment. Since BCAA are elevated
spontaneously in human obesity, our studies suggest a
potential mechanism for explaining the strong association of
obesity and mood disorders.},
Doi = {10.1152/ajpendo.00373.2012},
Key = {fds274204}
}
@article{fds274202,
Author = {Behl, M and Rao, D and Aagaard, K and Davidson, TL and Levin, ED and Slotkin, TA and Srinivasan, S and Wallinga, D and White, MF and Walker,
VR and Thayer, KA and Holloway, AC},
Title = {Evaluation of the association between maternal smoking,
childhood obesity, and metabolic disorders: a national
toxicology program workshop review.},
Journal = {Environ Health Perspect},
Volume = {121},
Number = {2},
Pages = {170-180},
Year = {2013},
Month = {February},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23232494},
Abstract = {BACKGROUND: An emerging literature suggests that
environmental chemicals may play a role in the development
of childhood obesity and metabolic disorders, especially
when exposure occurs early in life. OBJECTIVE: Here we
assess the association between these health outcomes and
exposure to maternal smoking during pregnancy as part of a
broader effort to develop a research agenda to better
understand the role of environmental chemicals as potential
risk factors for obesity and metabolic disorders. METHODS:
PubMed was searched up to 8 March 2012 for epidemiological
and experimental animal studies related to maternal smoking
or nicotine exposure during pregnancy and childhood obesity
or metabolic disorders at any age. A total of 101 studies-83
in humans and 18 in animals-were identified as the primary
literature. DISCUSSION: Current epidemiological data support
a positive association between maternal smoking and
increased risk of obesity or overweight in offspring. The
data strongly suggest a causal relation, although the
possibility that the association is attributable to
unmeasured residual confounding cannot be completely ruled
out. This conclusion is supported by findings from
laboratory animals exposed to nicotine during development.
The existing literature on human exposures does not support
an association between maternal smoking during pregnancy and
type 1 diabetes in offspring. Too few human studies have
assessed outcomes related to type 2 diabetes or metabolic
syndrome to reach conclusions based on patterns of findings.
There may be a number of mechanistic pathways important for
the development of aberrant metabolic outcomes following
perinatal exposure to cigarette smoke, which remain largely
unexplored. CONCLUSIONS: From a toxicological perspective,
the linkages between maternal smoking during pregnancy and
childhood overweight/obesity provide proof-of-concept of how
early-life exposure to an environmental toxicant can be a
risk factor for childhood obesity.},
Doi = {10.1289/ehp.1205404},
Key = {fds274202}
}
@article{fds274201,
Author = {Risher, M-L and Fleming, RL and Boutros, N and Semenova, S and Wilson,
WA and Levin, ED and Markou, A and Swartzwelder, HS and Acheson,
SK},
Title = {Long-term effects of chronic intermittent ethanol exposure
in adolescent and adult rats: radial-arm maze performance
and operant food reinforced responding.},
Journal = {PLoS One},
Volume = {8},
Number = {5},
Pages = {e62940},
Year = {2013},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23675442},
Abstract = {BACKGROUND: Adolescence is not only a critical period of
late-stage neurological development in humans, but is also a
period in which ethanol consumption is often at its highest.
Given the prevalence of ethanol use during this vulnerable
developmental period we assessed the long-term effects of
chronic intermittent ethanol (CIE) exposure during
adolescence, compared to adulthood, on performance in the
radial-arm maze (RAM) and operant food-reinforced responding
in male rats. METHODOLOGY/PRINCIPAL FINDINGS: Male Sprague
Dawley rats were exposed to CIE (or saline) and then allowed
to recover. Animals were then trained in either the RAM task
or an operant task using fixed- and progressive- ratio
schedules. After baseline testing was completed all animals
received an acute ethanol challenge while blood ethanol
levels (BECs) were monitored in a subset of animals. CIE
exposure during adolescence, but not adulthood decreased the
amount of time that animals spent in the open portions of
the RAM arms (reminiscent of deficits in risk-reward
integration) and rendered animals more susceptible to the
acute effects of an ethanol challenge on working memory
tasks. The operant food reinforced task showed that these
effects were not due to altered food motivation or to
differential sensitivity to the nonspecific
performance-disrupting effects of ethanol. However, CIE
pre-treated animals had lower BEC levels than controls
during the acute ethanol challenges indicating persistent
pharmacokinetic tolerance to ethanol after the CIE
treatment. There was little evidence of enduring effects of
CIE alone on traditional measures of spatial and working
memory. CONCLUSIONS/SIGNIFICANCE: These effects indicate
that adolescence is a time of selective vulnerability to the
long-term effects of repeated ethanol exposure on
neurobehavioral function and acute ethanol sensitivity. The
positive and negative findings reported here help to further
define the nature and extent of the impairments observed
after adolescent CIE and provide direction for future
research.},
Doi = {10.1371/journal.pone.0062940},
Key = {fds274201}
}
@article{fds274319,
Author = {Hussmann, GP and Turner, JR and Lomazzo, E and Venkatesh, R and Cousins,
V and Xiao, Y and Yasuda, RP and Wolfe, BB and Perry, DC and Rezvani, AH and Levin, ED and Blendy, JA and Kellar, KJ},
Title = {Chronic sazetidine-A at behaviorally active doses does not
increase nicotinic cholinergic receptors in rodent
brain.},
Journal = {J Pharmacol Exp Ther},
Volume = {343},
Number = {2},
Pages = {441-450},
Year = {2012},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22899752},
Abstract = {Chronic nicotine administration increases α4β2 neuronal
nicotinic acetylcholine receptor (nAChR) density in brain.
This up-regulation probably contributes to the development
and/or maintenance of nicotine dependence. nAChR
up-regulation is believed to be triggered at the ligand
binding site, so it is not surprising that other nicotinic
ligands also up-regulate nAChRs in the brain. These other
ligands include varenicline, which is currently used for
smoking cessation therapy. Sazetidine-A (saz-A) is a newer
nicotinic ligand that binds with high affinity and
selectivity at α4β2* nAChRs. In behavioral studies, saz-A
decreases nicotine self-administration and increases
performance on tasks of attention. We report here that,
unlike nicotine and varenicline, chronic administration of
saz-A at behaviorally active and even higher doses does not
up-regulate nAChRs in rodent brains. We used a newly
developed method involving radioligand binding to measure
the concentrations and nAChR occupancy of saz-A, nicotine,
and varenicline in brains from chronically treated rats. Our
results indicate that saz-A reached concentrations in the
brain that were ∼150 times its affinity for α4β2* nAChRs
and occupied at least 75% of nAChRs. Thus, chronic
administration of saz-A did not up-regulate nAChRs despite
it reaching brain concentrations that are known to bind and
desensitize virtually all α4β2* nAChRs in brain. These
findings reinforce a model of nicotine addiction based on
desensitization of up-regulated nAChRs and introduce a
potential new strategy for smoking cessation therapy in
which drugs such as saz-A can promote smoking cessation
without maintaining nAChR up-regulation, thereby potentially
increasing the rate of long-term abstinence from
nicotine.},
Doi = {10.1124/jpet.112.198085},
Key = {fds274319}
}
@article{fds274326,
Author = {Swartzwelder, NA and Risher, ML and Abdelwahab, SH and D'Abo, A and Rezvani, AH and Levin, ED and Wilson, WA and Swartzwelder, HS and Acheson, SK},
Title = {Effects of ethanol, Δ(9)-tetrahydrocannabinol, or their
combination on object recognition memory and object
preference in adolescent and adult male rats.},
Journal = {Neurosci Lett},
Volume = {527},
Number = {1},
Pages = {11-15},
Year = {2012},
Month = {October},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22959891},
Abstract = {Recent advances have been made in our understanding of the
deleterious effects of both ethanol and THC on adolescent
behavior and brain development. However, very little is
known about the combined effects of EtOH+THC during
adolescence, a time in which these drugs are often used
together. The purpose of this experiment was to: (1)
determine whether EtOH and/or THC induced greater working
memory impairment in adolescent than adult male rats using
the novel object recognition (NOR) task and (2) determine
whether the EtOH+THC combination would produce a more potent
additive effect in adolescents than adults when compared to
these drugs alone. NOR was performed with a 24h delay under
each of the four drug conditions: vehicle; 1.5g/kg ethanol;
1.0mg/kg THC; and 1.5g/kg EtOH+1.0mg/kg THC, at 72h
intervals. The results show that there was an age effect on
working memory in NOR after the EtOH+THC challenge.
Specifically, adolescent animals showed a preference for the
familiar object whereas adults showed no preference for the
novel or familiar object, the latter being characteristic of
a classic working memory deficit. These effects were not
dependent on changes in exploration across session, global
activity across drug condition, or total object exploration.
These novel findings clearly indicate that further
understanding of this age-drug interaction is crucial to
elucidating the influence that adolescent EtOH+THC use may
have on repeated drug use and abuse later in
life.},
Doi = {10.1016/j.neulet.2012.08.037},
Key = {fds274326}
}
@article{fds274318,
Author = {Rezvani, AH and Cauley, MC and Johnson, EC and Gatto, GJ and Levin,
ED},
Title = {Effects of AZD3480, a neuronal nicotinic acetylcholine
receptor agonist, and donepezil on dizocilpine-induced
attentional impairment in rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {223},
Number = {3},
Pages = {251-258},
Year = {2012},
Month = {October},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22526540},
Abstract = {BACKGROUND AND RATIONALE: Nicotinic acetylcholine systems
play major roles in cognitive function. Nicotine and a
variety of nicotinic agonists improve attention, and
nicotinic antagonist exposure impairs it. This study was
conducted to investigate the effect of a novel nicotinic
receptor agonist at α4β2 nicotinic receptors (AZD3480) on
attention and reversal of pharmacologically induced
attentional impairment produced by the NMDA glutamate
antagonist dizocilpine (MK-801). METHODS: Adult female
Sprague-Dawley rats were trained to perform an operant
visual signal detection task to a stable baseline of
accuracy. The rats were then injected subcutaneously
following a repeated measures, counter-balanced design with
saline, AZD3480 (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05
mg/kg), or their combinations 30 min before the test. The
effect of donepezil on the same pharmacologically induced
attentional impairment was also tested. A separate group of
rats was injected with donepezil (0.01, 0.1, and 1 mg/kg),
dizocilpine (0.05 mg/kg), or their combinations, and their
attention were assessed. Saline was the vehicle control.
RESULTS: Dizocilpine caused a significant (p < 0.0005)
impairment in percent correct performance. This attentional
impairment was significantly (p < 0.0005) reversed by
0.01 and 0.1 mg/kg of AZD3480. AZD3480 by itself did not
alter the already high baseline control performance.
Donepezil (0.01-1.0 mg/kg) also significantly
(p < 0.005) attenuated the dizocilpine-induced
attentional impairment. CONCLUSIONS: AZD3480, similar to
donepezil, showed significant efficacy for counteracting the
attentional impairment caused by the NMDA glutamate
antagonist dizocilpine. Low doses of AZD3480 may provide
therapeutic benefit for reversing attentional impairment in
patients suffering from cognitive impairment due to
glutamatergic dysregulation and likely other attentional
disorders.},
Doi = {10.1007/s00213-012-2712-2},
Key = {fds274318}
}
@article{fds274317,
Author = {Rezvani, AH and Lawrence, AJ and Arolfo, MP and Levin, ED and Overstreet, DH},
Title = {Novel medication targets for the treatment of alcoholism:
preclinical studies.},
Journal = {Recent Pat CNS Drug Discov},
Volume = {7},
Number = {2},
Pages = {151-162},
Year = {2012},
Month = {August},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22574676},
Abstract = {Alcoholism is a complex heterogeneous disease and a number
of neurotransmitter and neuromodulator systems have been
implicated in its manifestation. Consequently, it is
unlikely that existing medications such as disulfiram
(Antabuse®), naltrexone (ReVia®), acamprosate (Campral®))
can be efficacious in every individual. Thus, the
development of novel therapeutic agents with greater
selectivity and less unwanted effects for the treatment of
this disease is one of the major objectives of alcohol
research. This review summarizes the findings of five novel
compounds with different neuronal targets for treating
alcoholism. These compounds include sazetidine-A, which
selectively desensitizes α4β2 nicotinic receptors;
carisbamate, a novel anti-epileptic agent; JNJ5234801, a
novel anxiolytic agent; GS-455534, a highly selective
inhibitor of mitochondrial aldehyde dehydrogenase; and
JNJ-39220675, a selective histamine H3 antagonist. Inbred
alcohol-preferring rats (iP), Fawn-Hooded (FH) rats, and P
rats were used to evaluate the compounds. Naltrexone was
used as a positive control in some experiments. All five
compounds reduced alcohol consumption and preference. The
mechanisms thought to underlie these effects suggest that,
in addition to dopaminergic and opioidergic systems, other
neuronal systems such as sodium channels (carisbamate),
mitochondrial aldehyde dehydrogenase (GS-455534), 5-HT2
receptors (JNJ-5234801), histamine H3 receptors
(JNJ-39220675), and α4β2 nicotinic receptors
(sazetidine-A) can be involved in alcohol drinking. Further
work is necessary to confirm the exact mechanisms of action
of each drug and to determine any viable targets for
putative treatment of alcohol-use disorders. The article
presents some promising patents on novel medication targets
for the treatment of alcoholism.},
Doi = {10.2174/157488912800673182},
Key = {fds274317}
}
@article{fds274310,
Author = {Larrauri, JA and Levin, ED},
Title = {Differential effects of the antidepressant mirtazapine on
amphetamine- and dizocilpine-induced PPI
deficits.},
Journal = {Pharmacol Biochem Behav},
Volume = {102},
Number = {1},
Pages = {82-87},
Year = {2012},
Month = {July},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22469866},
Abstract = {Prepulse inhibition (PPI) refers to the decrease in motor
startle response to salient sensory stimuli (pulses) when
they are closely preceded in time by another more modest
sensory stimulus (prepulse). PPI deficits can be induced by
stimulation of dopamine receptors (e.g., amphetamine or
apomorphine) or blockade of NMDA glutamate receptors (e.g.,
dizocilpine or PCP). Previously we found that antagonists of
α(2)-noradrenergic and H(1)-histaminergic receptors
significantly attenuate PPI impairments caused by
amphetamine or dizocilpine. In the current study we assessed
the effects of the antidepressant mirtazapine, which has
combined antagonist effects at α(2)-noradrenergic,
H(1)-histaminergic and 5-HT serotonergic receptors, on
amphetamine- and dizocilpine-induced PPI deficits. In
Experiment 1, rats were tested for PPI of the startle
response to a tactile air-puff stimulus after auditory
prepulses of three different intensities. Drug treatments
consisted of combinations of amphetamine (0 and 1mg/kg) and
mirtazapine (0, 0.5, 1, 2, and 5mg/kg), with all rats
receiving all drug doses and combinations with different
counterbalanced orders. In Experiment 2, a different group
of rats was tested with drug treatments consisting of
combinations of dizocilpine (0 and 0.05 mg/kg) and
mirtazapine (0, 0.5, 1, 2, and 5 mg/kg). In Experiment 1
amphetamine (1 mg/kg) significantly reduced PPI whereas
mirtazapine caused the opposite effect, with the highest
dose of mirtazapine (5 mg/kg) effectively reversing the
amphetamine-induced PPI deficit. In Experiment 2 dizocilpine
(0.05 mg/kg) significantly reduced PPI, but mirtazapine did
not have a significant effect on the inhibition of the
startle response. These results indicate that the potential
beneficial effects of combined α-adrenergic, 5-HT, and H(1)
receptor blockade in counteracting PPI deficits may be
associated to cases of sensorimotor gating disorders
mediated by dopamine, but not necessarily to NMDA
glutamate-induced PPI impairments.},
Doi = {10.1016/j.pbb.2012.03.010},
Key = {fds274310}
}
@article{fds274316,
Author = {Johnson, JE and Slade, S and Wells, C and Petro, A and Sexton, H and Rezvani, AH and Brown, ML and Paige, MA and McDowell, BE and Xiao, Y and Kellar, KJ and Levin, ED},
Title = {Assessing the effects of chronic sazetidine-A delivery on
nicotine self-administration in both male and female
rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {222},
Number = {2},
Pages = {269-276},
Year = {2012},
Month = {July},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22297831},
Abstract = {RATIONALE: Sazetidine-A is a selective α4β2 nicotinic
receptor desensitizing agent and partial agonist. It has
been shown in previous studies to significantly reduce
nicotine self-administration in rats after acute or repeated
injections. However, the effects of continuous chronic
infusions of sazetidine-A on maintenance of nicotine
self-administration and relapse after abstinence have yet to
be examined. OBJECTIVES: This study evaluated the efficacy
of continuous sazetidine-A infusions (sc) over a period of 4
weeks to reduce nicotine self-administration in male and
female Sprague-Dawley rats. METHODS: Sazetidine-A was
administered via Alzet osmotic minipumps to young adult
female and male rats at doses of 0, 2 or 6 mg/kg/day for 4
weeks. The effects of sazetidine-A on IV nicotine
self-administration were examined in repeated 3-h sessions
over the first 2 weeks of infusion followed by 1 week of
forced abstinence from nicotine and 1 week of resumed
nicotine access. RESULTS: The 6 mg/kg/day sazetidine-A dose
significantly reduced overall nicotine self-administration
compared with vehicle control across the sessions for both
male (p < 0.001) and female (p < 0.05) rats. The
lower 2 mg/kg/day sazetidine-A infusion dose was effective
in reducing nicotine self-administration for male
(p < 0.001), but not female rats. No attenuation in
sazetidine-A effectiveness was seen over the course of the
4-week treatment. In the vehicle control group, male rats
self-administered significantly (p < 0.001) more
nicotine than females. CONCLUSIONS: The continuing
effectiveness of sazetidine-A in reducing nicotine
self-administration in both male and female rats supports
its promise as a new treatment to help people successfully
quit smoking.},
Doi = {10.1007/s00213-012-2642-z},
Key = {fds274316}
}
@article{fds274314,
Author = {Rezvani, AH and Timofeeva, O and Sexton, HG and DeCuir, D and Xiao, Y and Gordon, CJ and Kellar, KJ and Levin, ED},
Title = {Effects of sazetidine-A, a selective α4β2* nicotinic
receptor desensitizing agent, on body temperature regulation
in mice and rats.},
Journal = {Eur J Pharmacol},
Volume = {682},
Number = {1-3},
Pages = {110-117},
Year = {2012},
Month = {May},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22387853},
Abstract = {Nicotine-induced hypothermia is well established, but the
nicotinic receptor actions underlying this effect are not
clear. Nicotine causes activation and desensitization at a
variety of nicotinic receptor subtypes. Sazetidine-A
[6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol]
is a novel compound that potently and selectively
desensitizes α4β2* nicotinic receptors. The main goal of
this study was to investigate the effects of sazetidine-A,
on core body temperature (Tc) in mice and rats. Sazetidine-A
effects on Tc and the interactions of sazetidine-A with
nicotine and selective nicotinic antagonists were
investigated to determine the receptor actions underlying
nicotine-induced hypothermia. Adult male mice were injected
with different dose of nicotine (0.2, 0.4 and 0.8 mg/kg),
sazetidine-A (0.3, 1, and 3mg/kg), a mixture of nicotine
(0.4 or 0.8 mg/kg) and sazetidine-A (0.3 or 0.6 mg/kg) or
saline and Tc was monitored telemetrically. In another set
of experiments, the interaction between sazetidine-A and
dihydro-β-erythroidine (DHβE), an α4β2* nicotinic
receptors antagonist, and methyllycaconitine (MLA), an α7
antagonist, was investigated. Tc of mice was monitored
following DHβE (1, 3 and 6 mg/kg), a combination of DHβE
(3mg/kg) and sazetidine-A (0.6 mg/kg), MLA (1.5, 3 or 6
mg/kg) or combination of MLA (6 mg/kg) and sazetidine (0.6
mg/kg) or saline. The acute effect of sazetidine-A (1, 3,
and 6 mg/kg) on rats Tc was also studied. Acute sazetidine-A
caused a pronounced and long-lasting hypothermia in mice; Tc
decreased to about 28°C at 100 min and recovered within 230
min. The hypothermic effect of sazetidine in rats was much
less in magnitude (about 3°C) and shorter in duration
compared with that in mice. Nicotine co-administration with
low doses of sazetidine potentiated the magnitude and
duration of hypothermia in mice. The α4β2* nicotinic
receptors antagonist DHβE significantly prolonged
sazetidine-A-induced hypothermia but did not increase its
depth. The α7 antagonist MLA caused a modest degree of
hypothermia with relatively short duration in mice. MLA
failed to counteract the sazetidine-A-induced hypothermia.
Overall, our results show that pharmacological modulation of
α4β2* nicotinic receptors elicits changes in body
temperature that may involve desensitization of these
receptors.},
Doi = {10.1016/j.ejphar.2012.02.031},
Key = {fds274314}
}
@article{fds274315,
Author = {Levin, ED},
Title = {α7-Nicotinic receptors and cognition.},
Journal = {Curr Drug Targets},
Volume = {13},
Number = {5},
Pages = {602-606},
Year = {2012},
Month = {May},
ISSN = {1389-4501},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22300026},
Abstract = {Nicotinic α7 receptors have been shown in a variety of
studies with animal models to play important roles in
diverse components of cognitive function, including
learning, memory and attention. Mice with α7 receptor
knockouts show impairments in memory. Selective α7 agonists
significantly improve learning, memory and attention. α7
receptors in limbic structures such as the hippocampus and
amygdala have been demonstrated to play critical roles in
memory. Blockade of α7 receptors in these areas cause
memory impairments. In the brains of people with
schizophrenia α7 receptors are impaired. This may be
related to pronounced cognitive impairments seen with
schizophrenia. There has been a major effort to develop α7
nicotinic agonists for helping to reverse cognitive
impairment. These receptors are a promising target for
development of therapeutic treatments for a variety of
diseases of cognitive impairment including Alzheimer's
disease, attention deficit hyperactivity disorder (ADHD) and
schizophrenia.},
Doi = {10.2174/138945012800398937},
Key = {fds274315}
}
@article{fds274312,
Author = {Hall, FS and Markou, A and Levin, ED and Uhl, GR},
Title = {Mouse models for studying genetic influences on factors
determining smoking cessation success in
humans.},
Journal = {Ann N Y Acad Sci},
Volume = {1248},
Number = {1},
Pages = {39-70},
Year = {2012},
Month = {February},
ISSN = {0077-8923},
url = {http://dx.doi.org/10.1111/j.1749-6632.2011.06415.x},
Abstract = {Humans differ in their ability to quit using addictive
substances, including nicotine, the major psychoactive
ingredient in tobacco. For tobacco smoking, a substantial
body of evidence, largely derived from twin studies,
indicates that approximately half of these individual
differences in ability to quit are heritable genetic
influences that likely overlap with those for other
addictive substances. Both twin and molecular genetic
studies support overlapping influences on nicotine addiction
vulnerability and smoking cessation success, although there
is little formal analysis of the twin data that support this
important point. None of the current datasets provides
clarity concerning which heritable factors might provide
robust dimensions around which individuals differ in ability
to quit smoking. One approach to this problem is to test
mice with genetic variations in genes that contain human
variants that alter quit success. This review considers
which features of quit success should be included in a
comprehensive approach to elucidate the genetics of quit
success, and how those features may be modeled in
mice.},
Doi = {10.1111/j.1749-6632.2011.06415.x},
Key = {fds274312}
}
@article{fds274313,
Author = {Newhouse, P and Kellar, K and Aisen, P and White, H and Wesnes, K and Coderre, E and Pfaff, A and Wilkins, H and Howard, D and Levin,
ED},
Title = {Nicotine treatment of mild cognitive impairment: a 6-month
double-blind pilot clinical trial.},
Journal = {Neurology},
Volume = {78},
Number = {2},
Pages = {91-101},
Year = {2012},
Month = {January},
ISSN = {0028-3878},
url = {http://dx.doi.org/10.1212/WNL.0b013e31823efcbb},
Abstract = {OBJECTIVE: To preliminarily assess the safety and efficacy
of transdermal nicotine therapy on cognitive performance and
clinical status in subjects with mild cognitive impairment
(MCI). METHODS: Nonsmoking subjects with amnestic MCI were
randomized to transdermal nicotine (15 mg per day or
placebo) for 6 months. Primary outcome variables were
attentional improvement assessed with Connors Continuous
Performance Test (CPT), clinical improvement as measured by
clinical global impression, and safety measures. Secondary
measures included computerized cognitive testing and patient
and observer ratings. RESULTS: Of 74 subjects enrolled, 39
were randomized to nicotine and 35 to placebo. 67 subjects
completed (34 nicotine, 33 placebo). The primary cognitive
outcome measure (CPT) showed a significant nicotine-induced
improvement. There was no statistically significant effect
on clinician-rated global improvement. The secondary outcome
measures showed significant nicotine-associated improvements
in attention, memory, and psychomotor speed, and
improvements were seen in patient/informant ratings of
cognitive impairment. Safety and tolerability for
transdermal nicotine were excellent. CONCLUSION: This study
demonstrated that transdermal nicotine can be safely
administered to nonsmoking subjects with MCI over 6 months
with improvement in primary and secondary cognitive measures
of attention, memory, and mental processing, but not in
ratings of clinician-rated global impression. We conclude
that this initial study provides evidence for
nicotine-induced cognitive improvement in subjects with MCI;
however, whether these effects are clinically important will
require larger studies. CLASSIFICATION OF EVIDENCE: This
study provides Class I evidence that 6 months of transdermal
nicotine (15 mg/day) improves cognitive test performance,
but not clinical global impression of change, in nonsmoking
subjects with amnestic MCI.},
Doi = {10.1212/WNL.0b013e31823efcbb},
Key = {fds274313}
}
@article{fds274308,
Author = {Larrauri, JA and Rosenthal, MZ and Levin, ED and McClernon, FJ and Schmajuk, NA},
Title = {Effects of unexpected changes in visual scenes on the human
acoustic startle response and prepulse inhibition.},
Journal = {Behav Processes},
Volume = {89},
Number = {1},
Pages = {1-7},
Year = {2012},
Month = {January},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22001728},
Abstract = {Prepulse inhibition (PPI) refers to the process wherein
startle responses to salient stimuli (e.g., startling sound
pulses) are attenuated by the presentation of another
stimulus (e.g., a brief pre-pulse) immediately before the
startling stimulus. Accordingly, deficits in PPI reflect
atypical sensorimotor gating that is linked to
neurobehavioral systems underlying responsivity to
emotionally evocative cues. Little is known about the
effects of changes in visual contextual information in PPI
among humans. In this study, the effects of introducing
unexpected changes in the visual scenes presented on a
computer monitor on the human auditory startle response and
PPI were assessed in young adults. Based on our animal data
showing that unexpected transitions from a dark to a light
environment reduce the startle response and PPI in rats
after the illumination transition, it was hypothesized that
novel changes in visual scenes would produce similar effects
in humans. Results show that PPI decreased when elements
were added to or removed from visual scenes, and that this
effect declined after repeated presentations of the modified
scene, supporting the interpretation that the PPI reduction
was due to novel information being processed. These findings
are the first to demonstrate that novel visual stimuli can
impair sensorimotor gating of auditory stimuli in
humans.},
Doi = {10.1016/j.beproc.2011.09.011},
Key = {fds274308}
}
@article{fds274309,
Author = {Larrauri, JA and Levin, ED},
Title = {The α₂-adrenergic antagonist idazoxan counteracts
prepulse inhibition deficits caused by amphetamine or
dizocilpine in rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {219},
Number = {1},
Pages = {99-108},
Year = {2012},
Month = {January},
ISSN = {0033-3158},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21710169},
Abstract = {RATIONALE: Prepulse inhibition (PPI) is the reduction in
startle response magnitude when intense stimuli are closely
preceded by other weak stimuli. Animal models used to
investigate sensorimotor gating deficits include both the
stimulation of dopamine receptors (e.g., amphetamine or
apomorphine) and the blockade of NMDA-glutamate receptors
(e.g., dizocilpine or phencyclidine). OBJECTIVES: We
assessed the effects of idazoxan (an α(2)-adrenergic
antagonist) on amphetamine- and dizocilpine-induced PPI
disruptions in adult female Sprague-Dawley rats. METHODS: In
experiment 1, rats were tested for PPI in a bimodal paradigm
with an acoustic prepulse and a tactile startle stimulus.
Interactions of amphetamine (1 mg/kg) and idazoxan (0.5, 1,
and 2 mg/kg) were assessed, with all rats receiving all drug
doses in a counterbalanced order. In experiment 2,
dizocilpine (0.05 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg)
interactions were analyzed. RESULTS: Amphetamine (1 mg/kg)
caused a significant reduction in PPI. Both the 1- and
2-mg/kg doses of idazoxan significantly counteracted this
effect. Dizocilpine (.05 mg/kg) effectively inhibited PPI,
and the 2-mg/kg idazoxan dose significantly counteracted
this impairment. CONCLUSIONS: These results suggest that the
effectiveness of atypical antipsychotics such as clozapine
in counteracting sensorimotor gating deficits reported in
previous studies (e.g., Swerdlow and Geyer, Pharmacol
Biochem Behav 44:741-744, 1993; Bakshi et al., J Pharmacol
Exp Ther 271:787-794, 1994) may be related to their
α(2)-antagonist effects, which may be a critical mechanism
of the therapeutic effects of atypical antipsychotics in
schizophrenia.},
Doi = {10.1007/s00213-011-2377-2},
Key = {fds274309}
}
@article{fds274320,
Author = {Roy, NM and Arpie, B and Lugo, J and Linney, E and Levin, ED and Cerutti,
D},
Title = {Brief embryonic strychnine exposure in zebrafish causes
long-term adult behavioral impairment with indications of
embryonic synaptic changes.},
Journal = {Neurotoxicol Teratol},
Volume = {34},
Number = {6},
Pages = {587-591},
Year = {2012},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2012.08.001},
Abstract = {Zebrafish provide a powerful model of the impacts of
embryonic toxicant exposure on neural development that may
result in long-term behavioral dysfunction. In this study,
zebrafish embryos were treated with 1.5mM strychnine for
short embryonic time windows to induce transient changes in
inhibitory neural signaling, and were subsequently raised in
untreated water until adulthood. PCR analysis showed
indications that strychnine exposure altered expression of
some genes related to glycinergic, GABAergic and
glutamatergic neuronal synapses during embryonic
development. In adulthood, treated fish showed significant
changes in swimming speed and tank diving behavior compared
to controls. Taken together, these data show that a short
embryonic exposure to a neurotoxicant can alter development
of neural synapses and lead to changes in adult
behavior.},
Doi = {10.1016/j.ntt.2012.08.001},
Key = {fds274320}
}
@article{fds274307,
Author = {Levin, ED and Slade, S and Wells, C and Cauley, M and Petro, A and Vendittelli, A and Johnson, M and Williams, P and Horton, K and Rezvani,
AH},
Title = {Threshold of adulthood for the onset of nicotine
self-administration in male and female rats.},
Journal = {Behav Brain Res},
Volume = {225},
Number = {2},
Pages = {473-481},
Year = {2011},
Month = {December},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21854810},
Abstract = {The great majority of tobacco addiction begins during
adolescence. More heavily addicted smokers begin smoking
earlier, but differentiating the neurobehavioral impact of
nicotine self-administration during adolescence from
self-selection bias (whereby people more prone to heavy
addiction also begin earlier) cannot be ethically
unconfounded in humans. The goals of this research were to
determine the age threshold for the adult-like nicotine
self-administration and determine sex differences. Male and
female Sprague-Dawley rats were tested for nicotine
self-administration starting at 4, 5, 6, 7, and 8 weeks of
age in an operant FR1 schedule for IV nicotine (0.03
mg/kg/infusion) in 45-min sessions for 2 weeks, with 1 week
of enforced abstinence and 1 week of resumed access. This
study replicated our earlier work that nicotine
self-administration was increased in adolescent vs. adult
rats and that the effect was more pronounced in adolescent
males, but the increased nicotine self-administration was
more persistent in adolescent-onset females. The age
threshold for adult-like behavior was 6-7 weeks of age.
Adolescent-onset nicotine self-administration had persisting
effects of eggaurated increases of nicotine
self-administration when fixed-ratio requirements for
self-administration were lowered. Female rats that had begun
nicotine self-administration during adolescence showed
exaggerated increases in nicotine self-administration after
a switch back to FR1 from FR8, indicating a lessened control
over their self-administration. Adolescent-onset nicotine
self-administration was not found to potentiate cocaine
self-administration. Adolescent-onset nicotine
self-administration causes persistent increases in nicotine
self-administration in female rats even after they reach
adulthood and disrupts control over self-administration
behavior.},
Doi = {10.1016/j.bbr.2011.08.005},
Key = {fds274307}
}
@article{fds274306,
Author = {Timofeeva, OA and Levin, ED},
Title = {Glutamate and nicotinic receptor interactions in working
memory: importance for the cognitive impairment of
schizophrenia.},
Journal = {Neuroscience},
Volume = {195},
Pages = {21-36},
Year = {2011},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21884762},
Abstract = {This article reaches across disciplines to correlate results
in molecular, cellular, behavioral, and clinical research to
develop a more complete picture of how working memory (WM)
functions. It identifies a new idea that deserves further
investigation. NMDA glutamate receptors (NMDAR) are critical
for memory function. NMDAR inhibition effectively reproduces
principal manifestations of schizophrenia (SP), such as WM
impairment and GABAergic deficit (mainly reduction of
glutamic acid decarboxylase 67 (GAD67) and parvalbumin (PV)
content). Nicotine and selective α7 nicotinic acetylcholine
receptor (nAChR) agonists reduce WM impairments in patients
with SP and reverse WM deficits in animals treated with
NMDAR antagonists. The mechanism of this effect is unknown.
Importantly, WM recovery occurs even before restoration of
NMDAR blockade-induced molecular alterations, including
reduced GAD67 in interneurons. Our insight into the
cognitive-enhancing effect of α7 nAChR agonists,
particularly in the animal models of SP, combines reviews of
recent findings on glutamate and nicotinic receptor
expression in the neuronal circuits involved in WM, the
properties of these receptors, their implication in WM
regulation, generation of rhythmic neuronal activity,
resulting in a proposed hypothesis for further
investigations. We suggest that (1) cortical/hippocampal
interneurons, particularly PV positive, play a crucial role
in WM and that impairment of these cells in SP could be
behind the WM deficit; (2) activation of α7 nAChRs could
restore calcium signaling and intrinsic properties of these
interneurons, and associated with these events,
computational capacity, gamma rhythmic activity, and WM
would also be restored.},
Doi = {10.1016/j.neuroscience.2011.08.038},
Key = {fds274306}
}
@article{fds316113,
Author = {Rezvani, AH and Cauley, M and Johnson, E and Levin,
ED},
Title = {Attentional improvement in rats with the nicotinic agonist
AZ12564698 (AZD3480)},
Journal = {Biochemical Pharmacology},
Volume = {82},
Number = {8},
Pages = {1040-1041},
Publisher = {Elsevier BV},
Year = {2011},
Month = {October},
ISSN = {0006-2952},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000294513200069&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Doi = {10.1016/j.bcp.2011.07.046},
Key = {fds316113}
}
@article{fds316082,
Author = {Levin, ED},
Title = {Using zebrafish to fill the gap between in vitro and rodent
models for nicotinic drug development},
Journal = {Biochemical Pharmacology},
Volume = {82},
Number = {8},
Pages = {1038-1039},
Publisher = {Elsevier BV},
Year = {2011},
Month = {October},
ISSN = {0006-2952},
url = {http://dx.doi.org/10.1016/j.bcp.2011.07.040},
Doi = {10.1016/j.bcp.2011.07.040},
Key = {fds316082}
}
@article{fds274300,
Author = {Cippitelli, A and Rezvani, AH and Robinson, JE and Eisenberg, L and Levin, ED and Bonaventure, P and Motley, ST and Lovenberg, TW and Heilig, M and Thorsell, A},
Title = {The novel, selective, brain-penetrant neuropeptide Y Y2
receptor antagonist, JNJ-31020028, tested in animal models
of alcohol consumption, relapse, and anxiety.},
Journal = {Alcohol},
Volume = {45},
Number = {6},
Pages = {567-576},
Year = {2011},
Month = {September},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21145691},
Abstract = {Neuropeptide Y (NPY) signaling has been shown to modulate
stress responses and to be involved in regulation of alcohol
intake and dependence. The present study explores the
possibility that blockade of NPY Y2 autoreceptors using a
novel, blood-brain barrier penetrant NPY Y2 receptor
antagonist, JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide),
may achieve a therapeutically useful activation of the NPY
system in alcohol- and anxiety-related behavioral models. We
examined JNJ-31020028 in operant alcohol
self-administration, stress-induced reinstatement to alcohol
seeking, and acute alcohol withdrawal (hangover)-induced
anxiety. Furthermore, we tested its effects on voluntary
alcohol consumption in a genetic animal model of alcohol
preference, the alcohol-preferring (P) rat. Neither systemic
(0, 15, 30, and 40 mg/kg, subcutaneously [s.c.]) nor
intracerebroventricular (0.0, 0.3, and 1.0 nmol/rat)
administration of JNJ-31020028 affected alcohol-reinforced
lever pressing or relapse to alcohol seeking behavior
following stress exposure. Also, when its effects were
tested on unlimited access to alcohol in P rats, preference
for alcohol solution was transiently suppressed but without
affecting voluntary alcohol intake. JNJ-31020028 (15 mg/kg,
s.c.) did reverse the anxiogenic effects of withdrawal from
a single bolus dose of alcohol on the elevated plus-maze,
confirming the anxiolytic-like properties of NPY Y2
antagonism. Our data do not support Y2 antagonism as a
mechanism for reducing alcohol consumption or relapse-like
behavior, but the observed effects on withdrawal-induced
anxiety suggest that NPY Y2 receptor antagonists may be a
putative treatment for the negative affective states
following alcohol withdrawal.},
Doi = {10.1016/j.alcohol.2010.09.003},
Key = {fds274300}
}
@article{fds274301,
Author = {Levin, ED and Johnson, JE and Slade, S and Wells, C and Cauley, M and Petro, A and Rose, JE},
Title = {Lorcaserin, a 5-HT2C agonist, decreases nicotine
self-administration in female rats.},
Journal = {J Pharmacol Exp Ther},
Volume = {338},
Number = {3},
Pages = {890-896},
Year = {2011},
Month = {September},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21636655},
Abstract = {Lorcaserin, a selective 5-hydroxytryptamine(2C) (5-HT(2C))
agonist, has been shown to facilitate weight loss in obese
populations. It was assessed for its efficacy in reducing
nicotine self-administration in young adult female
Sprague-Dawley rats. The effect of short-term doses
(subcutaneous) on nicotine self-administration (0.03 mg/kg
per infusion) with a fixed ratio 1 schedule was assessed in
3-h sessions. Short-term lorcaserin doses (0.3125-20 mg/kg)
were administered in a counterbalanced order. Significant
reduction of nicotine self-administration was achieved with
all of the short-term doses in this range. Tests of
lorcaserin on locomotor activity detected prominent sedative
effects at doses greater than 1.25 mg/kg with more modest
transient effects seen at 0.625 to 1.25 mg/kg. Long-term
effects of lorcaserin on locomotor activity were tested with
repeated injections with 0.625 mg/kg lorcaserin 10 times
over 2 weeks. This low lorcaserin dose did not cause an
overall change in locomotor activity relative to that of
saline-injected controls. Long-term lorcaserin (0.625 mg/kg)
significantly reduced nicotine self-administration over a
2-week period of repeated injections. Long-term lorcaserin
at this same dose had no significant effects on food
self-administration over the same 2-week period of repeated
injections. These studies support development of the
5-HT(2C) agonist lorcaserin to aid tobacco smoking
cessation.},
Doi = {10.1124/jpet.111.183525},
Key = {fds274301}
}
@article{fds274299,
Author = {Levin, ED and Bushnell, PJ and Rezvani, AH},
Title = {Attention-modulating effects of cognitive
enhancers.},
Journal = {Pharmacol Biochem Behav},
Volume = {99},
Number = {2},
Pages = {146-154},
Year = {2011},
Month = {August},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21334367},
Abstract = {Attention can be readily measured in experimental animal
models. Animal models of attention have been used to better
understand the neural systems involved in attention, how
attention is impaired, and how therapeutic treatments can
ameliorate attentional deficits. This review focuses on the
ways in which animal models are used to better understand
the neuronal mechanism of attention and how to develop new
therapeutic treatments for attentional impairment. Several
behavioral test methods have been developed for experimental
animal studies of attention, including a 5-choice serial
reaction time task (5-CSRTT), a signal detection task (SDT),
and a novel object recognition (NOR) test. These tasks can
be used together with genetic, lesion, pharmacological and
behavioral models of attentional impairment to test the
efficacy of novel therapeutic treatments. The most prominent
genetic model is the spontaneously hypertensive rat (SHR).
Well-characterized lesion models include frontal cortical or
hippocampal lesions. Pharmacological models include
challenge with the NMDA glutamate antagonist dizocilpine
(MK-801), the nicotinic cholinergic antagonist mecamylamine
and the muscarinic cholinergic antagonist scopolamine.
Behavioral models include distracting stimuli and attenuated
target stimuli. Important validation of these behavioral
tests and models of attentional impairments for developing
effective treatments for attentional dysfunction is the fact
that stimulant treatments effective for attention deficit
hyperactivity disorder (ADHD), such as methylphenidate
(Ritalin®), are effective in the experimental animal
models. Newer lines of treatment including nicotinic
agonists, α4β2 nicotinic receptor desensitizers, and
histamine H₃ antagonists, have also been found to be
effective in improving attention in these animal models.
Good carryover has also been seen for the attentional
improvement caused by nicotine in experimental animal models
and in human populations. Animal models of attention can be
effectively used for the development of new treatments of
attentional impairment in ADHD and other syndromes in which
have attentional impairments occur, such as Alzheimer's
disease and schizophrenia.},
Doi = {10.1016/j.pbb.2011.02.008},
Key = {fds274299}
}
@article{fds274298,
Author = {Rezvani, AH and Cauley, M and Sexton, H and Xiao, Y and Brown, ML and Paige, MA and McDowell, BE and Kellar, KJ and Levin,
ED},
Title = {Sazetidine-A, a selective α4β2 nicotinic acetylcholine
receptor ligand: effects on dizocilpine and
scopolamine-induced attentional impairments in female
Sprague-Dawley rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {215},
Number = {4},
Pages = {621-630},
Year = {2011},
Month = {June},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21274704},
Abstract = {BACKGROUND: Neuronal nicotinic receptor systems have been
shown to play key roles in cognition. Nicotine and nicotinic
analogs improve attention and nicotinic antagonists impair
it. This study was conducted to investigate the role of
α4β2 nicotinic receptors in sustained attention using a
novel selective α4β2 nicotinic receptor ligand,
sazetidine-A. METHODS: Female rats were trained to perform
the signal detection task to a stable baseline of accuracy.
The rats were injected with saline, sazetidine-A (0.01,
0.03, and 0.1 mg/kg), dizocilpine (0.05 mg/kg), or their
combination; or, in another experiment, the rats were
injected with the same doses of sazetidine-A, scopolamine
(0.02 mg/kg), or their combination. RESULTS: Percent hit
and percent correct rejection showed that dizocilpine caused
significant (p < 0.025) impairments in performance,
which were significantly reversed by each of the
sazetidine-A doses. Response omissions were significantly
(p < 0.05) increased by dizocilpine, and this was also
significantly reversed by each of the sazetidine-A doses.
None of the sazetidine-A doses had significant effects on
hit, correct rejection, or response omissions when given
alone. Scopolamine also caused significant (p < 0.0005)
impairments in percent hit and percent correct rejection and
increased response omissions, which were significantly
attenuated by all the sazetidine-A doses for percent hit and
response omissions and by the highest dose of sazetidine-A
for percent correct rejection. Both scopolamine and
dizocilpine significantly (p < 0.0005) increased
response latency, an effect which was significantly
attenuated by sazetidine-A coadministration. CONCLUSIONS:
These studies imply an important role for α4β2 nicotinic
receptors in improving sustained attention under conditions
that disrupt it. Very low doses of sazetidine-A or drugs
with a similar profile may provide therapeutic benefit for
reversing attentional impairment in patients suffering from
mental disorders and/or cognitive impairment.},
Doi = {10.1007/s00213-010-2161-8},
Key = {fds274298}
}
@article{fds274323,
Author = {Schramm-Sapyta, NL and Cauley, MC and Stangl, DK and Glowacz, S and Stepp, KA and Levin, ED and Kuhn, CM},
Title = {Role of individual and developmental differences in
voluntary cocaine intake in rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {215},
Number = {3},
Pages = {493-504},
Year = {2011},
Month = {June},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21347641},
Abstract = {RATIONALE: Early-onset drug taking is associated with
increased likelihood of addiction, but it is unclear whether
early onset is causal in development of addiction. Many
other factors are associated with increased risk of
addiction and also promote early intake. Here, a rodent
model is used to explore the causality of early onset in
development of self-administration and addiction-like
behavior and to examine factors that promote
self-administration. METHODS: We used cocaine
self-administration to examine drug taking and
addiction-like behavior in adolescent and adult rats a
priori characterized for their locomotor responses to
novelty and cocaine and behavior in the light-dark task.
RESULTS: Adolescent animals initially sought more cocaine
than adults. However, as the adolescents matured, their
intake fell and they did not differ from adults in terms of
unreinforced lever-pressing, extinction or reinstatement
behavior. For both age groups, self-administration was
positively correlated with the locomotor response to
novelty, the locomotor response to cocaine, and with time in
light in the light-dark task. The rats that were insensitive
to cocaine's locomotor effects and that spent the least time
in light in the light-dark task sought the least cocaine,
appearing to be "protected" from the reinforcing effects of
cocaine. There was no difference between the two age groups
in appearance of this "protected" phenotype. CONCLUSIONS:
These results suggest that early onset of drug taking may
promote increased use, but does not promote progression to
addiction-like behavior. Furthermore, protective factors,
such as innate anxiety and insensitivity to cocaine's
pharmacological effects, function across developmental
stages.},
Doi = {10.1007/s00213-011-2216-5},
Key = {fds274323}
}
@article{fds274296,
Author = {Levin, ED and Slade, S and Wells, C and Petro, A and Rose,
JE},
Title = {D-cycloserine selectively decreases nicotine
self-administration in rats with low baseline levels of
response.},
Journal = {Pharmacol Biochem Behav},
Volume = {98},
Number = {2},
Pages = {210-214},
Year = {2011},
Month = {April},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21192967},
Abstract = {Expanding the variety of treatments available to aid smoking
cessation will allow the treatments to be customized to
particular types of smokers. The key is to understand which
subpopulations of smokers respond best to which treatment.
This study used adult female Sprague-Dawley rats to evaluate
the efficacy of D-cycloserine, a partial NMDA glutamate
receptor agonist, in reducing nicotine self-administration.
Rats were trained to self-administer nicotine (0.03
mg/kg/infusion, i.v.) via operant lever response (FR1) with
a secondary visual reinforcer. Two studies of D-cycloserine
effects on nicotine self-administration were conducted: an
acute dose-effect study (0, 10, 20 and 40 mg/kg, s.c.) and a
chronic study with 40 mg/kg given before each test session
for two weeks. Effects on rats with low or high pretreatment
baseline levels of nicotine self-administration were
assessed. In the acute study there was a significant
interaction of D-cycloserine×baseline level of nicotine
self-administration. In the low baseline group, 10 mg/kg
D-cycloserine significantly decreased nicotine
self-administration. In the high baseline group, 40 mg/kg
significantly increased nicotine self-administration. In the
repeated injection study, there was also a significant
interaction of d-cycloserine×baseline level of nicotine
self-administration. Chronic D-cycloserine significantly
reduced nicotine self-administration selectively in rats
with low baseline nicotine use, but was ineffective with the
rats with higher levels of baseline nicotine
self-administration. NMDA glutamate treatments may be
particularly useful in helping lighter smokers successfully
quit smoking, highlighting the need for diverse treatments
for different types of smokers.},
Doi = {10.1016/j.pbb.2010.12.023},
Key = {fds274296}
}
@article{fds274297,
Author = {Galici, R and Rezvani, AH and Aluisio, L and Lord, B and Levin, ED and Fraser, I and Boggs, J and Welty, N and Shoblock, JR and Motley, ST and Letavic, MA and Carruthers, NI and Dugovic, C and Lovenberg, TW and Bonaventure, P},
Title = {JNJ-39220675, a novel selective histamine H3 receptor
antagonist, reduces the abuse-related effects of alcohol in
rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {214},
Number = {4},
Pages = {829-841},
Year = {2011},
Month = {April},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21086115},
Abstract = {RATIONALE: A few recent studies suggest that brain histamine
levels and signaling via H(3) receptors play an important
role in modulation of alcohol stimulation and reward in
rodents. OBJECTIVE: The present study characterized the
effects of a novel, selective, and brain penetrant H(3)
receptor antagonist (JNJ-39220675) on the reinforcing
effects of alcohol in rats. METHODS: The effect of
JNJ-39220675 on alcohol intake and alcohol relapse-like
behavior was evaluated in selectively bred
alcohol-preferring (P) rats using the standard two-bottle
choice method. The compound was also tested on operant
alcohol self administration in non-dependent rats and on
alcohol-induced ataxia using the rotarod apparatus. In
addition, alcohol-induced dopamine release in the nucleus
accumbens was tested in freely moving rats. RESULTS:
Subcutaneous administration of the selective H(3) receptor
antagonist dose-dependently reduced both alcohol intake and
preference in alcohol-preferring rats. JNJ-39220675 also
reduced alcohol preference in the same strain of rats
following a 3-day alcohol deprivation. The compound
significantly and dose-dependently reduced alcohol
self-administration without changing saccharin
self-administration in alcohol non-dependent rats.
Furthermore, the compound did not change the ataxic effects
of alcohol, alcohol elimination rate, nor alcohol-induced
dopamine release in nucleus accumbens. CONCLUSIONS: These
results indicate that blockade of H(3) receptor should be
considered as a new attractive mechanism for the treatment
of alcoholism.},
Doi = {10.1007/s00213-010-2092-4},
Key = {fds274297}
}
@article{fds274293,
Author = {Levin, ED and Slade, S and Wells, C and Pruitt, M and Cousins, V and Cauley, M and Petro, A and Hampton, D and Rose, J},
Title = {Histamine H(1) antagonist treatment with pyrilamine reduces
nicotine self-administration in rats.},
Journal = {Eur J Pharmacol},
Volume = {650},
Number = {1},
Pages = {256-260},
Year = {2011},
Month = {January},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20951696},
Abstract = {Nicotine has been definitively shown to be critically
involved in the neural bases of tobacco addiction. However,
nicotine releases a wide variety of neurotransmitters.
Nicotine-induced dopamine release has been shown to play a
key role in facilitating nicotine self-administration. Other
transmitter systems may also play important roles in the
pharmacological effects of nicotine and may provide
important leads for combating nicotine self-administration.
Clozapine, an antipsychotic drug, which blocks a variety of
different transmitter receptors including serotonin 5HT(2)
and histamine H(1) receptors, has been found to decrease
smoking. Previously we found that the serotonin 5HT(2)
antagonist, ketanserin, significantly reduced nicotine
self-administration. In the current study, we assessed
histamine H(1) receptor interaction with nicotine
self-administration. Young adult female Sprague-Dawley rats
were fitted with IV catheters and trained to self-administer
nicotine (0.03mg/kg/infusion). Acute doses of 40mg/kg of
pyrilamine, a histamine H(1) antagonist, significantly
reduced nicotine self-administration. We also found that
repeated injections (20mg/kg) or chronic infusion via
osmotic minipumps (50mg/kg/day) of pyrilamine also
significantly decreased nicotine self-administration. The
peripherally restricted H(1) antagonist ebastine was
ineffective in reducing nicotine self-administration,
pointing to central H(1) receptor blockade as key for the
effectiveness of pyrilamine. H(1) antagonists may be a
promising avenue to explore for new treatments to aid
smoking cessation.},
Doi = {10.1016/j.ejphar.2010.10.013},
Key = {fds274293}
}
@article{fds274292,
Author = {Levin, ED},
Title = {Nicotinic receptor systems and neurobehavioral function in
zebrafish},
Journal = {Neuromethods},
Volume = {52},
Pages = {89-100},
Publisher = {Humana Press},
Year = {2011},
Month = {January},
ISSN = {0893-2336},
url = {http://dx.doi.org/10.1007/978-1-60761-922-2_4},
Abstract = {Nicotinic acetylcholine receptors appear to be quite ancient
phylogenetically and are used in the nervous systems of a
great number of species across broad parts of the animal
kingdom. They play important roles in a variety of
neurobehavioral functions from neuromuscular activation to
cognitive function. Nicotinic receptor function is an
excellent field in which to assess the potential
commonalities of neurobehavioral functions across animal
species. Nicotinic receptors are remarkably consistent
across species and the behavioral effects of nicotinic
treatments have been very well determined in mammals. Since
zebrafish are an emerging aquatic model for studying
neurobehavioral function, we have determined the effects of
nicotine, the prototypic nicotinic agonist as well as
nicotinic antagonists on cognitive function, exploratory
behavior and stress response in a series of behavioral tests
we have developed to reliably index these behavioral
functions. The overall hypothesis of this line of
investigation was that nicotine would have similar
behavioral effects in zebrafish as in mammals when analogous
tests of behavioral function are used. As with mammalian
species, nicotine significantly improves learning and memory
at low to moderate doses in zebrafish with an inverted
J-shaped dose-effect function. The nicotine-induced learning
improvement in zebrafish is reversed with the nicotinic
antagonist mecamylamine and is accompanied by increased
brain dopamine metabolite levels, an effect which is also
reversed with mecamylamine. Also, as in mammals, nicotine
has anxiolytic effects in zebrafish. Nicotine significantly
reduces bottom dwelling in the novel tank diving task. This
effect is reversed by either α7 or α4β2 nicotinic
antagonist coadministration. In many respects nicotine has
similar effects in zebrafish as in rodents and humans. These
studies point to the value of zebrafish as models of human
neurobehavioral function. © 2011 Springer Science+Business
Media, LLC.},
Doi = {10.1007/978-1-60761-922-2_4},
Key = {fds274292}
}
@article{fds274294,
Author = {Powers, CM and Levin, ED and Seidler, FJ and Slotkin,
TA},
Title = {Silver exposure in developing zebrafish produces persistent
synaptic and behavioral changes.},
Journal = {Neurotoxicol Teratol},
Volume = {33},
Number = {2},
Pages = {329-332},
Year = {2011},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21035540},
Abstract = {Environmental silver exposures are increasing due to the use
of silver nanoparticles, which exert antimicrobial actions
by releasing Ag+, a suspected developmental neurotoxicant.
We evaluated the long-term neurochemical and behavioral
effects of embryonic Ag+ exposure in zebrafish at
concentrations that had no overt effects on morphological
development. Exposure to 0.03, 0.1 or 0.3 μM Ag+ during the
first five days post-fertilization caused elevations in both
dopamine and serotonin turnover in the adult zebrafish brain
without affecting basal neurotransmitter levels. Consistent
with these synaptic effects, Ag+-exposed fish showed a
faster acquisition of avoidance behavior in a three-chamber
test apparatus, without any change in response latency or
overall swimming ability. Our results indicate that Ag+ is a
developmental neurotoxicant that causes persistent
neurobehavioral effects, reinforcing health concerns about
Ag+ released from silver nanoparticles.},
Doi = {10.1016/j.ntt.2010.10.006},
Key = {fds274294}
}
@article{fds274295,
Author = {Levin, ED},
Title = {Zebrafish assessment of cognitive improvement and
anxiolysis: filling the gap between in vitro and rodent
models for drug development.},
Journal = {Rev Neurosci},
Volume = {22},
Number = {1},
Pages = {75-84},
Year = {2011},
ISSN = {0334-1763},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21615262},
Abstract = {Zebrafish can provide a valuable animal model to screen
potential cognitive enhancing and anxiolytic drugs. They are
economical and can provide a relatively quick indication of
possible functional efficacy. In as much as they have a
complex nervous system and elaborate behavioral repertoire,
zebrafish can provide a good intermediate model between in
vitro receptor and cell-based assays and classic mammalian
models for drug screening. In addition, the variety of
molecular tools available in zebrafish makes them
outstanding models for helping to determine the
neuromolecular mechanisms for psychoactive drugs. However,
to use zebrafish as a translational model we must have
validated, sensitive and efficient behavioral tests. In a
series of studies, our lab has developed tests of cognitive
function and stress response, which are sensitive to drug
effects in a similar manner as rodent models and humans for
cognitive enhancement and alleviating stress response. In
particular, the three-chamber task for learning and memory
was shown to be sensitive to the cognitive enhancing effects
of nicotine and has been useful in helping to determine
neural mechanisms crucial for nicotinic-induced cognitive
enhancement. The novel tank diving test was shown to be a
valid and efficient test of stress response. It is sensitive
to the reduction in stress-related behaviors due to the
amxiolytic drugs diazepam and buspirone but not
chlordiazepoxide. Nicotine also causes stress alleviating
effects which can be interpreted as anxiolytic effects.
Zebrafish models of behavioral pharmacology can be useful to
efficiently screen test compounds for drug development and
can be useful in helping to determine the mechanisms crucial
for new therapeutic treatments of neurobehavioral
impairments.},
Doi = {10.1515/RNS.2011.009},
Key = {fds274295}
}
@article{fds274302,
Author = {Levin, ED and Sledge, D and Roach, S and Petro, A and Donerly, S and Linney, E},
Title = {Persistent behavioral impairment caused by embryonic
methylphenidate exposure in zebrafish.},
Journal = {Neurotoxicol Teratol},
Volume = {33},
Number = {6},
Pages = {668-673},
Year = {2011},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21741476},
Abstract = {As more adults take the stimulant medication methylphenidate
to treat attention deficit hyperactivity disorder (ADHD)
residual type, the risk arises with regard to exposure
during early development if people taking the medication
become pregnant. We studied the neurobehavioral effects of
methylphenidate in zebrafish. Zebrafish offer cellular
reporter systems, continuous visual access and molecular
interventions such as morpholinos to help determine critical
mechanisms underlying neurobehavioral teratogenicity.
Previously, we had seen that persisting neurobehavioral
impairment in zebrafish with developmental chlorpyrifos
exposure was associated with disturbed dopamine systems.
Because methylphenidate is an indirect dopamine agonist, it
was thought that it might also cause persistent behavioral
impairment after developmental exposure. Zebrafish embryos
were exposed to the ADHD stimulant medication
methylphenidate 0-5 days post fertilization (12.5-50mg/l).
They were tested for long-term behavioral effects as adults.
Methylphenidate exposure (50mg/l) caused significant
increases in dopamine, norepinepherine and serotonin on day
6 but not day 30 after fertilization. In the novel tank
diving test of predatory avoidance developmental
methylphenidate (50mg/l) caused a significant reduction in
the normal diving response. In the three-chamber spatial
learning task early developmental methylphenidate (50mg/l)
caused a significant impairment in choice accuracy. These
data show that early developmental exposure of zebrafish to
methylphenidate causes a long-term impairment in
neurobehavioral plasticity. The identification of these
functional deficits in zebrafish enables further studies
with this model to determine how molecular and cellular
mechanisms are disturbed to arrive at this compromised
state.},
Doi = {10.1016/j.ntt.2011.06.004},
Key = {fds274302}
}
@article{fds274303,
Author = {Sledge, D and Yen, J and Morton, T and Dishaw, L and Petro, A and Donerly,
S and Linney, E and Levin, ED},
Title = {Critical duration of exposure for developmental
chlorpyrifos-induced neurobehavioral toxicity.},
Journal = {Neurotoxicol Teratol},
Volume = {33},
Number = {6},
Pages = {742-751},
Year = {2011},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21745564},
Abstract = {Developmental exposure of rats to the pesticide chlorpyrifos
(CPF) causes persistent neurobehavioral impairment. In a
parallel series of studies with zebrafish, we have also
found persisting behavioral dysfunction after developmental
CPF exposure. We have developed a battery of measures of
zebrafish behavior, which are reliable and sensitive to
toxicant-induced damage. This study determined the critical
duration of developmental CPF exposure for causing
persisting neurobehavioral effects. Tests of sensorimotor
response (tap startle response and habituation), stress
response (novel tank diving test) and learning (3-chamber
tank spatial discrimination) were conducted with adult
zebrafish after early developmental CPF exposure. The CPF
exposure level was 100 ng/ml with durations of 0-1, 0-2,
0-3, 0-4 and 0-5 days after fertilization. Developmental CPF
exposure had persisting behavioral effects in zebrafish
tested as adults. In the tactile startle test, CPF exposed
fish showed decreased habituation to startle and a trend
toward increased overall startle response. In the novel tank
exploration test, exposed fish showed decreased escape
diving response and increased swimming activity. In the
3-chamber learning test, the 0-5 day CPF exposure group had
a significantly lower learning rate. There was evidence for
persisting declines in brain dopamine and norepinepherine
levels after developmental CPF exposure. In all of the
measures the clearest persistent effects were seen in fish
exposed for the full duration of five days after
fertilization. In a follow-up experiment there were some
indications for persisting behavioral effects after exposure
during only the later phase of this developmental window.
This study demonstrated the selective long-term
neurobehavioral alterations caused by exposure to CPF in
zebrafish. The zebrafish model can facilitate the
determination of the molecular mechanisms underlying
long-term neurobehavioral impairment after developmental
toxicant exposure.},
Doi = {10.1016/j.ntt.2011.06.005},
Key = {fds274303}
}
@article{fds274304,
Author = {Levin, ED and Tanguay, RL},
Title = {Introduction to zebrafish: current discoveries and emerging
technologies for neurobehavioral toxicology and
teratology.},
Journal = {Neurotoxicol Teratol},
Volume = {33},
Number = {6},
Pages = {607},
Year = {2011},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22117689},
Doi = {10.1016/j.ntt.2011.10.005},
Key = {fds274304}
}
@article{fds274305,
Author = {Yen, J and Donerly, S and Levin, ED and Linney, EA},
Title = {Differential acetylcholinesterase inhibition of
chlorpyrifos, diazinon and parathion in larval
zebrafish.},
Journal = {Neurotoxicol Teratol},
Volume = {33},
Number = {6},
Pages = {735-741},
Year = {2011},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22036888},
Abstract = {Zebrafish are increasingly used for developmental
neurotoxicity testing because early embryonic events are
easy to visualize, exposures are done without affecting the
mother and the rapid development of zebrafish allows for
high throughput testing. We used zebrafish to examine how
exposures to three different organophosphorus pesticides
(chlorpyrifos, diazinon and parathion) over the first five
days of embryonic and larval development of zebrafish
affected their survival, acetylcholinesterase (AChE)
activity and behavior. We show that at non-lethal, equimolar
concentrations, chlorpyrifos (CPF) is more effective at
equimolar concentrations than diazinon (DZN) and parathion
(PA) in producing AChE inhibition. As concentrations of DZN
and PA are raised, lethality occurs before they can produce
the degree of AChE inhibition observed with CPF at 300 nM.
Because of its availability outside the mother at the time
of fertilization, zebrafish provides a complementary model
for studying the neurotoxicity of very early developmental
exposures.},
Doi = {10.1016/j.ntt.2011.10.004},
Key = {fds274305}
}
@article{fds274289,
Author = {Levin, ED and Hampton, D and Rose, JE},
Title = {IV nicotine self-administration in rats using the
consummatory operant licking response.},
Journal = {Physiol Behav},
Volume = {101},
Number = {5},
Pages = {755-758},
Year = {2010},
Month = {December},
ISSN = {0031-9384},
url = {http://dx.doi.org/10.1016/j.physbeh.2010.08.016},
Abstract = {Nicotine self-administered by tobacco smoking or chewing is
very addictive in humans. Rat models have been developed in
which nicotine is self-administered IV by the rats pressing
a lever. However the reinforcing value of nicotine is much
less in these models than the addictiveness of human tobacco
use would indicate. The IV nicotine self-administration
operant lever press model does not fully capture important
aspects of tobacco use in humans. Conditioned oral
consumption actions of smoking or chewing tobacco may play
important roles in tobacco addiction. Neural circuitry
underlying essential food consummatory responses may
facilitate consummatory aspects of tobacco intake. To
capture this motor consummatory aspect of tobacco addiction
in the rat model of nicotine self-administration, we have
developed a method of using a licking response instead of a
lever press to self-administer IV nicotine. Sprague-Dawley
rats were trained to lick one of two waterspouts for IV
nicotine (0.03mg/kg/infusion). With the licking response
rats self-administered stable nicotine levels throughout 24
sessions (45min each) of testing. The number of total
licks/session significantly increased in a linear fashion
over that period. The number of licks/infusion was
substantial, rising steadily with training to an average of
over 100 licks/infusion. Including the consummatory motor
act with nicotine self-administration could help better
model the compulsive aspects of tobacco addiction in
humans.},
Doi = {10.1016/j.physbeh.2010.08.016},
Key = {fds274289}
}
@article{fds274191,
Author = {Timofeeva, OA and Levin, ED},
Title = {Lasting Behavioral Consequences of Organophosphate Pesticide
Exposure During Development},
Pages = {837-846},
Publisher = {Elsevier},
Year = {2010},
Month = {December},
url = {http://dx.doi.org/10.1016/B978-0-12-374367-1.00033-1},
Abstract = {This chapter defines the vulnerability of the developing
nervous system to organophosphate pesticides, in terms of
cognitive functions, social and sex-related behavioral
patterns, and body weight regulation. Impaired
neurobehavioral development of children has been
significantly linked in epidemiological studies with
exposure to pesticides. Environmental epidemiological
studies are essential for identifying toxic risks, but like
any single scientific approach they have limitations.
Determining the cause-and-effect relationship beyond
significant association is a challenge. Significant
behavioral alterations are reported after short-term,
low-dose exposure to a variety of organophosphates during
development. Because these effects were observed at doses
that do not significantly inhibit acetylcholinesterase,
other mechanisms in addition to inhibition of this important
enzyme should be considered. The aim of toxicology is to be
a predictive science, to prevent toxic damage. Animal model
studies can work in concert with epidemiological research to
resolve many of these issues. With regard to organophosphate
(OP) pesticide-induced developmental neurobehavioral
toxicity, laboratory animal model studies have clearly
demonstrated that the developing nervous system is quite
vulnerable to detrimental effects of OP pesticides, even if
exposure was short-term and at doses that did not cause much
inhibition of acetylcholinesterase. © 2010 Elsevier Inc.
All rights reserved.},
Doi = {10.1016/B978-0-12-374367-1.00033-1},
Key = {fds274191}
}
@article{fds274290,
Author = {Larrauri, JA and Levin, ED},
Title = {PPI deficit induced by amphetamine is attenuated by the
histamine H1 antagonist pyrilamine, but is exacerbated by
the serotonin 5-HT2 antagonist ketanserin.},
Journal = {Psychopharmacology (Berl)},
Volume = {212},
Number = {4},
Pages = {551-558},
Year = {2010},
Month = {December},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20811878},
Abstract = {RATIONALE: Prepulse inhibition (PPI) of the startle response
is a classic model of sensorimotor gating. Robust PPI
impairments can be induced by dopamine agonists such as the
indirect agonist amphetamine. The antipsychotic clozapine
can attenuate PPI impairment induced by dopamine agonists.
Clozapine is a complex drug with antagonistic effects on a
variety of receptors, including serotonin and histamine. The
relative contribution of its component actions to its
efficacy is still unclear. OBJECTIVES: To better
characterize the role of histamine and serotonin receptors
in the modulation of PPI in rats, we studied the effects of
the H(1) histamine antagonist pyrilamine (10, 20, and 40
mg/kg) on amphetamine-induced (1 mg/kg) PPI deficits
(Experiment 1); and the interaction of pyrilamine (20 mg/kg)
with the 5-HT(2) antagonist ketanserin (1 and 2 mg/kg) on
the amphetamine-induced PPI disruption (Experiment 2).
METHODS: Tactile startle stimuli consisted of 30 PSI
air-puffs. Three acoustic prepulse intensity levels were
used: 68, 71, and 77 dB, presented on a 65-dB background
noise. In both experiments, all animals received all drug
doses and combinations with different counterbalanced
orders. RESULTS: Pyrilamine (20 mg/kg) was effective in
counteracting the PPI impairment caused by amphetamine
administration, whereas ketanserin exacerbated the
amphetamine-induced PPI deficit. CONCLUSIONS: Based on its
ability to reverse amphetamine-induced PPI deficits,
blockade of histamine H(1) receptors seems to contribute to
the therapeutic effect of the antipsychotic clozapine.
Serotonin 5-HT(2)-receptor blockade, though, does not appear
to contribute to this effect, and may in fact detract from
it.},
Doi = {10.1007/s00213-010-2005-6},
Key = {fds274290}
}
@article{fds274291,
Author = {Aschner, M and Levin, ED and Suñol, C and Olopade, JO and Helmcke, KJ and Avila, DS and Sledge, D and Ali, RH and Upchurch, L and Donerly, S and Linney, E and Forsby, A and Ponnuru, P and Connor,
JR},
Title = {Gene-environment interactions: neurodegeneration in
non-mammals and mammals.},
Journal = {Neurotoxicology},
Volume = {31},
Number = {5},
Pages = {582-588},
Year = {2010},
Month = {September},
ISSN = {0161-813X},
url = {http://dx.doi.org/10.1016/j.neuro.2010.03.008},
Abstract = {The understanding of how environmental exposures interact
with genetics in central nervous system dysfunction has
gained great momentum in the last decade. Seminal findings
have been uncovered in both mammalian and non-mammalian
model in large result of the extraordinary conservation of
both genetic elements and differentiation processes between
mammals and non-mammalians. Emerging model organisms, such
as the nematode and zebrafish have made it possible to
assess the effects of small molecules rapidly,
inexpensively, and on a miniaturized scale. By combining the
scale and throughput of in vitro screens with the
physiological complexity and traditional animal studies,
these models are providing relevant information on molecular
events in the etiology of neurodegenerative disorders. The
utility of these models is largely driven by the functional
conservation seen between them and higher organisms,
including humans so that knowledge obtained using
non-mammalian model systems can often provide a better
understanding of equivalent processes, pathways, and
mechanisms in man. Understanding the molecular events that
trigger neurodegeneration has also greatly relied upon the
use of tissue culture models. The purpose of this summary is
to provide-state-of-the-art review of recent developments of
non-mammalian experimental models and their utility in
addressing issues pertinent to neurotoxicity (Caenorhabditis
elegans and Danio rerio). The synopses by Aschner and Levin
summarize how genetic mutants of these species can be used
to complement the understanding of molecular and cellular
mechanisms associated with neurobehavioral toxicity and
neurodegeneration. Next, studies by Suñol and Olopade
detail the predictive value of cultures in assessing
neurotoxicity. Suñol and colleagues summarize present novel
information strategies based on in vitro toxicity assays
that are predictive of cellular effects that can be
extrapolated to effects on individuals. Olopade and
colleagues describe cellular changes caused by sodium
metavanadate (SMV) and demonstrate how rat primary astrocyte
cultures can be used as predicitive tools to assess the
neuroprotective effects of antidotes on vanadium-induced
astrogliosis and demyelination.},
Doi = {10.1016/j.neuro.2010.03.008},
Key = {fds274291}
}
@article{fds274287,
Author = {Rezvani, AH and Slade, S and Wells, C and Petro, A and Lumeng, L and Li,
T-K and Xiao, Y and Brown, ML and Paige, MA and McDowell, BE and Rose, JE and Kellar, KJ and Levin, ED},
Title = {Effects of sazetidine-A, a selective alpha4beta2 nicotinic
acetylcholine receptor desensitizing agent on alcohol and
nicotine self-administration in selectively bred
alcohol-preferring (P) rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {211},
Number = {2},
Pages = {161-174},
Year = {2010},
Month = {August},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20535453},
Abstract = {RATIONALE: Manipulations of nicotinic cholinergic receptors
have been shown to influence both alcohol and nicotine
intake. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol]
is a novel compound that potently and selectively
desensitizes alpha4beta2 nicotinic receptors with only
modest receptor activation. OBJECTIVES: The goal of the
present study was to examine the effects of sazetidine-A on
alcohol and nicotine self-administration in
alcohol-preferring (P) rats. METHODS: P rats were given the
choice of water or alcohol. Once stable baselines were
established, the acute (0, 0.1, 0.3, 1, and 3 mg/kg, s.c.)
and chronic (3 mg/kg for 10 days) effects of sazetidine-A on
alcohol intake were assessed. Naltrexone (2.5 mg/kg) served
as a positive control. The effect of sazetidine-A (3 mg/kg)
and naltrexone (4 mg/kg) on saccharin (0.2%) preference was
also assessed. In addition, the acute effects of
sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on alcohol
intake after alcohol deprivation were evaluated. In another
experiment, the effects of sazetidine-A (0, 1, or 3 mg/kg)
on i.v. nicotine self-administration in P and NP rats were
assessed. RESULTS: Sazetidine-A caused a dose-dependent
reduction in alcohol intake. Chronic sazetidine-A also
effectively reduced alcohol intake until the seventh day of
treatment, when partial tolerance appeared to develop. In
the post-deprivation study, sazetidine-A significantly
reduced alcohol intake and preference. Sazetidine-A at 3
mg/kg significantly reduced nicotine self-administration in
both lines. CONCLUSIONS: Sazetidine-A significantly reduced
alcohol and nicotine intake in P rats that self-administer
higher levels of both drugs. Sazetidine-A may hold promise
for the treatment of alcohol and nicotine
addiction.},
Doi = {10.1007/s00213-010-1878-8},
Key = {fds274287}
}
@article{fds274288,
Author = {Adigun, AA and Wrench, N and Levin, ED and Seidler, FJ and Slotkin,
TA},
Title = {Neonatal parathion exposure and interactions with a high-fat
diet in adulthood: Adenylyl cyclase-mediated cell signaling
in heart, liver and cerebellum.},
Journal = {Brain Res Bull},
Volume = {81},
Number = {6},
Pages = {605-612},
Year = {2010},
Month = {April},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20074626},
Abstract = {Organophosphates are developmental neurotoxicants but recent
evidence points to additional adverse effects on metabolism
and cardiovascular function. One common mechanism is
disrupted cell signaling mediated through cyclic AMP,
targeting neurohumoral receptors, G-proteins and adenylyl
cyclase (AC) itself. Earlier, we showed that neonatal
parathion evokes later upregulation of the hepatic AC
pathway in adolescence but that the effect wanes by young
adulthood; nevertheless metabolic changes resembling
prediabetes persist. Here, we administered parathion to
neonatal rats (postnatal days 1-4, 0.1 or 0.2 mg/kg/day),
straddling the threshold for cholinesterase inhibition, but
we extended the studies to much later, 5 months of age. In
addition, we investigated whether metabolic challenge
imposed by consuming a high-fat diet for 7 weeks would
exacerbate neonatal parathion's effects. Parathion alone
increased the expression or function of G(i), thus reducing
AC responses to fluoride. Receptors controlling AC activity
were also affected: beta-adrenergic receptors (betaARs) in
skeletal muscle were increased, whereas those in the heart
were decreased, and the latter also showed an elevation of
m(2)-muscarinic acetylcholine receptors, which inhibit AC.
The high-fat diet also induced changes in AC signaling,
enhancing the hepatic AC response to glucagon while
impairing the cardiac response to fluoride or forskolin, and
suppressing betaARs and m(2)-muscarinic receptors; the only
change in the cerebellum was a decrease in betaARs. Although
there were no significant interactions between neonatal
parathion exposure and a high-fat diet, their convergent
effects on the same signaling cascade indicate that early OP
exposure, separately or combination with dietary factors,
may contribute to the worldwide increase in the incidence of
obesity and diabetes.},
Doi = {10.1016/j.brainresbull.2010.01.003},
Key = {fds274288}
}
@article{fds274286,
Author = {Levin, ED and Timofeeva, OA and Yang, L and Petro, A and Ryde, IT and Wrench, N and Seidler, FJ and Slotkin, TA},
Title = {Early postnatal parathion exposure in rats causes
sex-selective cognitive impairment and neurotransmitter
defects which emerge in aging.},
Journal = {Behav Brain Res},
Volume = {208},
Number = {2},
Pages = {319-327},
Year = {2010},
Month = {April},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20015457},
Abstract = {Developmental exposure of rats to the organophosphate (OP)
pesticides leads to altered neurobehavioral function in
juvenile and young adult stages. The current study was
conducted to determine whether effects of neonatal parathion
exposure on cognitive performance persist in older adult and
aged rats, and the relationship of behavioral changes to
underlying cholinergic and serotonergic mechanisms. We
administered parathion to rat pups on postnatal days 1-4, at
doses spanning the threshold for the initial signs of
systemic toxicity and for barely detectable cholinesterase
inhibition (0.1 or 0.2 mg/kg/day). Beginning at 14 months of
age and continuing until 19 months, the rats were trained in
the 16-arm radial maze. Controls showed the normal sex
difference in this spatial learning and memory task, with
the males committing significantly fewer working memory
errors than females. Neonatal parathion exposure eliminated
the sex difference primarily by causing impairment in males.
In association with the effects on cognitive performance,
neonatal parathion exposure elicited widespread
abnormalities in indices of serotonergic (5HT) and
cholinergic synaptic function, characterized by upregulation
of 5HT(2) receptors and the 5HT transporter, deficits in
choline acetyltransferase activity and nicotinic cholinergic
receptors, and increases in hemicholinium-3 binding to the
presynaptic choline transporter. Within-animal correlations
between behavior and neurochemistry indicated a specific
correlation between working memory performance and
hippocampal hemicholinium-3 binding; parathion exposure
eliminated this relationship. Like the behavioral effects,
males showed greater effects of parathion on neurochemical
parameters. This study demonstrates the sex-selective,
long-term behavioral alterations caused by otherwise
nontoxic neonatal exposure to parathion, with effects
increasingly expressed with aging.},
Doi = {10.1016/j.bbr.2009.11.007},
Key = {fds274286}
}
@article{fds274284,
Author = {Sanders, D and Simkiss, D and Braddy, D and Baccus, S and Morton, T and Cannady, R and Weaver, N and Rose, JE and Levin, ED},
Title = {Nicotinic receptors in the habenula: importance for
memory.},
Journal = {Neuroscience},
Volume = {166},
Number = {2},
Pages = {386-390},
Year = {2010},
Month = {March},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20034548},
Abstract = {The habenula is an epithalamic structure through which
descending connections pass from the telencephalon to the
brainstem, putting it in a key location to provide feedback
control over the brainstem monoaminergic projections
ascending to the telencephalon. Habenular nuclei lesions
have been shown to impair memory function. The habenular
nuclei have high concentrations of nicotinic receptors. In
this study we assessed the role of habenular nicotinic
receptors for working memory. Adult female Sprague-Dawley
rats were trained on a 16-arm maze to assess spatial working
and reference memory. All rats had at least 18 sessions of
training and then had bilateral chronic infusion cannulae
placed into the lateral habenula nucleus. These cannulae
were each connected to a slow delivery osmotic minipump that
chronically infused mecamylamine 100 microg/side/day (n=9)
or vehicle (aCSF) for controls (n=15) for a period of 4
weeks. Both mecamylamine-infused and control rats were
acutely injected (s.c.) with nicotine (0, 0.2 or 0.4 mg/kg)
in a repeated measures counterbalanced design twice at each
dose during the chronic local infusion period. There was a
significant (P<0.025) mecamylaminexnicotine interaction
effect on memory performance. Without nicotine injection the
chronic habenular mecamylamine infusion caused a significant
(P<0.05) increase in total memory errors. The 0.4 mg/kg
nicotine dose significantly (P<0.005) reversed the
mecamylamine-induced memory impairment, returning
performance back to levels seen in rats with control aCSF
habenular infusions. The current study determined that
nicotinic receptors in the lateral habenular nucleus are
important for spatial memory function. Descending
projections from the telencephalon through the habenula to
brainstem nuclei using nicotinic receptors appear to be a
key pathway for memory processing.},
Doi = {10.1016/j.neuroscience.2009.12.035},
Key = {fds274284}
}
@article{fds274282,
Author = {Levin, ED and Rezvani, AH and Xiao, Y and Slade, S and Cauley, M and Wells,
C and Hampton, D and Petro, A and Rose, JE and Brown, ML and Paige, MA and McDowell, BE and Kellar, KJ},
Title = {Sazetidine-A, a selective alpha4beta2 nicotinic receptor
desensitizing agent and partial agonist, reduces nicotine
self-administration in rats.},
Journal = {J Pharmacol Exp Ther},
Volume = {332},
Number = {3},
Pages = {933-939},
Year = {2010},
Month = {March},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20007754},
Abstract = {Adequate treatment of tobacco addiction remains problematic.
Part of the problem with treatment is a poor understanding
of the pharmacologic aspects of nicotine contributing to
addiction. In addition to activating nicotinic acetylcholine
receptors, nicotine also desensitizes them. It is currently
not known how much of each of nicotine's actions contribute
to its particular behavioral effects. Sazetidine-A (saz-A)
is a novel nicotinic receptor-desensitizing agent and
partial agonist with high selectivity for alpha4beta2
receptors. The current experiments were conducted to
determine whether saz-A would reduce nicotine
self-administration in rats and to characterize its
ancillary effects. Adult male Sprague-Dawley rats were
allowed to self-administer nicotine. After initial food
pellet training followed by 10 sessions of nicotine
self-administration training, the rats were administered
saz-A (0.1-3 mg/kg s.c.) or the saline vehicle in a
repeated-measures counterbalanced design. Saz-A at the 3
mg/kg dose significantly decreased nicotine
self-administration relative to performance of the same rats
after saline injections. In a second study, long-term
administration of this dose of sazetidine-A over the course
of 10 sessions significantly reduced nicotine
self-administration with no apparent diminution of effect.
Saz-A in this dose range had only modest effects on
locomotor activity, without any overall decrease in activity
over a 1-h-long session. Saz-A significantly reduced food
self-administration, but this effect was smaller than its
effect on nicotine self-administration. Saz-A, which is a
selective alpha4beta2-desensitizing agent and partial
agonist, effectively reduces nicotine self-administration.
This type of treatment holds promise for a new therapy to
aid smoking cessation.},
Doi = {10.1124/jpet.109.162073},
Key = {fds274282}
}
@article{fds274283,
Author = {Lassiter, TL and Ryde, IT and Levin, ED and Seidler, FJ and Slotkin,
TA},
Title = {Neonatal exposure to parathion alters lipid metabolism in
adulthood: Interactions with dietary fat intake and
implications for neurodevelopmental deficits.},
Journal = {Brain Res Bull},
Volume = {81},
Number = {1},
Pages = {85-91},
Year = {2010},
Month = {January},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19615431},
Abstract = {Organophosphates are developmental neurotoxicants but recent
evidence also points to metabolic dysfunction. We determined
whether neonatal parathion exposure in rats has long-term
effects on regulation of adipokines and lipid peroxidation.
We also assessed the interaction of these effects with
increased fat intake. Rats were given parathion on postnatal
days 1-4 using doses (0.1 or 0.2mg/kg/day) that straddle the
threshold for barely detectable cholinesterase inhibition
and the first signs of systemic toxicity. In adulthood,
animals were either maintained on standard chow or switched
to a high-fat diet for 7 weeks. We assessed serum leptin and
adiponectin, tumor necrosis factor-alpha (TNFalpha) in
adipose tissues, and thiobarbituric acid reactive species
(TBARS) in peripheral tissues and brain regions. Neonatal
parathion exposure uncoupled serum leptin levels from their
dependence on body weight, suppressed adiponectin and
elevated TNFalpha in white adipose tissue. Some of the
effects were offset by a high-fat diet. Parathion reduced
TBARS in the adipose tissues, skeletal muscle and
temporal/occipital cortex but not in heart, liver, kidney or
frontal/parietal cortex; it elevated TBARS in the
cerebellum; the high-fat diet again reversed many of the
effects. Neonatal parathion exposure disrupts the regulation
of adipokines that communicate metabolic status between
adipose tissues and the brain, while also evoking an
inflammatory adipose response. Our results are consistent
with impaired fat utilization and prediabetes, as well as
exposing a potential relationship between effects on fat
metabolism and on synaptic function in the
brain.},
Doi = {10.1016/j.brainresbull.2009.07.002},
Key = {fds274283}
}
@article{fds274281,
Author = {Timofeeva, OA and Eddins, D and Yakel, JL and Blackshear, PJ and Levin,
ED},
Title = {Hippocampal infusions of MARCKS peptides impair memory of
rats on the radial-arm maze.},
Journal = {Brain Res},
Volume = {1308},
Pages = {147-152},
Year = {2010},
Month = {January},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19854162},
Abstract = {In vitro hippocampal studies by Gay et al. (2008)
demonstrated that a myristoylated alanine-rich C kinase
substrate (MARCKS) peptide comprising the phosphorylation
site or effector domain of the protein acts as a powerful
inhibitor of alpha7 nicotinic acetylcholine receptors
(nAChRs), which are known to be critically involved in
memory function. However, behavioral consequences of
hippocampal MARCKS peptide infusions have not been
investigated. The purpose of the current study was to
determine if local infusions in the rat ventral hippocampus
of long (comprising amino acids 151-175) and short (amino
acids 159-165) forms of MARCKS peptides could affect memory
performance in the 16-arm radial maze. Our results
demonstrated a dramatic impairment of both working
(changing) and reference (constant) memory with
MARCKS(151-175) only. The shorter MARCKS peptide did not
affect memory performance. This is in line with in vitro
results reported by Gay et al. (2008) that long, but not
short, MARCKS peptides inhibit alpha7 nAChRs. We also found
that the effect of the MARCKS(151-175) peptide was
dose-dependent, with a robust memory impairment at 10
microg/side, and smaller inconsistent effects at lower
doses. Our present behavioral study, together with the
earlier in vitro study by Gay et al. (2008), suggests that
effector domain MARCKS peptides could play a significant
role in memory regulation and impairment.},
Doi = {10.1016/j.brainres.2009.10.040},
Key = {fds274281}
}
@article{fds274279,
Author = {Eddins, D and Cerutti, D and Williams, P and Linney, E and Levin,
ED},
Title = {Zebrafish provide a sensitive model of persisting
neurobehavioral effects of developmental chlorpyrifos
exposure: comparison with nicotine and pilocarpine effects
and relationship to dopamine deficits.},
Journal = {Neurotoxicol Teratol},
Volume = {32},
Number = {1},
Pages = {99-108},
Year = {2010},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19268529},
Abstract = {Chlorpyrifos (CPF) an organophosphate pesticide causes
persisting behavioral dysfunction in rat models when
exposure is during early development. In earlier work
zebrafish were used as a complementary model to study
mechanisms of CPF-induced neurotoxicity induced during early
development. We found that developmental (first five days
after fertilization) chlorpyrifos exposure significantly
impaired learning in zebrafish. However, this testing was
time and labor intensive. In the current study we tested the
hypothesis that persisting effects of developmental
chlorpyrifos could be detected with a brief automated
assessment of startle response and that this behavioral
index could be used to help determine the neurobehavioral
mechanisms for persisting CPF effects. The swimming activity
of adult zebrafish was assessed by a computerized
video-tracking device after a sudden tap to the test arena.
Ten consecutive trials (1/min) were run to determine startle
response and its habituation. Additionally, habituation
recovery trials were run at 8, 32 and 128 min after the end
of the initial trial set. CPF-exposed fish showed a
significantly (p<0.025) greater overall startle response
during the 10-trial session compared to controls (group
sizes: Control N=40, CPF N=24). During the initial recovery
period (8 min) CPF-exposed fish showed a significantly
(p<0.01) greater startle response compared to controls. To
elucidate the contributions of nicotinic and muscarinic
acetylcholine receptors to developmental CPF-mediated
effects, the effects of developmental nicotine and
pilocarpine exposure throughout the first five days after
fertilization were determined. Developmental nicotine and
pilocarpine exposure significantly increased startle
response, though nicotine (group sizes: Control N=32, 15 mM
N=12, 25 mM N=20) was much more potent than pilocarpine
(group sizes: Control N=20, 100 microM N=16, 1000 microM
N=12). Neither was as potent as CPF for developmental
exposure increasing startle response in adulthood. Lastly,
developmental CPF exposure decreased dopamine and serotonin
levels and increased transmitter turnover in developing
zebrafish larvae (N=4 batches of 50 embryos/treatment). Only
the decline in dopamine concentrations persisted into
adulthood (group sizes: Control N=14, CPF N=13). This study
shows that a quick automated test of startle can detect
persisting neurobehavioral impairments caused by
developmental exposure to CPF. This may be helpful in
screening for persisting neurobehavioral defects from a
variety of toxicants.},
Doi = {10.1016/j.ntt.2009.02.005},
Key = {fds274279}
}
@article{fds274280,
Author = {Aschner, M and Crofton, KM and Levin, ED},
Title = {Introduction to the special issue on emerging high
throughput and complementary model screens for
neurotoxicology.},
Journal = {Neurotoxicol Teratol},
Volume = {32},
Number = {1},
Pages = {1-3},
Year = {2010},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2009.08.006},
Doi = {10.1016/j.ntt.2009.08.006},
Key = {fds274280}
}
@article{fds274285,
Author = {Rezvani, AH and Sexton, H and Levin, ED},
Title = {Persistent high alcohol consumption in alcohol-preferring
(P) rats results from a lack of normal aversion to
alcohol.},
Journal = {Alcohol Alcohol},
Volume = {45},
Number = {3},
Pages = {219-222},
Year = {2010},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20356869},
Abstract = {AIMS: In this study, we tested the impact of pretreatment
with alcohol on subsequent alcohol drinking in outbred
Sprague-Dawley and selectively bred alcohol-preferring (P)
rats. METHODS: As a pretreatment, male Sprague-Dawley and P
rats were given a passive oral administration of either
alcohol (1.0 g/kg) or tap water. Then, they were given free
choice of drinking alcohol (5% v/v) or water in their home
cages, which was measured over 4 weeks. RESULTS: Without
alcohol pretreatment, there was no significant strain
difference in alcohol preference; both strains preferred 5%
(v/v) alcohol solution. The strain difference was only
apparent in the groups given alcohol pretreatment. This
arose from the fact that alcohol pretreatment significantly
reduced alcohol preference in the Sprague-Dawley rats to a
level well below 50%, while it did not alter drinking
behavior in P rats. The same effects were seen with total
alcohol consumption (g/kg/day). These effects persisted
throughout the 4 weeks of the study. CONCLUSIONS: The
principal difference between the Sprague-Dawley and P rats
was that the P rats did not show the normal aversion to
alcohol after forced exposure to alcohol that the
Sprague-Dawley rats showed. One of the potential
contributors to high alcohol intake and preference in P rats
may be lack of sensitivity to aversive effects of
alcohol.},
Doi = {10.1093/alcalc/agq020},
Key = {fds274285}
}
@article{fds274276,
Author = {Bencan, Z and Sledge, D and Levin, ED},
Title = {Buspirone, chlordiazepoxide and diazepam effects in a
zebrafish model of anxiety.},
Journal = {Pharmacol Biochem Behav},
Volume = {94},
Number = {1},
Pages = {75-80},
Year = {2009},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19643124},
Abstract = {Zebrafish are becoming more widely used to study
neurobehavioral pharmacology. We have developed a method to
assess novel environment diving behavior of zebrafish as a
model of stress response and anxiolytic drug effects. In a
novel tank, zebrafish dwell in the bottom of the tank
initially and then increase their swimming exploration to
higher levels over time. We previously found that nicotine,
which has anxiolytic effects in rodents and humans,
significantly lessens the novel tank diving response in
zebrafish. The specificity of the diving effect was
validated with a novel vs. non-novel test tank. The novel
tank diving response of zebrafish was tested when given
three anxiolytic drugs from two different chemical and
pharmacological classes: buspirone, chlordiazepoxide and
diazepam. When the test tank was novel the diving response
was clearly seen whereas it was significantly reduced when
the test tank was not novel. Buspirone, a serotonergic
(5HT(1A) receptor agonist) anxiolytic drug with some D(2)
dopaminergic effect, had a pronounced anxiolytic-like effect
in the zebrafish diving model at doses that did not have
sedative effects. In contrast, chlordiazepoxide, a
benzodiazepine anxiolytic drug, which is an effective
agonist at GABA-A receptors, did not produce signs of
anxiolysis in zebrafish over a broad dose range up to those
that caused sedation. Diazepam another benzodiazepine
anxiolytic drug did produce an anxiolytic effect at doses
that did not cause sedation. The zebrafish novel tank diving
task can be useful in discriminating anxiolytic drugs of
several classes (serotonergic, benzodiazepines and
nicotinic).},
Doi = {10.1016/j.pbb.2009.07.009},
Key = {fds274276}
}
@article{fds274277,
Author = {Cannady, R and Weir, R and Wee, B and Gotschlich, E and Kolia, N and Lau,
E and Brotherton, J and Levin, ED},
Title = {Nicotinic antagonist effects in the mediodorsal thalamic
nucleus: regional heterogeneity of nicotinic receptor
involvement in cognitive function.},
Journal = {Biochem Pharmacol},
Volume = {78},
Number = {7},
Pages = {788-794},
Year = {2009},
Month = {October},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19477167},
Abstract = {Nicotine has been found in many studies to improve cognitive
function. However, some studies have not found this effect
and others have seen nicotine-induced impairments. Systemic
administration bathes the brain with drugs. However, the
brain is quite intricately organized with various regions
playing very different roles in the bases of cognitive
function. We have examined the role of nicotinic receptors
in a variety of brain areas for memory. In the hippocampus
and amygdala, local infusions of both alpha7 and alpha4beta2
antagonists methyllyaconitine (MLA) and dihydro-beta-erythroidine
(DHbetaE) significantly impair memory. In the current
studies we locally infused acute and chronic doses of MLA
and DHbetaE into the mediodorsal thalamic nucleus and tested
memory function on a 16-arm radial maze. The rats also
received systemic nicotine to determine the impact of more
generalized nicotine effects. Since nicotinic treatments are
being developed for cognitive impairment of schizophrenia,
interactions were studied with the antipsychotic drug
clozapine. In the acute study, the 6.75 microg/side of
DHbetaE improved working memory. Co-administration of MLA
reversed the DHbetaE-induced improvement. Chronic DHbetaE
infusions into the mediodorsal thalamic nucleus also
improved working memory. Systemic nicotine reversed this
effect. Clozapine had no significant interaction. Nicotinic
alpha4beta2 receptors in the mediodorsal thalamic nucleus
appear to play an opposite role with regard to working
memory than those in the hippocampus and amygdala.
Heterogeneity in response to nicotinic drugs given
systemically may be due to anatomically distinct nicotinic
systems in the brain and their unique roles in the neural
bases of cognitive function.},
Doi = {10.1016/j.bcp.2009.05.021},
Key = {fds274277}
}
@article{fds274322,
Author = {Schramm-Sapyta, NL and Walker, QD and Caster, JM and Levin, ED and Kuhn,
CM},
Title = {Are adolescents more vulnerable to drug addiction than
adults? Evidence from animal models.},
Journal = {Psychopharmacology (Berl)},
Volume = {206},
Number = {1},
Pages = {1-21},
Year = {2009},
Month = {September},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19547960},
Abstract = {BACKGROUND AND RATIONALE: Epidemiological evidence suggests
that people who begin experimenting with drugs of abuse
during early adolescence are more likely to develop
substance use disorders (SUDs), but this correlation does
not guarantee causation. Animal models, in which age of
onset can be tightly controlled, offer a platform for
testing causality. Many animal models address drug effects
that might promote or discourage drug intake and
drug-induced neuroplasticity. METHODS: We have reviewed the
preclinical literature to investigate whether adolescent
rodents are differentially sensitive to rewarding,
reinforcing, aversive, locomotor, and withdrawal-induced
effects of drugs of abuse. RESULTS AND CONCLUSIONS: The
rodent model literature consistently suggests that the
balance of rewarding and aversive effects of drugs of abuse
is tipped toward reward in adolescence. However, increased
reward does not consistently lead to increased voluntary
intake: age effects on voluntary intake are drug and method
specific. On the other hand, adolescents are consistently
less sensitive to withdrawal effects, which could protect
against compulsive drug seeking. Studies examining neuronal
function have revealed several age-related effects but have
yet to link these effects to vulnerability to SUDs. Taken
together, the findings suggest factors which may promote
recreational drug use in adolescents, but evidence relating
to pathological drug-seeking behavior is lacking. A call is
made for future studies to address this gap using behavioral
models of pathological drug seeking and for neurobiologic
studies to more directly link age effects to SUD
vulnerability.},
Doi = {10.1007/s00213-009-1585-5},
Key = {fds274322}
}
@article{fds274325,
Author = {Levin, ED and Aschner, M and Heberlein, U and Ruden, D and Welsh-Bohmer,
KA and Bartlett, S and Berger, K and Chen, L and Corl, AB and Eddins, D and French, R and Hayden, KM and Helmcke, K and Hirsch, HVB and Linney, E and Lnenicka, G and Page, GP and Possidente, D and Possidente, B and Kirshner, A},
Title = {Genetic aspects of behavioral neurotoxicology.},
Journal = {Neurotoxicology},
Volume = {30},
Number = {5},
Pages = {741-753},
Year = {2009},
Month = {September},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19647018},
Abstract = {Considerable progress has been made over the past couple of
decades concerning the molecular bases of neurobehavioral
function and dysfunction. The field of neurobehavioral
genetics is becoming mature. Genetic factors contributing to
neurologic diseases such as Alzheimer's disease have been
found and evidence for genetic factors contributing to other
diseases such as schizophrenia and autism are likely. This
genetic approach can also benefit the field of behavioral
neurotoxicology. It is clear that there is substantial
heterogeneity of response with behavioral impairments
resulting from neurotoxicants. Many factors contribute to
differential sensitivity, but it is likely that genetic
variability plays a prominent role. Important discoveries
concerning genetics and behavioral neurotoxicity are being
made on a broad front from work with invertebrate and
piscine mutant models to classic mouse knockout models and
human epidemiologic studies of polymorphisms. Discovering
genetic factors of susceptibility to neurobehavioral
toxicity not only helps identify those at special risk, it
also advances our understanding of the mechanisms by which
toxicants impair neurobehavioral function in the larger
population. This symposium organized by Edward Levin and
Annette Kirshner, brought together researchers from the
laboratories of Michael Aschner, Douglas Ruden, Ulrike
Heberlein, Edward Levin and Kathleen Welsh-Bohmer conducting
studies with Caenorhabditis elegans, Drosophila, fish,
rodents and humans studies to determine the role of genetic
factors in susceptibility to behavioral impairment from
neurotoxic exposure.},
Doi = {10.1016/j.neuro.2009.07.014},
Key = {fds274325}
}
@article{fds274274,
Author = {Noyes, PD and McElwee, MK and Miller, HD and Clark, BW and Van Tiem and LA and Walcott, KC and Erwin, KN and Levin, ED},
Title = {The toxicology of climate change: environmental contaminants
in a warming world.},
Journal = {Environ Int},
Volume = {35},
Number = {6},
Pages = {971-986},
Year = {2009},
Month = {August},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19375165},
Abstract = {Climate change induced by anthropogenic warming of the
earth's atmosphere is a daunting problem. This review
examines one of the consequences of climate change that has
only recently attracted attention: namely, the effects of
climate change on the environmental distribution and
toxicity of chemical pollutants. A review was undertaken of
the scientific literature (original research articles,
reviews, government and intergovernmental reports) focusing
on the interactions of toxicants with the environmental
parameters, temperature, precipitation, and salinity, as
altered by climate change. Three broad classes of chemical
toxicants of global significance were the focus: air
pollutants, persistent organic pollutants (POPs), including
some organochlorine pesticides, and other classes of
pesticides. Generally, increases in temperature will enhance
the toxicity of contaminants and increase concentrations of
tropospheric ozone regionally, but will also likely increase
rates of chemical degradation. While further research is
needed, climate change coupled with air pollutant exposures
may have potentially serious adverse consequences for human
health in urban and polluted regions. Climate change
producing alterations in: food webs, lipid dynamics, ice and
snow melt, and organic carbon cycling could result in
increased POP levels in water, soil, and biota. There is
also compelling evidence that increasing temperatures could
be deleterious to pollutant-exposed wildlife. For example,
elevated water temperatures may alter the biotransformation
of contaminants to more bioactive metabolites and impair
homeostasis. The complex interactions between climate change
and pollutants may be particularly problematic for species
living at the edge of their physiological tolerance range
where acclimation capacity may be limited. In addition to
temperature increases, regional precipitation patterns are
projected to be altered with climate change. Regions subject
to decreases in precipitation may experience enhanced
volatilization of POPs and pesticides to the atmosphere.
Reduced precipitation will also increase air pollution in
urbanized regions resulting in negative health effects,
which may be exacerbated by temperature increases. Regions
subject to increased precipitation will have lower levels of
air pollution, but will likely experience enhanced surface
deposition of airborne POPs and increased run-off of
pesticides. Moreover, increases in the intensity and
frequency of storm events linked to climate change could
lead to more severe episodes of chemical contamination of
water bodies and surrounding watersheds. Changes in salinity
may affect aquatic organisms as an independent stressor as
well as by altering the bioavailability and in some
instances increasing the toxicity of chemicals. A paramount
issue will be to identify species and populations especially
vulnerable to climate-pollutant interactions, in the context
of the many other physical, chemical, and biological
stressors that will be altered with climate change.
Moreover, it will be important to predict tipping points
that might trigger or accelerate synergistic interactions
between climate change and contaminant exposures.},
Doi = {10.1016/j.envint.2009.02.006},
Key = {fds274274}
}
@article{fds274275,
Author = {Rezvani, AH and Overstreet, DH and Vaidya, AH and Zhao, B and Levin,
ED},
Title = {Carisbamate, a novel antiepileptic candidate compound,
attenuates alcohol intake in alcohol-preferring
rats.},
Journal = {Alcohol Clin Exp Res},
Volume = {33},
Number = {8},
Pages = {1366-1373},
Year = {2009},
Month = {August},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19413647},
Abstract = {BACKGROUND: Since 1994, when naltrexone (Revia) was approved
by the FDA for the treatment of alcoholism, only 2 other
drugs (Campral and Topamax have been approved for alcoholism
treatment. However, various experimental drugs, including
antiepileptic medications, have been tested in both animal
models and in humans with some promising results. The
purpose of this project was to study the effect of the novel
neuromodulator carisbamate, which is in development for
epilepsy treatment, on alcohol intake in selectively bred
alcohol-preferring rats. METHODS: Male alcohol-preferring
inbred P rats were allowed to freely drink water or alcohol
(10%, v/v) using a 2-bottle choice procedure. After stable
baselines for alcohol and water intakes were established,
the acute effects of oral carisbamate (0, 10, 30, 45, 60,
and 90 mg/kg) were assessed. Then, the chronic effect of the
compound (60 mg/kg/day for 14 consecutive days) on alcohol
intake was assessed in a separate group of male P rats. In
another set of experiments, the effects of carisbamate and
naltrexone on alcohol withdrawal-induced elevated drinking
of alcohol, an index of craving, were compared. Rats were
withdrawn from alcohol for 24 hours and were given vehicle,
20 mg/kg naltrexone or 60 mg/kg carisbamate 30 minutes
before re-exposure to alcohol. Alcohol and water intake was
measured 6 hours after alcohol re-exposure. To determine the
effects of carisbamate on saccharin preference, rats were
put on a 2-bottle choice of water versus a solution of 2%
saccharin. Then, the effect of the highest dose of
carisbamate (90 mg/kg) and naltrexone (20 mg/kg) and the
vehicle on saccharin preference was determined. RESULTS: Our
results showed that there was a selective dose-dependent
reduction in alcohol intake and preference in the
alcohol-preferring P rat after an acute oral administration
of carisbamate. There were no significant effects on food or
water intake. Chronic administration of carisbamate
significantly reduced alcohol intake and preference
initially, but partial tolerance developed after the 10th
treatment. The degree of tolerance development was less than
that observed for naltrexone. Acute administration of
carisbamate was more effective than naltrexone in reducing
enhanced alcohol intake after a period of alcohol
deprivation. Compared with control vehicle neither
carisbamate nor naltrexone had a significant effect on
saccharin intake and preference. CONCLUSION: The novel
neuromodulator compound carisbamate has a favorable profile
of effects on alcohol intake and related measures and should
be considered for testing on human alcoholics.},
Doi = {10.1111/j.1530-0277.2009.00966.x},
Key = {fds274275}
}
@article{fds274268,
Author = {Slotkin, TA and Lassiter, TL and Ryde, IT and Wrench, N and Levin, ED and Seidler, FJ},
Title = {Consumption of a high-fat diet in adulthood ameliorates the
effects of neonatal parathion exposure on acetylcholine
systems in rat brain regions.},
Journal = {Environ Health Perspect},
Volume = {117},
Number = {6},
Pages = {916-922},
Year = {2009},
Month = {June},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19590683},
Abstract = {BACKGROUND: Developmental exposure to a wide variety of
developmental neurotoxicants, including organophosphate
pesticides, evokes late-emerging and persistent
abnormalities in acetylcholine (ACh) systems. We are seeking
interventions that can ameliorate or reverse the effects
later in life. OBJECTIVES: We administered parathion to
neonatal rats and then evaluated whether a high-fat diet
begun in adulthood could reverse the effects on ACh systems.
METHODS: Neonatal rats received parathion on postnatal days
1-4 at 0.1 or 0.2 mg/kg/day, straddling the cholinesterase
inhibition threshold. In adulthood, half the animals were
switched to a high-fat diet for 8 weeks. We assessed three
indices of ACh synaptic function: nicotinic ACh receptor
binding, choline acetyltransferase activity, and
hemicholinium-3 binding. Determinations were performed in
brain regions comprising all the major ACh projections and
cell bodies. RESULTS: Neonatal parathion exposure evoked
widespread abnormalities in ACh synaptic markers,
encompassing effects in brain regions possessing ACh
projections and ACh cell bodies. In general, males were
affected more than females. Of 17 regional ACh marker
abnormalities (10 male, 7 female), 15 were reversed by the
high-fat diet. CONCLUSIONS: A high-fat diet reverses
neurodevelopmental effects of neonatal parathion exposure on
ACh systems. This points to the potential for
nonpharmacologic interventions to offset the effects of
developmental neurotoxicants. Further, cryptic
neurodevelopmental deficits evoked by environmental
exposures may thus engender a later preference for a
high-fat diet to maintain normal ACh function, ultimately
contributing to obesity.},
Doi = {10.1289/ehp.0800459},
Key = {fds274268}
}
@article{fds274324,
Author = {Eddins, D and Klein, RC and Yakel, JL and Levin, ED},
Title = {Hippocampal infusions of apolipoprotein E peptides induce
long-lasting cognitive impairment.},
Journal = {Brain Res Bull},
Volume = {79},
Number = {2},
Pages = {111-115},
Year = {2009},
Month = {April},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19185602},
Abstract = {The inheritance of the varepsilon4 allele of apolipoprotein
E (ApoE4) and cholinergic system dysfunction have long been
associated with the pathology of Alzheimer's disease (AD).
Recently, in vitro studies have established a direct link
between ApoE and cholinergic function in that synthetic
peptides containing segments of the ApoE protein
(ApoE(133-149) and ApoE(141-148)) interact with alpha7
nicotinic acetylcholine receptors (nAChRs) in the
hippocampus. This raises the possibility that ApoE peptides
may contribute to cognitive impairment in AD in that the
hippocampus plays a key role in cognitive functioning. To
test this, we acutely infused ApoE peptides into the ventral
hippocampus of female Sprague-Dawley rats and assessed the
resultant effects on radial-arm maze choice accuracy over a
period of weeks after the infusion. Local ventral
hippocampal infusion of ApoE peptides caused significant
cognitive impairment in radial-arm maze learning that
persisted several weeks after the acute infusion. This
persisting deficit may be an important model for
understanding the relationship between ApoE protein-induced
neurotoxicity and cognitive impairment as well as serve as a
platform for the development of new therapies to avoid
neurotoxicity and cognitive decline.},
Doi = {10.1016/j.brainresbull.2009.01.003},
Key = {fds274324}
}
@article{fds274272,
Author = {Rezvani, AH and Kholdebarin, E and Brucato, FH and Callahan, PM and Lowe, DA and Levin, ED},
Title = {Effect of R3487/MEM3454, a novel nicotinic alpha7 receptor
partial agonist and 5-HT3 antagonist on sustained attention
in rats.},
Journal = {Prog Neuropsychopharmacol Biol Psychiatry},
Volume = {33},
Number = {2},
Pages = {269-275},
Year = {2009},
Month = {March},
ISSN = {0278-5846},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19110025},
Abstract = {It is well established that nicotinic systems in the brain
are critically involved in attentional processes in both
animals and humans. The current study assessed the effects
of a novel nicotinic alpha7 receptor partial agonist and
5-HT3 antagonist, R3487/MEM3454 (also referred to as R3487
or MEM 3454) on sustained attention in rats performing an
operant visual signal detection task. The effects of
R3487/MEM3454 were compared to those of the
acetylcholinesterase inhibitor/nicotinic alpha7 allosteric
positive modulator galanthamine. Adult female Sprague-Dawley
rats were injected subcutaneously with R3487/MEM3454 (0.03,
0.1, 0.15, 0.3 and 0.6 mg/kg), galanthamine (0.25, 0.5, 1, 2
mg/kg) or vehicle 30 min before the attentional test. In the
second study, the time-dependent effects of R3487/MEM3454
were assessed by injecting the compound (0.6 mg/kg, s.c.) at
different pretreatment intervals (30, 60 or 90 min) before
the start of the attentional task. Our results show a
significant dose-effect for R3487/MEM3454 on percent hit
accuracy performance without any significant alteration on
percent correct rejection performance. In the time-dependent
test, R3487/MEM3454 significantly increased the percent hit
accuracy performance when animals were injected 60 min
before the start of the attentional task. Administration of
galanthamine failed to significantly increase percent hit
accuracy performance and increasing the dose of galanthamine
produced a decrease in percent correct rejection
performance. The present findings with R3487/MEM3454 suggest
that nicotinic alpha7 receptors and/or 5-HT3 receptors may
play an important role in modulating sustained attention and
that R3487/MEM3454 may have therapeutic potential in
improving sustained attention in humans.},
Doi = {10.1016/j.pnpbp.2008.11.018},
Key = {fds274272}
}
@article{fds274273,
Author = {Levin, ED and Perkins, A and Brotherton, T and Qazi, M and Berez, C and Montalvo-Ortiz, J and Davis, K and Williams, P and Christopher,
NC},
Title = {Chronic underactivity of medial frontal cortical
beta2-containing nicotinic receptors increases
clozapine-induced working memory impairment in female
rats.},
Journal = {Prog Neuropsychopharmacol Biol Psychiatry},
Volume = {33},
Number = {2},
Pages = {296-302},
Year = {2009},
Month = {March},
ISSN = {0278-5846},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19146909},
Abstract = {Nicotinic receptor decreases in the frontal cortex and
hippocampus are important mediators of cognitive impairment
in both schizophrenia and Alzheimer's disease. Drug
treatments for these diseases should take into account the
impacts of compromised brain function on drug response. This
study investigated the impact of compromised nicotinic
receptor activity in the frontal cortex in rats on memory
function. Since both Alzheimer's disease and schizophrenia
can involve psychosis, antipsychotic drugs are often given.
The impacts of antipsychotic drugs on cognitive function
have been found to be quite variable. It is the hypothesis
of this and previous studies that the cognitive effects of
antispychotic drugs on cognitive function depend on the
integrity of brain systems involved in cognition. Previously
in studies of the hippocampus, we found that chronic
inhibition of beta2-containing nicotinic receptors with
dihydro-beta-erythrodine (DHbetaE) impaired working memory
and that this effect was attenuated by the antipsychotic
drug clozapine. In contrast, chronic hippocampal alpha7
nicotinic receptor blockade with methyllycaconitine (MLA)
potentiated the clozapine-induced memory impairment which is
seen in rats without compromised nicotinic receptor
activity. The current study determined medial frontal
cortical alpha7 and beta2-containing nicotinic receptor
involvement in memory and the interactions with
antipsychotic drug therapy with clozapine. Chronic DHbetaE
and MLA infusion effects and interactions with systemic
clozapine were assessed in female rats tested for memory on
the radial-arm maze. Antipsychotic drug interactions with
chronic systemic nicotine were investigated because
nicotinic procognitive treatment has been proposed. The same
local infusion DHbetaE dose that impaired memory with
hippocampal infusion did not impair memory when infused in
the medial frontal cortex. Frontal DHbetaE infusion
potentiated clozapine-induced memory impairment, whereas
previously the memory impairment caused by hippocampal
DHbetaE infusion was attenuated by clozapine. Frontal
cortical MLA infusions at a dose that previously was found
to potentiate the clozapine-induced memory impairment with
hippocampal infusion had no significant effect when infused
into the medial frontal cortex. The location and subtype of
nicotinic receptor underactivity are critical determinates
for clozapine effects on memory. Patients with hippocampal
beta2-containing nicotinic receptor loss may be well treated
with clozapine therapy, while those with frontal cortical
beta2-containing receptor loss may have a potentiated memory
impairment caused by clozapine.},
Doi = {10.1016/j.pnpbp.2008.12.003},
Key = {fds274273}
}
@article{fds274271,
Author = {Rezvani, AH and Kholdebarin, E and Cauley, MC and Dawson, E and Levin,
ED},
Title = {Attenuation of pharmacologically-induced attentional
impairment by methylphenidate in rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {92},
Number = {1},
Pages = {141-146},
Year = {2009},
Month = {March},
ISSN = {0091-3057},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19041337},
Abstract = {Methylphenidate is widely used as a treatment option for
attention deficit hyperactivity disorder. In animal models
of attentional impairment, it is an important validation to
determine whether this clinically effective treatment
attenuates deficits. The purpose of the current study was to
determine whether methylphenidate can diminish attentional
impairment induced by three pharmacological agents with
different mechanisms of action: scopolamine, mecamylamine,
and dizocilpine. Female rats were trained on an operant
visual signal detection task. Ten min before the test, the
rats were injected subcutaneously with methylphenidate (0,
0.1, 0.3 mg/kg), scopolamine (0, 0.005, 0.01 mg/kg),
mecamylamine (0, 2, 4 mg/kg), dizocilpine (0, 0.025, 0.05
mg/kg) or combinations of methylphenidate with these drugs.
In each of the experiments, all rats received every
treatment in a repeated measures counterbalanced order.
Correction rejection accuracy was impaired by all three of
the antagonists and these effects were attenuated by
methylphenidate. Both scopolamine at 0.01 and dizocilpine at
0.05 mg/kg significantly impaired percent correct rejection
choice accuracy, an effect that was ameliorated by
methylphenidate. Mecamylamine (4 mg/kg) impaired attentional
performance by reducing percent hit and percent correct
rejection. Co-administration of methylphenidate failed to
significantly affect the mecamylamine-induced attentional
impairment. Methylphenidate alone at 0.3 mg/kg significantly
improved percent hit choice accuracy only in low-performing
rats in one experiment, an effect which was reversed by
scopolamine. These data show that methylphenidate
effectively reverses the attentional impairment caused by
scopolamine and dizocilpine. These findings further validate
the operant visual signal detection task for assessing
attentional impairments and their reversal.},
Doi = {10.1016/j.pbb.2008.11.005},
Key = {fds274271}
}
@article{fds274269,
Author = {Schmajuk, NA and Larrauri, JA and De la Casa and LG and Levin,
ED},
Title = {Attenuation of auditory startle and prepulse inhibition by
unexpected changes in ambient illumination through
dopaminergic mechanisms.},
Journal = {Behav Brain Res},
Volume = {197},
Number = {2},
Pages = {251-261},
Year = {2009},
Month = {February},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18801390},
Abstract = {We investigated the role of dopaminergic mechanisms in the
attenuation of the acoustic startle response and prepulse
inhibition (PPI) in rats by the introduction of unexpected
changes in environment illumination. Experiment 1 showed
that Dark-to-Light transitions robustly reduce startle
responses and PPI. Experiment 2 showed that this phenomenon
habituates across repeated testing sessions and reappears
after an interval without testing. Experiment 3 demonstrated
that haloperidol blocks the startle and PPI-reducing effect
of the Dark-to-Light transition. We show how a computational
model of acoustic startle response and prepulse inhibition
can be extended to incorporate the empirical effects
demonstrated in this study. We conclude that sensory gating
as measured by prepulse inhibition is markedly attenuated in
situations where novel stimuli are introduced during a test
session and that dopaminergic systems may be involved in the
dynamic changes evoked by the onset of illumination.},
Doi = {10.1016/j.bbr.2008.08.030},
Key = {fds274269}
}
@article{fds274270,
Author = {Levin, ED and Petro, A and Rezvani, AH and Pollard, N and Christopher,
NC and Strauss, M and Avery, J and Nicholson, J and Rose,
JE},
Title = {Nicotinic alpha7- or beta2-containing receptor knockout:
effects on radial-arm maze learning and long-term nicotine
consumption in mice.},
Journal = {Behav Brain Res},
Volume = {196},
Number = {2},
Pages = {207-213},
Year = {2009},
Month = {January},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18831991},
Abstract = {Classically, it has been thought that high-affinity
nicotinic receptors-containing beta2 subunits are the most
important receptor subtypes for nicotinic involvement in
cognitive function and nicotine self-administration, while
low affinity alpha7-containing nicotinic receptors have not
been thought to be important. In the current study, we found
that knockout of either beta2 or alpha7 subunits caused
significant deficits in spatial discrimination in mice. The
character of the impairment in the two knockouts was
different. The beta2 knockout preferentially impaired
cognition in males while the alpha7 caused impairment
regardless of sex. Both beta2- and alpha7-containing
nicotinic receptors also are important for nicotine
self-administration, also in different ways. Most animal
model studies of nicotine self-administration are relatively
short-term whereas the problem of tobacco addiction is
considerably longer-term. To better model the impact of
nicotinic receptor subtypes on nicotine self-administration
over the long-term, we studied the impact of genetic
knockout of low affinity alpha7 receptors vs. high-affinity
beta2-containing nicotinic receptors. Mice with knockouts of
either of these receptors and their wildtype counter parts
were given free access to a choice of nicotine-containing
and nicotine-free solution in their home cages on a
continuous basis over a period of 5 months. During the first
few weeks, the beta2-containing nicotinic receptor knockout
mice showed a significant decrease in nicotine consumption
relative to wildtype mice, whereas the alpha7 knockout mice
did not significantly differ from wildtype controls at the
beginning of their access to nicotine. Interestingly, in the
longer-term after the first few weeks of nicotine access,
the beta2 knockout mice returned to wildtype mouse levels of
nicotine consumption, whereas the alpha7 knockout mice
developed an emergent decrease in nicotine consumption. The
alpha7 receptor knockout-induced decrease in nicotine
consumption persisted for the 5-month period of the study.
Both alpha7- and beta2-containing nicotinic receptors play
critical roles in cognitive function and nicotine
self-administration. Regarding cognitive function,
beta2-containing receptors are important for maintaining
normal sex differences in spatial learning and memory,
whereas alpha7 receptors are important for cognitive
function regardless of sex. Regarding nicotine
self-administration high-affinity beta2-containing nicotinic
receptors are important for consumption during the initial
phase of nicotine access, but it is the alpha7 nicotinic
receptors that are important for the longer-term regulation
of nicotine consumption.},
Doi = {10.1016/j.bbr.2008.08.048},
Key = {fds274270}
}
@article{fds274265,
Author = {Eddins, D and Petro, A and Williams, P and Cerutti, DT and Levin,
ED},
Title = {Nicotine effects on learning in zebrafish: the role of
dopaminergic systems.},
Journal = {Psychopharmacology (Berl)},
Volume = {202},
Number = {1-3},
Pages = {103-109},
Year = {2009},
Month = {January},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18716760},
Abstract = {RATIONALE: Nicotine improves cognitive function in a number
of animal models including rats, mice, monkeys, and
recently, zebrafish. The zebrafish model allows higher
throughput and ease in discovering mechanisms of cognitive
improvement. MATERIALS AND METHODS: To further characterize
the neural bases of nicotine effects on learning in
zebrafish, we determined changes in dopaminergic systems
that accompany nicotine-enhanced learning. RESULTS: Nicotine
improved learning and increased brain levels of
dihydroxyphenylacetic acid (DOPAC), the primary dopamine
metabolite. There was a significant correlation between
choice accuracy and DOPAC levels. The nicotinic antagonist
mecamylamine blocked the nicotine-induced increase in DOPAC
concentrations, in line with our previous finding that
mecamylamine reversed nicotine-induced learning improvement.
CONCLUSIONS: Dopamine systems are related to learning in
zebrafish; nicotine exposure increases both learning rates
and DOPAC levels; and nicotinic antagonist administration
blocks nicotine-induced rises in DOPAC concentrations. Rapid
cognitive assessment of drugs with zebrafish could serve as
a useful screening tool for the development of new
therapeutics for cognitive dysfunction.},
Doi = {10.1007/s00213-008-1287-4},
Key = {fds274265}
}
@article{fds274267,
Author = {Slotkin, TA and Levin, ED and Seidler, FJ},
Title = {Developmental neurotoxicity of parathion: progressive
effects on serotonergic systems in adolescence and
adulthood.},
Journal = {Neurotoxicol Teratol},
Volume = {31},
Number = {1},
Pages = {11-17},
Year = {2009},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18773955},
Abstract = {Neonatal exposures to organophosphates that are not acutely
symptomatic or that produce little or no cholinesterase
inhibition can nevertheless compromise the development and
later function of critical neural pathways, including
serotonin (5HT) systems that regulate emotional behaviors.
We administered parathion to newborn rats on postnatal days
(PN) 1-4 at doses spanning the threshold for detectable
cholinesterase inhibition (0.1 mg/kg/day) and the first
signs of loss of viability (0.2 mg/kg/day). In adolescence
(PN30), young adulthood (PN60) and full adulthood (PN100),
we measured radioligand binding to 5HT(1A) and 5HT(2)
receptors, and to the 5HT transporter in the brain regions
comprising all the major 5HT projections and 5HT cell
bodies. Parathion caused a biphasic effect over later
development with initial, widespread upregulation of 5HT(1A)
receptors that peaked in the frontal/parietal cortex by
PN60, followed by a diminution of that effect in most
regions and emergence of deficits at PN100. There were
smaller, but statistically significant changes in 5HT(2)
receptors and the 5HT transporter. These findings stand in
strong contrast to previous results with neonatal exposure
to a different organophosphate, chlorpyrifos, which evoked
parallel upregulation of all three 5HT synaptic proteins
that persisted from adolescence through full adulthood and
that targeted males much more than females. Our results
support the view that the various organophosphates have
disparate effects on 5HT systems, distinct from their shared
property as cholinesterase inhibitors, and the targeting of
5HT function points toward the importance of studying the
impact of these agents on 5HT-linked behaviors.},
Doi = {10.1016/j.ntt.2008.08.004},
Key = {fds274267}
}
@article{fds274278,
Author = {Slotkin, TA and Wrench, N and Ryde, IT and Lassiter, TL and Levin, ED and Seidler, FJ},
Title = {Neonatal parathion exposure disrupts serotonin and dopamine
synaptic function in rat brain regions: modulation by a
high-fat diet in adulthood.},
Journal = {Neurotoxicol Teratol},
Volume = {31},
Number = {6},
Pages = {390-399},
Year = {2009},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19616088},
Abstract = {The consequences of exposure to developmental neurotoxicants
are influenced by environmental factors. In the present
study, we examined the role of dietary fat intake. We
administered parathion to neonatal rats and then evaluated
whether a high-fat diet begun in adulthood could modulate
the persistent effects on 5HT and DA systems. Neonatal rats
received parathion on postnatal days 1-4 at 0.1 or 0.2
mg/kg/day, straddling the cholinesterase inhibition
threshold. In adulthood, half the animals in each exposure
group were given a high-fat diet for 8 weeks. We assessed
5HT and DA concentrations and turnover in brain regions
containing their respective cell bodies and projections. In
addition, we monitored 5HT1A and 5HT2 receptor binding and
the concentration of 5HT presynaptic transporters. Neonatal
parathion exposure evoked widespread increases in
neurotransmitter turnover, indicative of presynaptic
hyperactivity, further augmented by 5HT receptor
upregulation. In control rats, consumption of a high-fat
diet recapitulated many of the changes seen with neonatal
parathion exposure; the effects represented convergent
mechanisms, since the high-fat diet often obtunded further
increases caused by parathion. Neonatal parathion exposure
causes lasting hyperactivity of 5HT and DA systems
accompanied by 5HT receptor upregulation, consistent with
"miswiring" of neuronal projections. A high-fat diet obtunds
the effect of parathion, in part by eliciting similar
changes itself. Thus, dietary factors may produce similar
synaptic changes as do developmental neurotoxicants,
potentially contributing to the increasing incidence of
neurodevelopmental disorders.},
Doi = {10.1016/j.ntt.2009.07.003},
Key = {fds274278}
}
@article{fds274266,
Author = {Timofeeva, OA and Sanders, D and Seemann, K and Yang, L and Hermanson,
D and Regenbogen, S and Agoos, S and Kallepalli, A and Rastogi, A and Braddy, D and Wells, C and Perraut, C and Seidler, FJ and Slotkin, TA and Levin, ED},
Title = {Persistent behavioral alterations in rats neonatally exposed
to low doses of the organophosphate pesticide,
parathion.},
Journal = {Brain Res Bull},
Volume = {77},
Number = {6},
Pages = {404-411},
Year = {2008},
Month = {December},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18817854},
Abstract = {Although developmental exposures of rats to low levels of
the organophosphate pesticides (OPs), chlorpyrifos (CPF) or
diazinon (DZN), both cause persistent neurobehavioral
effects, there are important differences in their
neurotoxicity. The current study extended investigation to
parathion (PTN), an OP that has higher systemic toxicity
than either CPF or DZN. We gave PTN on postnatal days (PND)
1-4 at doses spanning the threshold for systemic toxicity
(0, 0.1 or 0.2 mg/kg/day, s.c.) and performed a battery of
emotional and cognitive behavioral tests in adolescence
through adulthood. The higher PTN dose increased time spent
on the open arms and the number of center crossings in the
plus maze, indicating greater risk-taking and overall
activity. This group also showed a decrease in tactile
startle response without altering prepulse inhibition,
indicating a blunted acute sensorimotor reaction without
alteration in sensorimotor plasticity. T-maze spontaneous
alternation, novelty-suppressed feeding, preference for
sweetened chocolate milk, and locomotor activity were not
significantly affected by neonatal PTN exposure. During
radial-arm maze acquisition, rats given the lower PTN dose
committed fewer errors compared to controls and displayed
lower sensitivity to the amnestic effects of the NMDA
receptor blocker, dizocilpine. No PTN effects were observed
with regard to the sensitivity to blockade of muscarinic and
nicotinic cholinergic receptors, or serotonin 5HT(2)
receptors. This study shows that neonatal PTN exposure
evokes long-term changes in behavior, but the effects are
less severe, and in some incidences opposite in nature, to
those seen earlier for CPF or DZN, findings consistent with
our neurochemical studies showing different patterns of
effects and less neurotoxic damage with PTN. Our results
reinforce the conclusion that low dose exposure to different
OPs can have quite different neurotoxic effects, obviously
unconnected to their shared property as cholinesterase
inhibitors.},
Doi = {10.1016/j.brainresbull.2008.08.019},
Key = {fds274266}
}
@article{fds274263,
Author = {Levin, ED and Slade, S and Johnson, M and Petro, A and Horton, K and Williams, P and Rezvani, AH and Rose, JE},
Title = {Ketanserin, a 5-HT2 receptor antagonist, decreases nicotine
self-administration in rats.},
Journal = {Eur J Pharmacol},
Volume = {600},
Number = {1-3},
Pages = {93-97},
Year = {2008},
Month = {December},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18950618},
Abstract = {Nicotine intake constitutes a principal mechanism for
tobacco addiction. In addition to primary effects on
nicotinic acetylcholine receptors, nicotine has cascading
effects, which may also underlie its neurobehavioral
actions. Nicotine induces serotonin (5-HT) release, which
has not classically been thought to be involved in tobacco
addiction as dopamine has. However, addiction can be
characterized more as a disorder of compulsion than a
disorder of enjoyment. 5-HT mechanisms play key roles in
compulsive disorders. Nicotine-induced 5-HT release may be a
key to tobacco addiction. Ketanserin, a 5-HT2a and 5-HT2c
receptor antagonist, significantly attenuates nicotine
effects on attention and memory. These studies were
conducted to determine if ketanserin would reduce nicotine
self-administration in rats. Male Sprague-Dawley rats (N=12)
were given initial food pellet training and then 10 sessions
of nicotine self-administration training (0.03
mg/kg/infusion, i.v.). Then the rats were administered
ketanserin (1 or 2 mg/kg, s.c.) or the saline vehicle.
Ketanserin (2 mg/kg) significantly decreased nicotine
self-administration. This did not seem to be due to sedative
or amnestic effects of ketanserin. In a second study, the
effects of repeated administration of 2 mg/kg ketanserin
(N=11) vs. saline injections (N=10) were examined. In the
initial phase, the acute effectiveness of ketanserin in
significantly reducing nicotine self-administration was
replicated. The effect became attenuated during the
following several sessions, but the significant effect
became re-established during the final phases of this
two-week study. 5-HT mechanisms play critical roles in the
maintenance of nicotine self-administration. Better
understanding of those roles may help lead to new 5-HT-based
treatments for tobacco addiction.},
Doi = {10.1016/j.ejphar.2008.10.016},
Key = {fds274263}
}
@article{fds274249,
Author = {Lassiter, TL and Ryde, IT and Mackillop, EA and Brown, KK and Levin, ED and Seidler, FJ and Slotkin, TA},
Title = {Exposure of neonatal rats to parathion elicits sex-selective
reprogramming of metabolism and alters the response to a
high-fat diet in adulthood.},
Journal = {Environ Health Perspect},
Volume = {116},
Number = {11},
Pages = {1456-1462},
Year = {2008},
Month = {November},
ISSN = {0091-6765},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19057696},
Abstract = {BACKGROUND: Developmental exposures to organophosphate
pesticides are virtually ubiquitous. These agents are
neurotoxicants, but recent evidence also points to lasting
effects on metabolism. OBJECTIVES: We administered parathion
to neonatal rats. In adulthood, we assessed the impact on
weight gain, food consumption, and glucose and lipid
homeostasis, as well as the interaction with the effects of
a high-fat diet. METHODS: Neonatal rats were given parathion
on postnatal days 1-4 using doses (0.1 or 0.2 mg/kg/day)
that straddle the threshold for barely detectable
cholinesterase inhibition and the first signs of systemic
toxicity. In adulthood, animals were either maintained on
standard lab chow or switched to a high-fat diet for 7
weeks. RESULTS: In male rats on a normal diet, the low-dose
parathion exposure caused increased weight gain but also
evoked signs of a prediabetic state, with elevated fasting
serum glucose and impaired fat metabolism. The higher dose
of parathion reversed the weight gain and caused further
metabolic defects. Females showed greater sensitivity to
metabolic disruption, with weight loss at either parathion
dose, and greater imbalances in glucose and lipid
metabolism. At 0.1 mg/kg/day parathion, females showed
enhanced weight gain on the high-fat diet; This effect was
reversed in the 0.2-mg/kg/day parathion group, and was
accompanied by even greater deficits in glucose and fat
metabolism. CONCLUSIONS: Neonatal low-dose parathion
exposure disrupts glucose and fat homeostasis in a
persistent and sex-selective manner. Early-life toxicant
exposure to organophosphates or other environmental
chemicals may play a role in the increased incidence of
obesity and diabetes.},
Doi = {10.1289/ehp.11673},
Key = {fds274249}
}
@article{fds274264,
Author = {Bencan, Z and Levin, ED},
Title = {The role of alpha7 and alpha4beta2 nicotinic receptors in
the nicotine-induced anxiolytic effect in
zebrafish.},
Journal = {Physiol Behav},
Volume = {95},
Number = {3},
Pages = {408-412},
Year = {2008},
Month = {October},
ISSN = {0031-9384},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18671990},
Abstract = {Zebrafish (Danio rerio) have been widely used to study the
molecular mechanisms of development including
neurodevelopment. More recently, they have begun to be used
to study neuropharmacology and neurotoxicology. Critical for
this line of research are methods to study behavioral
function in zebrafish. Previous studies have compared
zebrafish with mammalian models to determine similarities
and differences in locomotor behavior, learning and memory.
Relatively little research has been conducted on stress
response and anxiety behavior as well as the pharmacologic
response in zebrafish. We have developed a test for
zebrafish to assess stress response and anxiety: the novel
tank diving test. In this short test normally zebrafish dive
to the bottom of a novel tank and then gradually over the
5-min test begin exploring higher levels of the tank.
Nicotine, which has anxiolytic effects in rodents and humans
was found to diminish this novel tank diving response in
zebrafish. The current study examined the nicotinic receptor
subtype selectivity involved in the actions of nicotine. Two
nicotinic receptor subtype selective antagonists were used:
MLA (an alpha7 antagonist) and DHbetaE (an alpha4beta2
antagonist). We replicated our previous finding of the
anxiolytic effect of nicotine with significantly less bottom
dwelling by the fish after nicotine treatment. This
nicotine-induced anxiolytic effect was reversed by both MLA
and DHbetaE, indicating that both nicotinic alpha7 and
alpha4beta2 receptors are involved in the nicotinic effect
on anxiety in zebrafish.},
Doi = {10.1016/j.physbeh.2008.07.009},
Key = {fds274264}
}
@article{fds274248,
Author = {Slotkin, TA and Bodwell, BE and Ryde, IT and Levin, ED and Seidler,
FJ},
Title = {Exposure of neonatal rats to parathion elicits sex-selective
impairment of acetylcholine systems in brain regions during
adolescence and adulthood.},
Journal = {Environ Health Perspect},
Volume = {116},
Number = {10},
Pages = {1308-1314},
Year = {2008},
Month = {October},
ISSN = {0091-6765},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18941570},
Abstract = {BACKGROUND: Organophosphates elicit developmental
neurotoxicity through multiple mechanisms other than their
shared property as cholinesterase inhibitors. Accordingly,
these agents may differ in their effects on specific brain
circuits. OBJECTIVES: We gave parathion to neonatal rats
[postnatal days (PNDs) 1-4], at daily doses of 0.1 or 0.2
mg/kg, spanning the threshold for barely detectable
cholinesterase inhibition and systemic effects. METHODS: We
assessed neurochemical indices related to the function of
acetylcholine (ACh) synapses (choline acetyltransferase,
presynaptic high-affinity choline transporter, nicotinic
cholinergic receptors) in brain regions comprising all the
major ACh projections, with determinations carried out from
adolescence to adulthood (PNDs 30, 60, and 100). RESULTS:
Parathion exposure elicited lasting alterations in ACh
markers in the frontal/parietal cortex, temporal/occipital
cortex, midbrain, hippocampus, and striatum. In
cerebrocortical areas, midbrain, and hippocampus, effects in
males were generally greater than in females, whereas in the
striatum, females were targeted preferentially. Superimposed
on this general pattern, the cerebrocortical effects showed
a nonmonotonic dose-response relationship, with regression
of the defects at the higher parathion dose; this
relationship has been seen also after comparable treatments
with chlorpyrifos and diazinon and likely represents the
involvement of cholinesterase-related actions that mask or
offset the effects of lower doses. CONCLUSIONS: Neonatal
exposure to parathion, at doses straddling the threshold for
cholinesterase inhibition, compromises indices of ACh
synaptic function in adolescence and adulthood. Differences
between the effects of parathion compared with chlorpyrifos
or diazinon and the non-monotonic dose-effect relationships
reinforce the conclusion that various organophosphates
diverge in their effects on neurodevelopment, unrelated to
their anticholinesterase actions.},
Doi = {10.1289/ehp.11451},
Key = {fds274248}
}
@article{fds274262,
Author = {Timofeeva, OA and Levin, ED},
Title = {Idazoxan blocks the nicotine-induced reversal of the memory
impairment caused by the NMDA glutamate receptor antagonist
dizocilpine.},
Journal = {Pharmacol Biochem Behav},
Volume = {90},
Number = {3},
Pages = {372-381},
Year = {2008},
Month = {September},
ISSN = {0091-3057},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18456310},
Abstract = {RATIONALE: Alpha2-adrenoreceptor (alpha(2)-AR) antagonists
have been shown to improve, while alpha(2)-AR agonists
impair cognitive function in subjects with functioning NMDA
receptors (NMDAR). In subjects with inhibited NMDAR (a model
of schizophrenia) alpha(2)-AR agonists attenuate the
cognitive impairments. The effect with alpha(2)-AR
antagonists remains unclear. OBJECTIVES: We investigated the
effects of the alpha(2)-AR antagonist idazoxan on memory
function in rats treated/not treated with NMDAR antagonist
dizocilpine or a combination of dizocilpine and nicotine to
clarify noradrenergic/cholinergic regulation of memory
function. METHODS: Female Sprague-Dawley rats (n=12) were
trained for food reward on the radial maze. Working and
reference memory errors and response latency were assessed
after injections of idazoxan (0.5, 1.0 mg/kg), dizocilpine
(0.05 mg/kg), nicotine (0.2, 0.4 mg/kg) or vehicle, alone or
in combination. RESULTS: Dizocilpine potently impaired
memory. Nicotine (0.4 mg/kg) reversed this impairment.
Idazoxan at the doses tested did not affect performance when
given alone or with dizocilpine, but it did block the
nicotine reversal of the dizocilpine-induced memory
impairment. Three rats after 10-12 drug treatments developed
limbic seizures. Our findings suggest that combination of
drugs which block alpha(2)-AR with nicotinic agonists in
schizophrenia may prevent therapeutic effect of nicotinic
agonists and increase risk for convulsive activity with
repeated administration.},
Doi = {10.1016/j.pbb.2008.03.011},
Key = {fds274262}
}
@article{fds274261,
Author = {Rezvani, AH and Eddins, D and Slade, S and Hampton, DS and Christopher,
NC and Petro, A and Horton, K and Johnson, M and Levin,
ED},
Title = {Neonatal 6-hydroxydopamine lesions of the frontal cortex in
rats: persisting effects on locomotor activity, learning and
nicotine self-administration.},
Journal = {Neuroscience},
Volume = {154},
Number = {3},
Pages = {885-897},
Year = {2008},
Month = {June},
ISSN = {0306-4522},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18511204},
Abstract = {Dopaminergic innervation of the frontal cortex in adults is
important for a variety of cognitive functions and
behavioral control. However, the role of frontal cortical
dopaminergic innervation for neurobehavioral development has
received little attention. In the current study, rats were
given dopaminergic lesions in the frontal cortex with local
micro-infusions of 6-hydroxydopamine (6-OHDA) at 1 week of
age. The long-term behavioral effects of neonatal frontal
cortical 6-OHDA lesions were assessed in a series of tests
of locomotor activity, spatial learning and memory, and i.v.
nicotine self-administration. In addition, neurochemical
indices were assessed with tissue homogenization and HPLC in
the frontal cortex, striatum, and nucleus accumbens of
neonatal and adult rats after neonatal 6-OHDA lesions. In
neonatal rats, frontal 6-OHDA lesions as intended caused a
significant reduction in frontal cortical dopamine without
effects on frontal cortical 5-HT and norepinephrine. The
frontal cortical dopamine depletion increased 5-HT and
norepinephrine levels in the nucleus accumbens. Locomotor
activity assessment during adulthood in the figure-8 maze
showed that lesioned male rats were hyperactive relative to
sham-lesioned males. Locomotor activity of female rats was
not significantly affected by the neonatal frontal 6-OHDA
lesion. Learning and memory in the radial-arm maze was also
affected by neonatal frontal 6-OHDA lesions. There was a
general trend toward impaired performance in early maze
acquisition and a paradoxical improvement at the end of
cognitive testing. Nicotine self-administration showed
significant lesion x sex interactions. The sex difference in
nicotine self-administration with females self-administering
significantly more nicotine than males was reversed by
neonatal 6-OHDA frontal cortical lesions. Neurochemical
studies in adult rats showed that frontal cortical dopamine
and DOPAC levels significantly correlated with nicotine
self-administration in the 6-OHDA-lesioned animals but not
in the controls. Frontal cortical 5-HT and 5HIAA showed
inverse correlations with nicotine self-administration in
the 6-OHDA-lesioned animals but not in the controls. These
results show that interfering with normal dopamine
innervation of the frontal cortex during early postnatal
development has persisting behavioral effects, which are
sex-specific.},
Doi = {10.1016/j.neuroscience.2008.04.020},
Key = {fds274261}
}
@article{fds274257,
Author = {Morey, JS and Ryan, JC and Bottein Dechraoui and M-Y and Rezvani, AH and Levin, ED and Gordon, CJ and Ramsdell, JS and Van Dolah,
FM},
Title = {Liver genomic responses to ciguatoxin: evidence for
activation of phase I and phase II detoxification pathways
following an acute hypothermic response in
mice.},
Journal = {Toxicol Sci},
Volume = {103},
Number = {2},
Pages = {298-310},
Year = {2008},
Month = {June},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18353800},
Abstract = {Ciguatoxins (CTX) are polyether neurotoxins that target
voltage-gated sodium channels and are responsible for
ciguatera, the most common fish-borne food poisoning in
humans. This study characterizes the global transcriptional
response of mouse liver to a symptomatic dose (0.26 ng/g) of
the highly potent Pacific ciguatoxin-1 (P-CTX-1). At 1 h
post-exposure 2.4% of features on a 44K whole genome array
were differentially expressed (p < or = 0.0001), increasing
to 5.2% at 4 h and decreasing to 1.4% by 24 h post-CTX
exposure. Data were filtered (/fold change/ > or = 1.5 and p
< or = 0.0001 in at least one time point) and a trend set of
1550 genes were used for further analysis. Early gene
expression was likely influenced prominently by an acute 4
degrees C decline in core body temperature by 1 h, which
resolved by 8 h following exposure. An initial
downregulation of 32 different solute carriers, many
involved in sodium transport, was observed. Differential
gene expression in pathways involving eicosanoid
biosynthesis and cholesterol homeostasis was also noted.
Cytochrome P450s (Cyps) were of particular interest due to
their role in xenobiotic metabolism. Twenty-seven genes,
mostly members of Cyp2 and Cyp4 families, showed significant
changes in expression. Many Cyps underwent an initial
downregulation at 1 h but were quickly and strongly
upregulated at 4 and 24 h post-exposure. In addition to
Cyps, increases in several glutathione S-transferases were
observed, an indication that both phase I and phase II
metabolic reactions are involved in the hepatic response to
CTX in mice.},
Doi = {10.1093/toxsci/kfn055},
Key = {fds274257}
}
@article{fds274259,
Author = {Rezvani, AH and Tizabi, Y and Getachew, B and Hauser, SR and Caldwell,
DP and Hunter, C and Levin, ED},
Title = {Chronic nicotine and dizocilpine effects on nicotinic and
NMDA glutamatergic receptor regulation: interactions with
clozapine actions and attentional performance in
rats.},
Journal = {Prog Neuropsychopharmacol Biol Psychiatry},
Volume = {32},
Number = {4},
Pages = {1030-1040},
Year = {2008},
Month = {May},
ISSN = {0278-5846},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18343006},
Abstract = {Blockade of NMDA glutamate receptors with dizocilpine
(MK-801) has been shown to cause substantial cognitive
deficits and has been used to model symptoms of
schizophrenia. Nicotine or nicotinic agonists, in contrast,
may enhance cognitive or attentional functions and be of
therapeutic potential in schizophrenia. Nicotinic-glutamatergic
interactions, therefore, may have important implications in
cognitive functions and antipsychotic treatments. Clozapine,
a widely used antipsychotic drug, has been shown in some
studies to be effective in ameliorating the cognitive
deficits associated with schizophrenia. However, there is
some evidence to suggest that clozapine similar to
haloperidol may impair sustained attention in rats. In this
study, we sought to determine whether chronic nicotine or
dizocilpine may modify the effects of acute clozapine on
attentional parameters and whether the behavioral effects
would correlate with nicotinic or NMDA receptor densities in
discrete brain regions. Adult female rats trained on an
operant visual signal detection task were given 4 weeks of
nicotine (5 mg/kg/day), dizocilpine (0.15 mg/kg/day), the
same doses of both nicotine and dizocilpine as a mixture, or
saline by osmotic minipump. While on chronic treatment, rats
received acute injections of various doses of clozapine (0,
0.625, 1.25, 2.5 mg/kg, sc) 10 min prior to tests on
attentional tasks. The pumps were removed on day 28 and 24 h
later the animals were sacrificed for measurements of
receptor densities in specific brain regions. The percent
correct hit as a measure of sustained attention was
significantly impaired by clozapine in a dose-related
manner. Neither chronic nicotine nor dizocilpine affected
this measure on their own or modified the effects of
clozapine. Both nicotine and dizocilpine affected the
receptor bindings in a region specific manner and their
combination further modified the effects of each other in
selective regions. Attentional performance was inversely
correlated with alpha-bungarotoxin binding in the frontal
cortex only. In conclusion, the data suggest attentional
impairments with clozapine alone and no modification of this
effect with nicotine or dizocilpine. Moreover, cortical low
affinity nicotinic receptors may have a role in attentional
functions.},
Doi = {10.1016/j.pnpbp.2008.01.018},
Key = {fds274259}
}
@article{fds274258,
Author = {West, AK and Hidalgo, J and Eddins, D and Levin, ED and Aschner,
M},
Title = {Metallothionein in the central nervous system: Roles in
protection, regeneration and cognition.},
Journal = {Neurotoxicology},
Volume = {29},
Number = {3},
Pages = {489-503},
Year = {2008},
Month = {May},
ISSN = {0161-813X},
url = {http://dx.doi.org/10.1016/j.neuro.2007.12.006},
Abstract = {Metallothionein (MT) is an enigmatic protein, and its
physiological role remains a matter of intense study and
debate 50 years after its discovery. This is particularly
true of its function in the central nervous system (CNS),
where the challenge remains to link its known biochemical
properties of metal binding and free radical scavenging to
the intricate workings of brain. In this compilation of four
reports, first delivered at the 11th International
Neurotoxicology Association (INA-11) Meeting, June 2007, the
authors present the work of their laboratories, each of
which gives an important insight into the actions of MT in
the brain. What emerges is that MT has the potential to
contribute to a variety of processes, including
neuroprotection, regeneration, and even cognitive functions.
In this article, the properties and CNS expression of MT are
briefly reviewed before Dr Hidalgo describes his pioneering
work using transgenic models of MT expression to demonstrate
how this protein plays a major role in the defence of the
CNS against neurodegenerative disorders and other CNS
injuries. His group's work leads to two further questions,
what are the mechanisms at the cellular level by which MT
acts, and does this protein influence higher order issues of
architecture and cognition? These topics are addressed in
the second and third sections of this review by Dr West, and
Dr Levin and Dr Eddins, respectively. Finally, Dr Aschner
examines the ability of MT to protect against a specific
toxicant, methylmercury, in the CNS.},
Doi = {10.1016/j.neuro.2007.12.006},
Key = {fds274258}
}
@article{fds274255,
Author = {Bottein Dechraoui and M-Y and Rezvani, AH and Gordon, CJ and Levin, ED and Ramsdell, JS},
Title = {Repeat exposure to ciguatoxin leads to enhanced and
sustained thermoregulatory, pain threshold and motor
activity responses in mice: relationship to blood ciguatoxin
concentrations.},
Journal = {Toxicology},
Volume = {246},
Number = {1},
Pages = {55-62},
Year = {2008},
Month = {April},
ISSN = {0300-483X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18280027},
Abstract = {Ciguatera is a common illness in tropical and subtropical
regions that manifests in complex and long-lived symptoms
which are more severe in subsequent exposures. This study
measures central and peripheral neurologic signs, in
parallel with blood toxin levels, in mice exposed once or
twice (at 3 days interval) to a sublethal dose of ciguatoxin
P-CTX-1 (0.26ng/g via i.p.). Mice were implanted with
radiotransmitters to monitor motor activity and core
temperature. A single exposure to ciguatoxin elicited an
immediate and transient decrease in motor activity and
temperature, and subsequent long-lasting thermoregulatory
dysfunction resulting in stabilized body temperature around
36.0 degrees C with no observable circadian rhythm. The
hypothermic response and the reduced activity were enhanced
with a second exposure with 30% of the mice dying within 7h.
Measurement of the peripheral nervous system by the tail
flick assay revealed increased latency with a single
ciguatoxin exposure, and a greater effect following the
second exposure. Toxin was measurable in blood up to 3 days
following the first exposure; at the 1h time point the
concentrations were significantly elevated after a second
exposure. These findings indicate an early response to
ciguatoxin manifest in a central response to lower body
temperature and reduce motor activity and a more persistent
effect on the peripheral system leading to spinal heat
antinociception and delayed fever-like response. The greater
neurological response to a second ciguatoxin exposure was
associated with elevated concentrations of ciguatoxin in the
blood solely over the first hour of exposure. In conclusion,
a single exposure to toxin exerts a significant neurological
response which may be enhanced with subsequent
exposure.},
Doi = {10.1016/j.tox.2007.12.013},
Key = {fds274255}
}
@article{fds274253,
Author = {Slotkin, TA and Ryde, IT and Levin, ED and Seidler,
FJ},
Title = {Developmental neurotoxicity of low dose diazinon exposure of
neonatal rats: effects on serotonin systems in adolescence
and adulthood.},
Journal = {Brain Res Bull},
Volume = {75},
Number = {5},
Pages = {640-647},
Year = {2008},
Month = {March},
ISSN = {0361-9230},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18355640},
Abstract = {The developmental neurotoxicity of organophosphate
pesticides targets serotonin (5HT) systems, which are
involved in emotional and appetitive behaviors. We exposed
neonatal rats to daily doses of diazinon on postnatal days
1-4, using doses (0.5 or 2mg/kg) spanning the threshold for
barely-detectable cholinesterase inhibition. We then
evaluated the effects on 5HT(1A) and 5HT(2) receptors, and
on the 5HT transporter in cerebral cortical regions and the
brainstem in adolescence through adulthood. Diazinon evoked
a lasting deficit in 5HT(1A) receptors in males only,
whereas it caused a small but significant increase in 5HT
transporters in females; neither effect showed a significant
regional selectivity. This pattern differed substantially
from that seen in earlier work with another organophosphate,
chlorpyrifos, which at pharmacodynamically similar doses
spanning the threshold for cholinesterase inhibition, evoked
a much more substantial, global upregulation of 5HT receptor
expression; with chlorpyrifos, effects on receptors were
seen in females, albeit to a lesser extent than in males,
and were also regionally distinct. The effects of diazinon
were nonmonotonic, showing larger alterations at the lower
dose, likely reflecting positive trophic effects of
cholinergic stimulation once the threshold for
cholinesterase inhibition is exceeded. Our results reinforce
the idea that different organophosphates have fundamentally
distinct effects on the developmental trajectories of
specific neurotransmitter systems, unrelated to their shared
action as cholinesterase inhibitors. The effects on 5HT
circuits expand the scope of behavioral endpoints that need
to be considered in evaluating the developmental
neurotoxicity of organophosphates.},
Doi = {10.1016/j.brainresbull.2007.10.008},
Key = {fds274253}
}
@article{fds274254,
Author = {Slotkin, TA and Bodwell, BE and Levin, ED and Seidler,
FJ},
Title = {Neonatal exposure to low doses of diazinon: long-term
effects on neural cell development and acetylcholine
systems.},
Journal = {Environ Health Perspect},
Volume = {116},
Number = {3},
Pages = {340-348},
Year = {2008},
Month = {March},
ISSN = {0091-6765},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18335101},
Abstract = {BACKGROUND: The developmental neurotoxicity of
organophosphate pesticides involves mechanisms other than
their shared property of cholinesterase inhibition.
OBJECTIVES: We gave diazinon (DZN) to newborn rats on
postnatal days 1-4, using doses (0.5 or 2 mg/kg) spanning
the threshold for barely detectable cholinesterase
inhibition. METHODS: We then evaluated the lasting effects
on indices of neural cell number and size, and on functional
markers of acetylcholine (ACh) synapses (choline
acetyltransferase, presynaptic high-affinity choline
transporter, nicotinic cholinergic receptors) in a variety
of brain regions. RESULTS: DZN exposure produced a
significant overall increase in cell-packing density in
adolescence and adulthood, suggestive of neuronal loss and
reactive gliosis; however, some regions (temporal/occipital
cortex, striatum) showed evidence of net cell loss,
reflecting a greater sensitivity to neurotoxic effects of
DZN. Deficits were seen in ACh markers in cerebrocortical
areas and the hippocampus, regions enriched in ACh
projections. In contrast, there were no significant effects
in the midbrain, the major locus for ACh cell bodies. The
striatum showed a unique pattern, with robust initial
elevations in the ACh markers that regressed in adulthood to
normal or subnormal values. CONCLUSIONS: These results
indicate that developmental exposures to apparently nontoxic
doses of DZN compromise neural cell development and alter
ACh synaptic function in adolescence and adulthood. The
patterns seen here differ substantially from those seen in
earlier work with chlorpyrifos, reinforcing the concept that
the various organophosphates have fundamentally different
effects on the developmental trajectories of specific
neurotransmitter systems, unrelated to their shared action
as cholinesterase inhibitors.},
Doi = {10.1289/ehp.11005},
Key = {fds274254}
}
@article{fds274251,
Author = {Rezvani, AH and Kholdebarin, E and Dawson, E and Levin,
ED},
Title = {Nicotine and clozapine effects on attentional performance
impaired by the NMDA antagonist dizocilpine in female
rats.},
Journal = {Int J Neuropsychopharmacol},
Volume = {11},
Number = {1},
Pages = {63-70},
Year = {2008},
Month = {February},
ISSN = {1461-1457},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17295931},
Abstract = {Cognitive impairment is very prevalent in schizophrenia and
is currently undertreated in most patients. Attentional
deficit is one of the hallmark symptoms of schizophrenia.
Antipsychotic drugs, which can be quite effective in
combating hallucinations are often ineffective in reducing
cognitive impairment and can potentiate cognitive
impairment. Previously, we found that the antipsychotic drug
clozapine impaired, while nicotine improved, the accuracy of
rats performing a visual signal detection attentional task
in normal rats. For the current study, in a model of
cognitive impairment of schizophrenia with the NMDA
antagonist dizocilpine (0.05 mg/kg), we examined the effects
of clozapine and nicotine on significantly impaired
attentional hit accuracy. This dizocilpine-induced
impairment was significantly (p<0.05) reversed by either
clozapine (1.25 mg/kg) or nicotine (0.025 mg/kg).
Interestingly, when clozapine and nicotine were given
together, they blocked each other's beneficial effects. When
the effective doses of 1.25 mg/kg clozapine and 0.025 mg/kg
nicotine were given together the combination no longer
significantly reversed the dizocilpine-induced hit-accuracy
impairment. Given that the great majority of people with
schizophrenia smoke, the potential beneficial effects of
clozapine on attentional function may be largely blocked by
self-administered nicotine. In addition, there are promising
results concerning the development of nicotinic treatments
to reverse cognitive deficits including attentional
impairment. This is supported in the current study by the
reversal of the dizocilpine-induced attentional impairment
by nicotine. However, in schizophrenia the efficacy of
nicotinic treatments may be limited by co-treatment with
antipsychotic drugs like clozapine. It will be important to
determine which of the complex effects of clozapine and
nicotine are key in reversing attentional impairment and how
they block each other's effects for the development of
therapy to combat the attentional impairment of
schizophrenia.},
Doi = {10.1017/S1461145706007528},
Key = {fds274251}
}
@article{fds274250,
Author = {Roegge, CS and Timofeeva, OA and Seidler, FJ and Slotkin, TA and Levin,
ED},
Title = {Developmental diazinon neurotoxicity in rats: later effects
on emotional response.},
Journal = {Brain Res Bull},
Volume = {75},
Number = {1},
Pages = {166-172},
Year = {2008},
Month = {January},
ISSN = {0361-9230},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18158111},
Abstract = {Developmental exposure to the organophosphorus pesticides
chlorpyrifos and diazinon (DZN) alters serotonergic synaptic
function at doses below the threshold for cholinesterase
inhibition, however there are some indications that the two
agents may differ in several important attributes.
Previously, we found that low-dose chlorpyrifos exposure in
neonatal rats causes lasting changes in emotional response
and in the current study we did a comparable evaluation for
DZN. Male and female Sprague-Dawley rat pups (N=10-12 of
each sex per treatment group) were given 0, 0.5 or 2 mg/(kg
day) of DZN s.c. daily on postnatal days (PND) 1-4. These
doses bracket the threshold for barely-detectable
cholinesterase inhibition. Starting on PND 52, these rats
began a battery of tests to assess emotional reactivity. In
the elevated plus maze, there was a slight decrease in the
time spent in the open arms for DZN-exposed males, while
DZN-exposed females were not different from control females.
In the novelty-suppressed feeding test, DZN-exposed males
had significantly shorter latencies to begin eating than did
control males, reducing the values to those normally seen in
females. DZN-exposed rats of either sex showed reduced
preference for chocolate milk in the anhedonia test that
compared the consumption of chocolate milk to water. These
findings show that neonatal exposures to DZN at a dose range
below the threshold for cholinesterase inhibition
nevertheless evokes specific, later alterations in emotional
behaviors, particularly in males. The effects show not only
some similarities to those of chlorpyrifos but also some
differences, in keeping with neurochemical findings
comparing the two agents.},
Doi = {10.1016/j.brainresbull.2007.08.008},
Key = {fds274250}
}
@article{fds274247,
Author = {Timofeeva, OA and Roegge, CS and Seidler, FJ and Slotkin, TA and Levin,
ED},
Title = {Persistent cognitive alterations in rats after early
postnatal exposure to low doses of the organophosphate
pesticide, diazinon.},
Journal = {Neurotoxicol Teratol},
Volume = {30},
Number = {1},
Pages = {38-45},
Year = {2008},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18096363},
Abstract = {BACKGROUND: Developmental neurotoxicity of organophosphorous
insecticides (OPs) involves multiple mechanisms in addition
to cholinesterase inhibition. We have found persisting
effects of developmental chlorpyrifos (CPF) and diazinon
(DZN) on cholinergic and serotonergic neurotransmitter
systems and gene expression as well as behavioral function.
Both molecular/neurochemical and behavioral effects of
developmental OP exposure have been seen at doses below
those which cause appreciable cholinesterase inhibition.
OBJECTIVES: We sought to determine if developmental DZN
exposure at doses which do not produce significant
acetylcholinesterase inhibition cause persisting cognitive
deficits. METHODS: Rats were exposed to DZN on postnatal
days 1-4 at doses (0.5 and 2 mg/kg/d) that span the
threshold for cholinesterase inhibition. They were later
examined with a cognitive battery tests similar to that used
with CPF. RESULTS: In the T-maze DZN caused significant
hyperactivity in the initial trials of the session, but not
later. In a longer assessment of locomotor activity no
DZN-induced changes were seen over a 1-hour session.
Prepulse inhibition was reduced by DZN exposure selectively
in males vs. females; DZN eliminated the sex difference
present in controls. In the radial maze, the lower but not
higher DZN dose significantly impaired spatial learning.
This type of nonmonotonic dose-effect function has
previously been seen with CPF as well. The lower dose DZN
group also showed significantly greater sensitivity to the
memory-impairing effects of scopolamine a muscarinic
acetylcholine antagonist. CONCLUSIONS: Neonatal DZN exposure
below the threshold for appreciable cholinesterase
inhibition caused persisting neurocognitive deficits in
adulthood. The addition of some inhibition of AChE with a
higher dose reversed the cognitive impairment. This
non-monotonic dose-effect function has also been seen with
neurochemical effects. Some of the DZN effects on cognition
resemble those seen earlier for CPF, some differ. Our data
suggest that DZN and CPF affect transmitter systems
supporting memory function, differently, implying
participation of mechanisms other than their common
inhibition of cholinesterase.},
Doi = {10.1016/j.ntt.2007.10.002},
Key = {fds274247}
}
@article{fds274252,
Author = {Eddins, D and Petro, A and Pollard, N and Freedman, JH and Levin,
ED},
Title = {Mercury-induced cognitive impairment in metallothionein-1/2
null mice.},
Journal = {Neurotoxicol Teratol},
Volume = {30},
Number = {2},
Pages = {88-95},
Year = {2008},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18226494},
Abstract = {Metallothioneins are central for the metabolism and
detoxification of transition metals. Exposure to mercury
during early neurodevelopment is associated with
neurocognitive impairment. Given the importance of
metallothioneins in mercury detoxification, metallothioneins
may be a protective factor against mercury-induced
neurocognitive impairment. Deletion of the murine
metallothionein-1 and metallothionein-2 genes causes choice
accuracy impairments in the 8-arm radial maze. We
hypothesize that deletions of metallothioneins genes will
make metallothionein-null mice more vulnerable to
mercury-induced cognitive impairment. We tested this
hypothesis by exposing MT1/MT2-null and wild-type mice to
developmental mercury (HgCl(2)) and evaluated the resultant
effects on cognitive performance on the 8-arm radial maze.
During the early phase of learning metallothionein-null mice
were more susceptible to mercury-induced impairment compared
to wildtype mice. Neurochemical analysis of the frontal
cortex revealed that serotonin levels were higher in
metallothionein-null mice compared to wild-type mice. This
effect was independent of mercury exposure. However,
dopamine levels in mercury-exposed metallothionein-null mice
were lower compared to mercury-exposed wild-type mice. This
work shows that deleting metallothioneins increase the
vulnerability to developmental mercury-induced
neurocognitive impairment. Metallothionein effects on
monoamine transmitters may be related to this cognitive
effect.},
Doi = {10.1016/j.ntt.2007.12.005},
Key = {fds274252}
}
@article{fds274260,
Author = {Crofton, KM and Foss, JA and Hass, U and Jensen, KF and Levin, ED and Parker, SP},
Title = {Undertaking positive control studies as part of
developmental neurotoxicity testing: a report from the ILSI
Research Foundation/Risk Science Institute expert working
group on neurodevelopmental endpoints.},
Journal = {Neurotoxicol Teratol},
Volume = {30},
Number = {4},
Pages = {266-287},
Year = {2008},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2007.06.002},
Abstract = {Developmental neurotoxicity testing involves functional and
neurohistological assessments in offspring during and
following maternal and/or neonatal exposure. Data from
positive control studies are an integral component in
developmental neurotoxicity risk assessments. Positive
control data are crucial for evaluating a laboratory's
capability to detect chemical-induced changes in measured
endpoints. Positive control data are also valuable in a
weight-of-evidence approach to help determine the biological
significance of results and provide confidence in negative
results from developmental neurotoxicity (DNT) studies. This
review is a practical guide for the selection and use of
positive control agents in developmental neurotoxicology.
The advantages and disadvantages of various positive control
agents are discussed for the endpoints in developmental
neurotoxicity studies. Design issues specific to positive
control studies in developmental neurotoxicity are
considered and recommendations on how to interpret and
report positive control data are made. Positive control
studies should be conducted as an integral component of the
incorporation and use of developmental neurotoxicity testing
methods in laboratories that generate data used in risk
decisions.},
Doi = {10.1016/j.ntt.2007.06.002},
Key = {fds274260}
}
@article{fds274244,
Author = {Ryan, JC and Bottein Dechraoui and M-Y and Morey, JS and Rezvani, A and Levin, ED and Gordon, CJ and Ramsdell, JS and Van Dolah,
FM},
Title = {Transcriptional profiling of whole blood and serum protein
analysis of mice exposed to the neurotoxin Pacific
Ciguatoxin-1.},
Journal = {Neurotoxicology},
Volume = {28},
Number = {6},
Pages = {1099-1109},
Year = {2007},
Month = {November},
ISSN = {0161-813X},
url = {http://dx.doi.org/10.1016/j.neuro.2007.05.013},
Abstract = {Ciguatoxins (CTX) are a suite of cyclic polyether toxins
produced by the marine dinoflagellate Gambierdiscus sp., are
potent activators of voltage-gated sodium channels and a
leading cause of human poisoning from food fish. This report
characterizes the genomic and proteomic response in whole
blood of adult male mice exposed i.p. to 264 ng/kg of the
Pacific congener of CTX (P-CTX-1) at 1, 4 and 24h. Whole
genome microarray expression data were filtered by tightness
of fit between replicates, fold change (1.8) and p-value
(10(-5)), resulting in 183 annotated genes used for trending
analysis, K-means clustering and ontology classification.
Genes involved with cytokine signaling, proteasome complex
and ribosomal function were dominant. qPCR performed on 19
genes of interest had a correlation of 0.95 to array results
by Pearson's correlation coefficient. Serum protein analysis
showed small but significant changes in 6 of 60 proteins
assayed: Ccl2, Ccl12, CD40, IL-10, leptin and M-CSF. In
large part, the gene expression was consistent with a Th2
immune response with interesting similarities to expression
seen in asthmatic models.},
Doi = {10.1016/j.neuro.2007.05.013},
Key = {fds274244}
}
@article{fds274245,
Author = {Levin, ED and Rezvani, AH},
Title = {Nicotinic interactions with antipsychotic drugs, models of
schizophrenia and impacts on cognitive function.},
Journal = {Biochem Pharmacol},
Volume = {74},
Number = {8},
Pages = {1182-1191},
Year = {2007},
Month = {October},
ISSN = {0006-2952},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17714691},
Abstract = {People with schizophrenia often have substantial cognitive
impairments, which may be related to nicotinic receptor
deficits, (alpha7 and alpha4beta2), documented in the brains
of people with schizophrenia. The large majority of people
with schizophrenia smoke cigarettes. Thus, nicotinic
interactions with antipsychotic drugs are widespread.
Complementary co-therapies of novel nicotinic ligands are
being developed to add to antipsychotic therapy to treat the
cognitive impairment of schizophrenia. Thus, it is critical
to understand the interaction between nicotinic treatments
and antipsychotic drugs. Nicotinic interactions with
antipsychotic drugs, are complex since both nicotine and
antipsychotics have complex actions. Nicotine stimulates and
desensitizes nicotinic receptors of various subtypes and
potentiates the release of different neurotransmitters.
Antipsychotics also act on a verity of receptor systems. For
example, clozapine acts as an antagonist at a variety of
neurotransmitter receptors such as those for dopamine,
serotonin, norepinepherine and histamine. In a series of
studies, we have found that in normally functioning rats,
moderate doses of clozapine impair working memory and that
clozapine blocks nicotine-induced memory and attentional
improvement. Clozapine and nicotine can attenuate each
other's beneficial effects in reversing the memory
impairment caused by the psychototmimetic drug dizocilpine.
A key to the clozapine-induced attenuation of
nicotine-induced cognitive improvement appears to be its
5HT(2) antagonist properties. The selective 5HT(2)
antagonist ketanserin has a similar action of blocking
nicotine-induced memory and attentional improvements. It is
important to consider the interactions between nicotinic and
antipsychotic drugs to develop the most efficacious
treatment for cognitive improvement in people with
schizophrenia.},
Doi = {10.1016/j.bcp.2007.07.019},
Key = {fds274245}
}
@article{fds274246,
Author = {Kholdebarin, E and Caldwell, DP and Blackwelder, WP and Kao, M and Christopher, NC and Levin, ED},
Title = {Interaction of nicotinic and histamine H(3) systems in the
radial-arm maze repeated acquisition task.},
Journal = {Eur J Pharmacol},
Volume = {569},
Number = {1-2},
Pages = {64-69},
Year = {2007},
Month = {August},
ISSN = {0014-2999},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17544392},
Abstract = {Nicotinic systems have been found in a variety of studies to
play important roles in cognitive function. Nicotinic
involvement in different aspects of cognitive function such
as learning vs. memory may differ. We have found in rats
that the spatial repeated acquisition task in the radial-arm
maze is significantly improved by low doses of the nicotinic
receptor antagonist mecamylamine, the atypical nicotinic
receptor ligand lobeline, as well as the alpha7 nicotinic
receptor agonist ARR-17779. Interestingly, nicotine in the
same dose range that improves working memory in the
win-shift radial maze task was not effective in improving
repeated acquisition performance. Nicotinic systems interact
with a variety of other neural systems. Differential
involvement of these extended effects with learning vs.
memory may help explain differential effects of nicotinic
drugs with these cognitive functions. Histamine H(3)
receptor antagonists have been shown by some studies to
improve cognitive function, but others have not found this
effect and some have found impairment. Nicotine stimulates
the release of histamine. This effect may counter other
cascading effects of nicotine in the performance of learning
and memory tasks. A specific test of this hypothesis
involves our study of nicotine (0.1-0.4 mg/kg) interactions
with the histamine H(3) receptor antagonist thioperamide
(2.5-10 mg/kg) on learning memory in the repeated
acquisition test in the radial-arm maze. The highest dose of
thioperamide tested caused a significant choice accuracy
impairment, which was most evident during the later portions
of the learning curve. The highest dose of nicotine did not
change overall errors but did cause a significant impairment
in learning over trials. The choice accuracy impairment
induced by thioperamide was significantly attenuated by
nicotine (0.4 mg/kg). The learning impairment caused by the
highest dose of nicotine was significantly attenuated by
thioperamide. Thioperamide also caused a slowing of
response, an effect, which was attenuated by nicotine
co-administration. The repeated acquisition test can help
differentiate acute drug effects on learning. Nicotine and
thioperamide effectively reversed each other's choice
accuracy impairment even though each by itself impaired
accuracy.},
Doi = {10.1016/j.ejphar.2007.04.051},
Key = {fds274246}
}
@article{fds274243,
Author = {Roegge, CS and Perraut, C and Hao, X and Levin, ED},
Title = {Histamine H1 receptor involvement in prepulse inhibition and
memory function: relevance for the antipsychotic actions of
clozapine.},
Journal = {Pharmacol Biochem Behav},
Volume = {86},
Number = {4},
Pages = {686-692},
Year = {2007},
Month = {April},
ISSN = {0091-3057},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17382376},
Abstract = {Histamine H(1) blockade is one of the more prominent actions
of the multi-receptor acting antipsychotic clozapine. It is
currently not known how much this H(1) antagonism of
clozapine contributes to the therapeutic or adverse side
effects of clozapine. The current studies with
Sprague-Dawley rats were conducted to determine the
participation of histaminergic H(1) receptor subtype in
sensorimotor plasticity and memory function affected by
clozapine using tests of prepulse inhibition (PPI) and
radial-arm maze choice accuracy. The PPI impairment caused
by the glutamate antagonist dizocilpine (MK-801) was
significantly attenuated by clozapine. In the current
project, we found that the selective H(1) antagonist
pyrilamine also reversed the dizocilpine-induced impairment
in PPI of tactile startle with an auditory prepulse. In the
radial-arm maze (RAM), pyrilamine, like clozapine, impaired
working memory and caused a significant dose-related slowing
of response. Pyrilamine, however, decreased the number of
reference memory errors. We have previously shown that
nicotine effectively attenuates the clozapine-induced
working memory impairment, but in the current study,
nicotine did not significantly alter the effects of
pyrilamine on the RAM. In summary, the therapeutic effect of
clozapine in reversing PPI impairment was mimicked by the
H(1) antagonist pyrilamine, while pyrilamine had a mixed
effect on cognition. Pyrilamine impaired working memory but
improved reference memory in rats. Thus, H(1) antagonism
seems to play a role in part of the beneficial actions of
antipsychotics, such as clozapine.},
Doi = {10.1016/j.pbb.2007.02.014},
Key = {fds274243}
}
@article{fds274241,
Author = {Levin, ED and Caldwell, DP and Perraut, C},
Title = {Clozapine treatment reverses dizocilpine-induced deficits of
pre-pulse inhibition of tactile startle response.},
Journal = {Pharmacol Biochem Behav},
Volume = {86},
Number = {3},
Pages = {597-605},
Year = {2007},
Month = {March},
ISSN = {0091-3057},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17355891},
Abstract = {Pre-pulse inhibition (PPI) is a phenomenon of
neurobehavioral plasticity in which the motor response to a
startling sensory stimulus is inhibited by a preceding
sensory stimulus of a lower intensity. The current
experiment used tactile startle rather than acoustic startle
to determine the generality of PPI across sensory
modalities. PPI is easily modeled in experimental animals
and serves as a useful method for determining the neural
bases for sensorimotor plasticity, which can be disturbed in
sensory modulation disorders. In the current study, female
Sprague-Dawley rats were tested for tactile startle PPI
after an auditory pre-pulse. The glutamate NMDA receptor
antagonist dizocilpine (MK-801, 0.05 mg/kg) caused a nearly
total blockade of the PPI effect (p<0.0005). The
antipsychotic drug clozapine (1.25 mg/kg, p<0.001 and 2.5
mg/kg p<0.05) significantly attenuated the
dizocilpine-induced PPI impairment. Interestingly, the lower
clozapine dose did not by self enhance PPI and the higher
clozapine dose when given alone caused a significant
(p<0.05) PPI impairment relative to control. Nicotine (0.2
and 0.4 mg/kg) did not significantly interact with the other
treatments, though the higher nicotine dose did show a trend
toward attenuating the PPI impairment caused by the high
clozapine dose. These effects were replicated in a second
experiment of clozapine-dizocilpine interactions without
nicotine treatment. This study shows that PPI of tactile
startle is dramatically impaired by blocking NMDA activation
and that the prototypic atypical antipsychotic drug
clozapine can correct this deficit. This may be relevant to
the action of clozapine in attenuating sensory gating
deficits in schizophrenia and may point to new avenues of
treatment for sensory modulation disorders in which there is
excessive tactile response.},
Doi = {10.1016/j.pbb.2007.02.005},
Key = {fds274241}
}
@article{fds274240,
Author = {Matta, SG and Balfour, DJ and Benowitz, NL and Boyd, RT and Buccafusco,
JJ and Caggiula, AR and Craig, CR and Collins, AC and Damaj, MI and Donny,
EC and Gardiner, PS and Grady, SR and Heberlein, U and Leonard, SS and Levin, ED and Lukas, RJ and Markou, A and Marks, MJ and McCallum, SE and Parameswaran, N and Perkins, KA and Picciotto, MR and Quik, M and Rose,
JE and Rothenfluh, A and Schafer, WR and Stolerman, IP and Tyndale, RF and Wehner, JM and Zirger, JM},
Title = {Guidelines on nicotine dose selection for in vivo
research.},
Journal = {Psychopharmacology (Berl)},
Volume = {190},
Number = {3},
Pages = {269-319},
Year = {2007},
Month = {February},
ISSN = {0033-3158},
url = {http://dx.doi.org/10.1007/s00213-006-0441-0},
Abstract = {RATIONALE: This review provides insight for the judicious
selection of nicotine dose ranges and routes of
administration for in vivo studies. The literature is
replete with reports in which a dosaging regimen chosen for
a specific nicotine-mediated response was suboptimal for the
species used. In many cases, such discrepancies could be
attributed to the complex variables comprising
species-specific in vivo responses to acute or chronic
nicotine exposure. OBJECTIVES: This review capitalizes on
the authors' collective decades of in vivo nicotine
experimentation to clarify the issues and to identify the
variables to be considered in choosing a dosaging regimen.
Nicotine dose ranges tolerated by humans and their animal
models provide guidelines for experiments intended to
extrapolate to human tobacco exposure through cigarette
smoking or nicotine replacement therapies. Just as important
are the nicotine dosaging regimens used to provide a
mechanistic framework for acquisition of drug-taking
behavior, dependence, tolerance, or withdrawal in animal
models. RESULTS: Seven species are addressed: humans,
nonhuman primates, rats, mice, Drosophila, Caenorhabditis
elegans, and zebrafish. After an overview on nicotine
metabolism, each section focuses on an individual species,
addressing issues related to genetic background, age, acute
vs chronic exposure, route of administration, and behavioral
responses. CONCLUSIONS: The selected examples of successful
dosaging ranges are provided, while emphasizing the
necessity of empirically determined dose-response
relationships based on the precise parameters and conditions
inherent to a specific hypothesis. This review provides a
new, experimentally based compilation of species-specific
dose selection for studies on the in vivo effects of
nicotine.},
Doi = {10.1007/s00213-006-0441-0},
Key = {fds274240}
}
@article{fds274239,
Author = {Levin, ED and Bencan, Z and Cerutti, DT},
Title = {Anxiolytic effects of nicotine in zebrafish.},
Journal = {Physiol Behav},
Volume = {90},
Number = {1},
Pages = {54-58},
Year = {2007},
Month = {January},
ISSN = {0031-9384},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17049956},
Abstract = {Anxiolytic effects of nicotine have been documented in
studies with rodents and humans. Understanding the neural
basis of nicotine-induced anxiolysis can help both with
developing better aids for smoking cessation as well as with
the potential development of novel nicotinic ligands for
treating anxiety. Complementary non-mammalian models may be
useful for determining the molecular bases of nicotine
effects on neurobehavioral function. The current project
examined whether a zebrafish model of anxiety would be
sensitive to nicotine. When zebrafish are placed in a novel
environment, they dive to the bottom of the tank. In the
wild, diving could help to escape predation. We tested the
anxiolytic effect of nicotine on the novelty-elicited diving
response and subsequent habituation. Zebrafish placed in a
novel tank spent the majority of time at the bottom third of
the tank during the first minute of a 5-min session and then
show a gradual decrease in time spent at the tank bottom.
Nicotine treatment at 100 mg/l for 3 min by immersion before
testing caused a significant decrease in diving throughout
the session, while 50 mg/l was effective during the first
minute when the greatest bottom dwelling was seen in
controls. Nicotine effects were reversed by the nicotinic
antagonist mecamylamine given together with nicotine, but
not when administered shortly before the test session after
prior nicotine dosing. This implies that the effect of
nicotine on diving was due to net stimulation at nicotinic
receptors, an effect that is blocked by mecamylamine; and
that once invoked, this effect is no longer dependent on
continuing activation of nicotinic receptors. The effect of
nicotine on diving did not seem to be the result of a
general disorientation of the fish. The 100 mg/ml nicotine
dose was shown in our earlier study to significantly improve
spatial-discrimination learning in zebrafish.
Nicotine-induced anxiolytic effects can be modeled in the
zebrafish. This preparation will help in the investigation
of the molecular bases of this effect.},
Doi = {10.1016/j.physbeh.2006.08.026},
Key = {fds274239}
}
@article{fds274238,
Author = {Rezvani, AH and Overstreet, DH and Levin, ED and Rosenthal, DI and Kordik, CP and Reitz, AB and Vaidya, AH},
Title = {Effects of atypical anxiolytic N-phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide
(JNJ-5234801) on alcohol intake in alcohol-preferring P
rats.},
Journal = {Alcohol Clin Exp Res},
Volume = {31},
Number = {1},
Pages = {57-63},
Year = {2007},
Month = {January},
ISSN = {0145-6008},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17207102},
Abstract = {BACKGROUND: N-Phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide
(JNJ-5234801) is a structurally novel atypical anxiolytic
with an overall in vivo profile in animals suggestive of the
potential to show anxiolytic efficacy in humans at doses
that will not cause CNS-related side effects. Furthermore,
unlike the benzodiazepines, JNJ-5234801 does not have an
adverse interaction with ethanol even at doses 20 to 40
times the minimal effective dose in the rat elevated plus
maze (MED=1.0 mg/kg, p.o.). METHODS: In the present study,
JNJ-5234801 was evaluated for potential efficacy in reducing
alcohol intake in alcohol-preferring rats.
Alcohol-preferring P rats were allowed to drink water or
alcohol (10%, v/v) in a 2-bottle choice procedure. Once
stable baselines were established, the acute effects of
JNJ-5234801 [(10-40 mg/kg, intraperitoneally (i.p.)] were
assessed. In a separate study, chronic treatment with
JNJ-5234801 (40 mg/kg once daily, i.p.) for 12 consecutive
days was compared with naltrexone (20 mg/kg, twice daily,
i.p.). RESULTS: There was a selective dose-dependent
reduction in alcohol intake in the alcohol-preferring (P)
rats after acute administration of JNJ-5234801 (10-40 mg/kg,
i.p.). There were no significant effects on food or water
intake. When administered subchronically, both JNJ-5234801
(40 mg/kg once daily, i.p.) and naltrexone (20 mg/kg, twice
daily, i.p.) considerably reduced alcohol intake, but
tolerance to the alcohol-suppressing effects appeared to
occur sooner in the naltrexone-treated group. While both
compounds slightly but significantly reduced food intake at
the beginning, only JNJ-5234801 increased water intake and
decreased alcohol preference. CONCLUSIONS: The novel
atypical anxiolytic JNJ-5234801 has a favorable profile
effects on alcohol intake and related measures compared with
naltrexone, which is recommended for the treatment of
alcoholism.},
Doi = {10.1111/j.1530-0277.2006.00264.x},
Key = {fds274238}
}
@article{fds274242,
Author = {Levin, ED and Lawrence, SS and Petro, A and Horton, K and Rezvani, AH and Seidler, FJ and Slotkin, TA},
Title = {Adolescent vs. adult-onset nicotine self-administration in
male rats: duration of effect and differential nicotinic
receptor correlates.},
Journal = {Neurotoxicol Teratol},
Volume = {29},
Number = {4},
Pages = {458-465},
Year = {2007},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17433619},
Abstract = {Adolescence is the life stage when tobacco addiction
typically begins. Adolescent neurobehavioral development may
be altered by nicotine self-administration in a way that
persistently potentiates addiction. Previously, we showed
that female adolescent rats self-administer more nicotine
than do adults and that the increased nicotine intake then
persists through the transition to adulthood [E.D. Levin, A.
Rezvani, D. Montoya, J. Rose, H. Swartzwelder,
Adolescent-onset nicotine self-administration modeled in
female rats, Psychopharmacology 169 (2003) 141-149.]. In the
current study, male Sprague-Dawley rats were given access to
nicotine via the standard operant IV self-administration
procedure (nicotine bitartrate dose of 0.03 mg/kg/infusion).
One group of male rats started during adolescence the other
group started in young adulthood. After the end of the
four-week period of self-administration brain regions of the
rats were assessed for alpha4beta2 nicotinic receptor
binding. We found that male rats, like females, show higher
nicotine self-administration when starting during
adolescence as compared to starting in adulthood (p<0.001).
Indeed, the effect in adolescent males was even greater than
that in females, with more than triple the rate of nicotine
self-administration vs. the adult-onset group during the
first 2 weeks. The adolescent onset nicotine-self-administering
rats also had significantly greater high affinity nicotinic
receptor binding in the midbrain and the striatum, whereas
hippocampal binding did not differ between the age groups.
Striatal values significantly correlated with nicotine
self-administration during the first 2 weeks in the
adult-onset group but not the adolescent-onset rats,
suggesting that the differences in self-administration may
depend in part on underlying disparities in synaptic
responses to nicotine. After the initial 2 weeks, nicotine
self-administration in male rats declined toward adult-like
levels, as the adolescent rats approached adulthood. This
study showed that adolescent male rats self-administer
significantly more nicotine than do male adult rats, but
that adolescent-onset nicotine self-administration in male
rats declines over weeks of continued use to approach
adult-onset levels. In a previous study, we found that
female rats also show greater nicotine self-administration
with adolescent onset vs. adult onset, but that the females
continued higher rates of self-administration into
adulthood. Our results thus reinforce the concept that the
adolescent brain is unusually receptive to the effects of
nicotine in a manner that reinforces the potential for
addiction.},
Doi = {10.1016/j.ntt.2007.02.002},
Key = {fds274242}
}
@article{fds274234,
Author = {McClernon, FJ and Hiott, FB and Westman, EC and Rose, JE and Levin,
ED},
Title = {Transdermal nicotine attenuates depression symptoms in
nonsmokers: a double-blind, placebo-controlled
trial.},
Journal = {Psychopharmacology (Berl)},
Volume = {189},
Number = {1},
Pages = {125-133},
Year = {2006},
Month = {November},
ISSN = {0033-3158},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16977477},
Abstract = {RATIONALE: Despite established links between nicotine
dependence and depression, little research has examined the
effects of nicotine on depression symptoms. OBJECTIVE: This
study evaluated the acute and chronic effects of transdermal
nicotine in nonsmokers with baseline depression symptoms
during a 4-week, double-blind, placebo-controlled trial.
METHODS: Nonsmokers with scores >or=10 on the Center for
Epidemiological Studies Depression scale (CES-D) were
recruited from the community. Mood and cognitive performance
were measured at baseline (day 0) and at 1, 8, 21, and 28
days. Participants were randomly assigned to wear a placebo
or nicotine patch for 4 weeks (3.5 mg/day during weeks 1 and
4; 7 mg/day during weeks 2 and 3). The final sample
consisted of 11 nonsmokers with a mean baseline CES-D score
of 27.36 (SD=10.53). RESULTS: Salivary nicotine levels
indicated the majority of participants were compliant with
treatment. Acute nicotine did not alter mood. After
adjusting for baseline values, chronic nicotine resulted in
a significant decline in CES-D scores at day 8 (3.5 mg/day),
but returned to placebo levels by the last visit. This
return to baseline levels was coincident with a decrease in
nicotine administration from 7 to 3.5 mg/day. A similar
trend for improved response inhibition as measured by the
Conners Continuous Performance Task was also observed.
Reported side effects were infrequent and minimal.
CONCLUSION: These findings suggest a role for nicotinic
receptor systems in the pathophysiology of depression and
that nicotinic compounds should be evaluated for treating
depression symptoms.},
Doi = {10.1007/s00213-006-0516-y},
Key = {fds274234}
}
@article{fds274236,
Author = {Levin, ED and Lawrence, S and Petro, A and Horton, K and Seidler, FJ and Slotkin, TA},
Title = {Increased nicotine self-administration following prenatal
exposure in female rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {85},
Number = {3},
Pages = {669-674},
Year = {2006},
Month = {November},
ISSN = {0091-3057},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17196243},
Abstract = {There is a significant association between maternal
cigarette smoking during pregnancy and greater subsequent
risk of smoking in female offspring. In animal models,
prenatal nicotine exposure causes persistent alterations in
cholinergic and monoaminergic systems, both of which are
important for nicotine actions underlying tobacco addiction.
Accordingly, the current study was conducted to determine if
there is a cause-and-effect relationship between prenatal
nicotine exposure and nicotine self-administration starting
in adolescence. Pregnant rats were administered nicotine (6
mg/kg/day) by osmotic minipump infusion throughout gestation
and then, beginning in adolescence and continuing into
adulthood, female offspring were given access to nicotine
via a standard operant IV self-administration procedure
(0.03 mg/kg/infusion). Gestational nicotine exposure did not
alter the initial rate of nicotine self-administration.
However, when animals underwent one week of forced
abstinence and then had a second opportunity to
self-administer nicotine, the prenatally-exposed animals
showed a significantly greater rate of self-administration
than did the controls. Prenatal nicotine exposure causes
increased nicotine self-administration, which is revealed
only when the animals are allowed to experience a period of
nicotine abstinence. This supports a cause-and-effect
relationship between the higher rates of smoking in the
daughters of women who smoke cigarettes during pregnancy and
implicates a role for nicotine in this effect. Our results
further characterize the long-term liabilities of maternal
smoking but also point to the potential liabilities of
nicotine-based treatments for smoking cessation during
pregnancy.},
Doi = {10.1016/j.pbb.2006.11.006},
Key = {fds274236}
}
@article{fds274237,
Author = {Pocivavsek, A and Icenogle, L and Levin, ED},
Title = {Ventral hippocampal alpha7 and alpha4beta2 nicotinic
receptor blockade and clozapine effects on memory in female
rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {188},
Number = {4},
Pages = {597-604},
Year = {2006},
Month = {November},
ISSN = {0033-3158},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16715255},
Abstract = {RATIONALE: Nicotinic systems in the hippocampus play
important roles in memory function. Decreased hippocampal
nicotinic receptor concentration is associated with
cognitive impairment in schizophrenia and Alzheimer's
disease. METHODS: We modeled in rats the cognitive effects
of chronic decrease in hippocampal alpha7 or alpha4beta2
receptors with 4-week continuous bilateral local infusions
of the alpha7 nicotinic antagonist methyllycaconitine (MLA)
or the alpha4beta2 antagonist dihydro-beta-erythroidine
(DHbetaE). The working memory effects of these infusions
were assessed by performance on the radial-arm maze. To test
the effect of antipsychotic medication, we gave acute
injections of clozapine and to determine the impact of
nicotine, which is widely used by people with schizophrenia
approximately half of the rats received chronic systemic
infusions of nicotine. RESULTS: Chronic ventral hippocampal
DHbetaE infusion caused a significant (p < 0.001) working
memory impairment. Acute systemic clozapine (2.5 mg/kg)
caused a significant (p < 0.005) working memory impairment
in rats given control aCSF hippocampal infusions. Clozapine
significantly (p < 0.025) attenuated the memory deficit
caused by chronic hippocampal DHbetaE infusions. Chronic
ventral hippocampal infusions with MLA did not significantly
affect the working memory performance in the radial-arm
maze, but it did significantly (p < 0.05) potentiate the
memory impairment caused by 1.25 mg/kg of clozapine. Chronic
systemic nicotine did not significantly interact with these
effects. CONCLUSIONS: The state of nicotinic receptor
activation in the ventral hippocampus significantly affected
the impact of clozapine on working memory with blockade of
alpha7 nicotinic receptors potentiating clozapine-induced
memory impairment and blockade of alpha4beta2 receptors
reversing the clozapine effect from impairing to improving
memory.},
Doi = {10.1007/s00213-006-0416-1},
Key = {fds274237}
}
@article{fds274233,
Author = {Slotkin, TA and Tate, CA and Ryde, IT and Levin, ED and Seidler,
FJ},
Title = {Organophosphate insecticides target the serotonergic system
in developing rat brain regions: disparate effects of
diazinon and parathion at doses spanning the threshold for
cholinesterase inhibition.},
Journal = {Environ Health Perspect},
Volume = {114},
Number = {10},
Pages = {1542-1546},
Year = {2006},
Month = {October},
ISSN = {0091-6765},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17035140},
Abstract = {BACKGROUND: In the developing brain, serotonin (5HT) systems
are among the most sensitive to disruption by
organophosphates. OBJECTIVES: We exposed neonatal rats to
daily doses of diazinon or parathion on postnatal days
(PND)1-4 and evaluated 5HT receptors and the 5HT transporter
in brainstem and forebrain on PND5, focusing on doses of
each agent below the maximum tolerated dose and spanning the
threshold for cholinesterase inhibition: 0.5, 1, or 2 mg/kg
for diazinon, and 0.02, 0.05, and 0.1 mg/kg for parathion.
RESULTS: Diazinon evoked up-regulation of 5HT1A and 5HT2
receptor expression even at doses devoid of effects on
cholinesterase activity, a pattern similar to that seen
earlier for another organophosphate, chlorpyrifos. In
contrast, parathion decreased 5HT1A receptors, again at
doses below those required for effects on cholinesterase.
The two agents also differed in their effects on the 5HT
transporter. Diazinon evoked a decrease in the brainstem and
an increase in the forebrain, again similar to that seen for
chlorpyrifos; this pattern is typical of damage of nerve
terminals and reactive sprouting. Parathion had smaller,
nonsignificant effects. CONCLUSIONS: Our results buttress
the idea that, in the developing brain, the various
organophosphates target specific neurotransmitter systems
differently from each other and without the requirement for
cholinesterase inhibition, their supposed common mechanism
of action.},
Doi = {10.1289/ehp.9337},
Key = {fds274233}
}
@article{fds274232,
Author = {Levin, ED and Caldwell, DP},
Title = {Low-dose mecamylamine improves learning of rats in the
radial-arm maze repeated acquisition procedure.},
Journal = {Neurobiol Learn Mem},
Volume = {86},
Number = {1},
Pages = {117-122},
Year = {2006},
Month = {July},
ISSN = {1074-7427},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16632386},
Abstract = {The nicotinic antagonist mecamylamine has been widely shown
to cause cognitive impairment. However, these effects are
mainly seen with high doses. There have been scattered
findings that low doses of mecamylamine can have the
opposite effect. This may be due to opposite effects of low
doses of mecamylamine. In the current study, an extensive
dose-effect function of mecamylamine was characterized in
the low-dose range. Adult female Sprague-Dawley rats were
trained on a repeated acquisition procedure on an automated
8-arm radial maze. Three of the eight arms were designated
as correct for any particular session. Five trials per
session were run. The number of errors per trial to find the
three correct arms was determined. The rats were trained on
the repeated acquisition procedure for at least 18 sessions
at which time they showed reliable learning each session.
Then, the effect of low doses of mecamylamine between 0 and
1 mg/kg were assessed in a repeated measures counterbalanced
design. This dose range of mecamylamine did not affect
performance on the first trial when the rats were naïve to
the array to be learned. On trials 2-5 a significant
(p<.025) quadratic dose-effect function was seen over this
dose range. The most substantial effect was seen with 0.125
mg/kg of mecamylamine, which caused a significant (p<.05)
improvement relative to the saline control condition. The
effect diminished with increasing mecamylamine doses and
with the 1 mg/kg dose choice accuracy was back to control
levels. This study showed that low doses of mecamylamine can
effectively improve learning. A U-shaped dose-effect curve
was documented. This suggests possible low-dose nicotinic
antagonist lines of treatment for cognitive
impairment.},
Doi = {10.1016/j.nlm.2006.01.007},
Key = {fds274232}
}
@article{fds274230,
Author = {Schmajuk, NA and Larrauri, JA and Hagenbuch, N and Levin, ED and Feldon,
J and Yee, BK},
Title = {Startle and prepulse inhibition as a function of background
noise: a computational and experimental analysis.},
Journal = {Behav Brain Res},
Volume = {170},
Number = {2},
Pages = {182-196},
Year = {2006},
Month = {June},
ISSN = {0166-4328},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16569445},
Abstract = {Schmajuk and Larrauri [Schmajuk NA, Larrauri JA. Neural
network model of prepulse inhibition. Behav Neurosci
2005;119:1546-62.] introduced a real-time model of acoustic
startle, prepulse inhibition (PPI) and facilitation (PPF) in
animals and humans. The model assumes that (1) positive
values of changes in noise level activate an excitatory and
a facilitatory pathway, and (2) absolute values of changes
in noise level activate an inhibitory pathway. The model
describes many known properties of the phenomena and the
effect of brain lesions on startle, PPI, and PPF. The
purpose of the present study is to (a) establish the
magnitude of startle and PPI as a function of pulse,
prepulse, and background intensity, and (b) test the model
predictions regarding an inverted-U function that relates
startle to the intensity of the background
noise.},
Doi = {10.1016/j.bbr.2006.02.021},
Key = {fds274230}
}
@article{fds274231,
Author = {Slotkin, TA and Levin, ED and Seidler, FJ},
Title = {Comparative developmental neurotoxicity of organophosphate
insecticides: effects on brain development are separable
from systemic toxicity.},
Journal = {Environ Health Perspect},
Volume = {114},
Number = {5},
Pages = {746-751},
Year = {2006},
Month = {May},
ISSN = {0091-6765},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16675431},
Abstract = {A comparative approach to the differences between systemic
toxicity and developmental neurotoxicity of organophosphates
is critical to determine the degree to which multiple
mechanisms of toxicity carry across different members of
this class of insecticides. We contrasted neuritic outgrowth
and cholinergic synaptic development in neonatal rats given
different organophosphates (chlorpyrifos, diazinon,
parathion) at doses spanning the threshold for impaired
growth and viability. Animals were treated daily on
postnatal days 1-4 by subcutaneous injection so as to bypass
differences in first-pass activation to the oxon or
catabolism to inactive products. Evaluations occurred on day
5. Parathion (maximum tolerated dose, 0.1 mg/kg) was far
more systemically toxic than was chlorpyrifos or diazinon
(maximum tolerated dose, 1-5 mg/kg). Below the maximum
tolerated dose, diazinon impaired neuritic outgrowth in the
forebrain and brainstem, evidenced by a deficit in the ratio
of membrane protein to total protein. Diazinon also
decreased choline acetyltransferase activity, a cholinergic
neuronal marker, whereas it did not affect hemicholinium-3
binding to the presynaptic choline transporter, an index of
cholinergic neuronal activity. There was no
m(subscript)2(/subscript)-muscarinic acetylcholine receptor
down-regulation, as would have occurred with chronic
cholinergic hyperstimulation. The same pattern was found
previously for chlorpyrifos. In contrast, parathion did not
elicit any of these changes at its maximum tolerated dose.
These results indicate a complete dichotomy between the
systemic toxicity of organophosphates and their propensity
to elicit developmental neurotoxicity. For parathion, the
threshold for lethality lies below that necessary for
adverse effects on brain development, whereas the opposite
is true for chlorpyrifos and diazinon.},
Doi = {10.1289/ehp.8828},
Key = {fds274231}
}
@article{fds274228,
Author = {Nott, A and Levin, ED},
Title = {Dorsal hippocampal alpha7 and alpha4beta2 nicotinic
receptors and memory.},
Journal = {Brain Res},
Volume = {1081},
Number = {1},
Pages = {72-78},
Year = {2006},
Month = {April},
ISSN = {0006-8993},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16556437},
Abstract = {Nicotinic receptor systems have been shown to be important
for working memory. In general, nicotinic agonists have been
shown to improve memory, and nicotinic antagonists impair
it. All of the neuronal substrates for nicotinic involvement
in memory still remain to be discovered. The amygdala and
ventral hippocampus have both been found to be important for
nicotinic involvement in memory function. Local infusion of
the nicotinic antagonist methyllycaconitine (MLA) to block
alpha7 nicotinic receptors and dihydro-beta-erythrodine
(DHbetaE) to block alpha4beta2 nicotinic receptors into the
basolateral amygdala and the ventral hippocampus have been
found to impair working memory function, with no additive
effects being observed. The current project assessed the
roles of alpha7 and alpha4beta2 nicotinic receptors in the
dorsal hippocampus for memory function. Adult female
Sprague-Dawley rats were trained on the 16-arm radial maze.
The rats (n = 10) had bilateral cannulae implanted into the
dorsal hippocampus. The rats were given acute infusions of
DHbetaE (0, 1.69, 3.38, and 6.75 microg/side) and MLA (6.75
microg/side) alone and in combination in a repeated measures
counter-balanced design. DHbetaE and MLA infusion into the
dorsal hippocampus significantly increased working memory
errors. However, when the two drugs were given in
combination, an attenuated effect was seen. No significant
effects of MLA or DHbetaE were seen with reference memory
errors or response latency. These results confirm the
importance of alpha4beta2 and alpha7 nicotinic acetylcholine
receptors in the dorsal hippocampus for appetitively-motivated
spatial cognitive function.},
Doi = {10.1016/j.brainres.2006.01.052},
Key = {fds274228}
}
@article{fds274229,
Author = {Levin, ED and Perraut, C and Pollard, N and Freedman,
JH},
Title = {Metallothionein expression and neurocognitive function in
mice.},
Journal = {Physiol Behav},
Volume = {87},
Number = {3},
Pages = {513-518},
Year = {2006},
Month = {March},
ISSN = {0031-9384},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16430929},
Abstract = {Transition metals have been associated with impaired
neurological development, and neurobehavioral activity.
Metallothioneins are central components in the metabolism
and detoxification of a variety of metals, however, little
is known concerning their role in cognitive function. To
determine the role of metallothionein in learning and
memory, mice with deletions of two metallothionein genes
(MT-1 and MT-2) were trained on a win-shift task in an 8-arm
radial maze. The parental strain of mice learned the maze at
a normal rate over an 18-session acquisition period. In
contrast, the MT-1/MT-2-null mice, which had a similar
choice accuracy level at the beginning of training, showed a
poorer rate of learning during the training period. In
addition, the MT-1/MT-2-null mice showed significantly less
choice accuracy than the parental strain. The MT-1/MT-2-null
mice also showed a significant hypoactivity during the early
and middle parts of acquisition training, but they were not
different from the wildtype controls during the final phase
of training. Nicotine treatment, which can improve working
memory, eliminated the impairment associated with the
deletion of the MT-1 and MT-2 genes in a dose-related
fashion after acquisition training in the aging adult mice.
These results suggest that metallothioneins, through there
roles in metal physiology or cellular protection, are
involved in spatial learning and memory function.},
Doi = {10.1016/j.physbeh.2005.11.014},
Key = {fds274229}
}
@article{fds274224,
Author = {Levin, ED and McClernon, FJ and Rezvani, AH},
Title = {Nicotinic effects on cognitive function: behavioral
characterization, pharmacological specification, and
anatomic localization.},
Journal = {Psychopharmacology (Berl)},
Volume = {184},
Number = {3-4},
Pages = {523-539},
Year = {2006},
Month = {March},
ISSN = {0033-3158},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16220335},
Abstract = {RATIONALE: Nicotine has been shown in a variety of studies
in humans and experimental animals to improve cognitive
function. Nicotinic treatments are being developed as
therapeutic treatments for cognitive dysfunction.
OBJECTIVES: Critical for the development of nicotinic
therapeutics is an understanding of the neurobehavioral
bases for nicotinic involvement in cognitive function.
METHODS: Specific and diverse cognitive functions affected
by nicotinic treatments are reviewed, including attention,
learning, and memory. The neural substrates for these
behavioral actions involve the identification of the
critical pharmacologic receptor targets, in particular brain
locations, and how those incipient targets integrate with
broader neural systems involved with cognitive function.
RESULTS: Nicotine and nicotinic agonists can improve working
memory function, learning, and attention. Both alpha4beta2
and alpha7 nicotinic receptors appear to be critical for
memory function. The hippocampus and the amygdala in
particular have been found to be important for memory, with
decreased nicotinic activity in these areas impairing
memory. Nicotine and nicotinic analogs have shown promise
for inducing cognitive improvement. Positive therapeutic
effects have been seen in initial studies with a variety of
cognitive dysfunctions, including Alzheimer's disease,
age-associated memory impairment, schizophrenia, and
attention deficit hyperactivity disorder. CONCLUSIONS:
Discovery of the behavioral, pharmacological, and anatomic
specificity of nicotinic effects on learning, memory, and
attention not only aids the understanding of nicotinic
involvement in the basis of cognitive function, but also
helps in the development of novel nicotinic treatments for
cognitive dysfunction. Nicotinic treatments directed at
specific receptor subtypes and nicotinic cotreatments with
drugs affecting interacting transmitter systems may provide
cognitive benefits most relevant to different syndromes of
cognitive impairment such as Alzheimer's disease,
schizophrenia, and attention deficit hyperactivity disorder.
Further research is necessary in order to determine the
efficacy and safety of nicotinic treatments of these
cognitive disorders.},
Doi = {10.1007/s00213-005-0164-7},
Key = {fds274224}
}
@article{fds274225,
Author = {Rezvani, AH and Caldwell, DP and Levin, ED},
Title = {Chronic nicotine interactions with clozapine and risperidone
and attentional function in rats.},
Journal = {Prog Neuropsychopharmacol Biol Psychiatry},
Volume = {30},
Number = {2},
Pages = {190-197},
Year = {2006},
Month = {March},
ISSN = {0278-5846},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16310917},
Abstract = {Although antipsychotic drugs are therapeutically effective
in attenuating the hallmark symptoms of schizophrenia, these
improvements do not return most patients to normative
standards of cognitive function. Thus, complementary drug
treatment may be needed to treat the attentional deficits of
schizophrenia as well as to counteract the potential
attentional impairments caused by some antipsychotic drugs.
Nicotine, a drug commonly self-administered by a great
majority of individuals with schizophrenia, has been shown
to significantly improve cognitive function in some studies.
The current study was conducted to determine the interactive
effects of the atypical antipsychotic drugs clozapine and
risperidone with chronic nicotine administration on
attentional performance. Adult female Sprague-Dawley rats
(N=35) were trained to perform an attentional task using an
operant visual signal detection task. After training, rats
were infused with a dose of 5 mg/kg/day (s.c.) nicotine base
(n=18) or saline (n=17) for 28 consecutive days via osmotic
pump. In Exp. 1, while being administered chronic nicotine
or saline, rats were given acute doses of clozapine (0,
0.625, 1.25 and 2.5 mg/kg, s.c.) and were tested for
attentional function. In Exp. 2, while on chronic nicotine
or saline, other rats were challenged with acute doses of
risperidone (0, 0.025, 0.05 and 0.1 mg/kg, s.c.) and were
tested for attentional function. Results showed that acute
administration of clozapine caused a significant
dose-dependent impairment in choice accuracy (percent hit)
in animals treated with chronic saline. Chronic nicotine
treatment itself lowered accuracy, but attenuated further
declines with acute clozapine treatment. Acute
administration of risperidone at high dose significantly
reduced performance (percent correct rejection) in
chronically saline-treated rats, but in a similar fashion as
in Exp. 1, chronic nicotine lowered accuracy but attenuated
further impairment with acute risperidone. In summary,
atypical antipsychotic drugs clozapine and risperidone
significantly impaired choice accuracy in the visual signal
detection task. Clozapine was more detrimental than
risperidone but the adverse effects of both clozapine and
risperidone on attentional performance were masked in rats
chronically treated with nicotine.},
Doi = {10.1016/j.pnpbp.2005.10.017},
Key = {fds274225}
}
@article{fds274226,
Author = {Levin, ED and Christopher, NC},
Title = {Effects of clozapine on memory function in the rat neonatal
hippocampal lesion model of schizophrenia.},
Journal = {Prog Neuropsychopharmacol Biol Psychiatry},
Volume = {30},
Number = {2},
Pages = {223-229},
Year = {2006},
Month = {March},
ISSN = {0278-5846},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16356617},
Abstract = {Clozapine is an effective atypical antipsychotic drug used
to treat schizophrenia. It has the advantage of producing
fewer extrapyramidal motor side effects than typical
antipsychotic drugs such as haloperidol. Schizophrenia
involves more than the hallmark symptom of psychosis.
Substantial cognitive impairment is also seen. Effective
drug treatments against the cognitive impairment of
schizophrenia need to be developed. The current study was
conducted to determine the effects of clozapine on working
memory in the rat neonatal hippocampal lesion model of
schizophrenia, which includes symptoms of cognitive
impairment. Infant Sprague-Dawley rats were given ibotenic
acid lesions of the hippocampus on day 7 of age (using the
day of birth as day 0). Controls were given vehicle
infusions. In adulthood, the rats were trained on the 8-arm
radial maze using the win-shift procedure. After 6 sessions
of training, the lesioned rats and their controls were
administered repeated injections of saline or clozapine (2.5
mg/kg) for the next 12 sessions of training. The females had
significant radial-arm maze choice accuracy impairments
caused by either clozapine or the hippocampal lesion, but
the combination of the two treatments had no additive
effect. The males showed a different pattern of effects.
Intact males did not show a significant clozapine-induced
impairment, whereas males with hippocampal lesions did show
significant clozapine-induced impairment although
hippocampal lesions by themselves did not significantly
impair male choice accuracy. These data show that clozapine
can cause memory impairment and it potentiates rather than
reverses hippocampal lesion-induced deficits. There are
critical sex-related differences in these
effects.},
Doi = {10.1016/j.pnpbp.2005.10.018},
Key = {fds274226}
}
@article{fds274227,
Author = {Levin, ED and Limpuangthip, J and Rachakonda, T and Peterson,
M},
Title = {Timing of nicotine effects on learning in
zebrafish.},
Journal = {Psychopharmacology (Berl)},
Volume = {184},
Number = {3-4},
Pages = {547-552},
Year = {2006},
Month = {March},
ISSN = {0033-3158},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16175402},
Abstract = {RATIONALE: Nicotine has been shown in many, but not all,
studies to improve cognitive function in a number of species
including rats, mice, monkeys, and humans. Recently, we have
found that nicotine also improves memory in zebrafish.
Nicotinic agonists are being developed as novel treatments
for Alzheimer's disease and other cognitive impairments.
OBJECTIVES: In screening the therapeutic potential of novel
nicotinic agonists, it is important to have a rapid assay of
cognitive improvement. Zebrafish can help with this effort.
METHODS: We have developed a method of rapidly assessing
spatial position discrimination learning in zebrafish in one
session of seven trials. We used this method to determine
the cognitive effects of nicotine. RESULTS: Nicotine (100
mg/l administered during 3 min of immersion) caused a
significant improvement in percent correct performance. This
dose was within the effective range we found to improve the
choice accuracy performance of zebrafish using the more
time-intensive delayed spatial alternation procedure.
Interestingly, the positive effect of nicotine was seen at
20-40 min postadministration, but not earlier, and declined
at 80 and 160 min posttreatment. At the 40-min postdosing
interval, 200 mg/l nicotine was also found to significantly
improve choice accuracy. Nicotine-induced accuracy
improvement was reversed by the nicotinic antagonist
mecamylamine given shortly before testing but not when given
concurrently with nicotine. CONCLUSIONS: This position
discrimination procedure in zebrafish effectively
demonstrated the cognitive-enhancing effects of nicotine.
This model may be useful in the early screening of novel
nicotinic compounds for treatment of cognitive
dysfunction.},
Doi = {10.1007/s00213-005-0162-9},
Key = {fds274227}
}
@article{fds274400,
Author = {Timme-Laragy, AR and Levin, ED and Di Giulio and RT},
Title = {Developmental and behavioral effects of embryonic exposure
to the polybrominated diphenylether mixture DE-71 in the
killifish (Fundulus heteroclitus).},
Journal = {Chemosphere},
Volume = {62},
Number = {7},
Pages = {1097-1104},
Year = {2006},
Month = {February},
ISSN = {0045-6535},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16045967},
Keywords = {Animals • Behavior, Animal • Embryo, Nonmammalian
• Fundulidae • Maze Learning • Phenyl Ethers
• Polybrominated Biphenyls • Swimming • Water
Pollutants, Chemical • drug effects • drug
effects* • embryology • growth & development*
• toxicity*},
Abstract = {Exposures to penta polybrominated diphenylether (PeBDE)
cause neurobehavioral toxicity in developing mice and rats.
As levels of these ubiquitous contaminants are increasing in
the environment, this raises concern that wildlife may also
suffer such effects, with consequences for their ability to
catch prey and avoid predators. PeBDE levels in wild-caught
fish have been steadily escalating over the past fifteen
years. To our knowledge, behavioral consequences of piscine
embryonic exposure to PeBDE has not yet been studied. The
objectives of this investigation were to characterize
effects on development in an environmentally relevant fish
model, and test for latent behavioral effects following
cessation of exposure. Embryos from the estuarine minnow,
Fundulus heteroclitus, were exposed from day 0-7 post
fertilization to the industrial PeBDE mixture, DE-71 (0.001
to 100 microg l(-1)). Embryos were assayed for hatching
success, development, and microsomal enzyme cytochrome
P4501A (CYP1A) activity, which was determined by analysis of
in ovo ethoxy-resorufin-O-deethylase (EROD) activation in
embryos. Larval fish were assayed for predation ability,
activity level, and fright response to a simulated predator.
Juvenile fish were assayed for learning ability in a
three-chambered fish maze. No induction of embryonic EROD
activity was observed, nor was a high dose of DE-71 able to
inhibit EROD activity induced by beta-naphthoflavone. No
deformities were detected, but a subtle developmental
asymmetry with respect to tail curvature direction was
observed, and a hatching delay of up to 4.5 days was noted.
Behavioral test results suggest that embryonic exposure to
DE-71 may alter activity level, fright response, predation
rates, and learning ability in subsequent life
stages.},
Doi = {10.1016/j.chemosphere.2005.05.037},
Key = {fds274400}
}
@article{fds274223,
Author = {Levin, ED and Rezvani, AH},
Title = {Nicotinic-antipsychotic drug interactions and cognitive
function.},
Journal = {EXS},
Volume = {98},
Pages = {185-205},
Year = {2006},
ISSN = {1023-294X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17019889},
Abstract = {In summary, neuronal nicotinic systems are important for a
variety of aspects of cognitive function impacted by
antipsychotic drugs. It has been demonstrated that
antipsychotic drugs have memory and attentional impairing
effects when given to unimpaired subjects. Nicotine can
reduce some of these impairments, but antipsychotic drug
administration can also attenuate nicotine effects. We have
found that nicotinic agonists selective for alpha7 and
alpha4beta2 receptor subtypes significantly improve learning
and memory. Serotonergic actions of antipsychotic drugs may
decrease efficacy of nicotinic co-treatments. When the
antipsychotic drug clozapine and nicotine are administered
to subjects with cognitive impairments caused by NMDA
glutamate receptor blockade or hippocampal dysfunction they
can significantly attenuate the attentional and memory
impairments. Nicotine has been shown in our studies to
reverse the memory impairment caused by acute
clozapine-induced memory improvement. Acute risperidone and
haloperidol has been shown to attenuate nicotine-induced
memory improvement. We have determined the role of
hippocampal alpha7 and alpha4beta2 nicotinic receptors in
the neural basis of nicotinic antipsychotic interactions.
Local acute and chronic hippocampal infusion of either
nicotinic alpha7 or alpha4beta2 antagonists cause
significant spatial working memory impairment. Chronic
hippocampal nicotinic antagonist infusions have served as a
model of persistent decreases in nicotinic receptor level
seen in schizophrenia and Alzheimer's disease. Clozapine
attenuated the memory deficit caused by chronic suppression
of hippocampal alpha4beta2 receptors while the amnestic
effects of clozapine were potentiated by chronic suppression
of hippocampal alpha7 receptors. Nicotinic co-treatment may
be a useful adjunct in the treatment of schizophrenia, to
attenuate cognitive impairment of schizophrenia. Nicotine as
well as selective nicotinic alpha7 and alpha4beta2 receptor
agonists significantly improve working memory and
attentional function. Nicotine treatment was found to be
effective in attenuating the attentional and memory
impairments caused by the psychototmimetic NMDA antagonist
dizocilpine (MK-801), a model of the cognitive impairment of
schizophrenia. Studies of the interactions of antipsychotic
drugs with nicotinic agents provided quite useful
information concerning possible co-treatment of people with
schizophrenia with nicotinic therapy. Nicotine was found to
significantly attenuate the memory impairments caused by the
antipsychotic drugs clozapine and olanzapine. Interestingly,
nicotine-induced cognitive improvement was significantly
attenuated by the antipsychotic drug clozapine. One of the
principal effects of clozapine is to block 5HT2 receptors.
Ketanserin a 5HT2 antagonist significantly attenuated
nicotine-induced improvements in attention and memory. Thus
it appears that antipsychotic drugs with actions blocking
5HT2 receptors may limit the efficacy of nicotinic
co-treatments for cognitive enhancement.},
Doi = {10.1007/978-3-7643-7772-4_10},
Key = {fds274223}
}
@article{fds274235,
Author = {Levin, ED and Pang, WG and Harrison, J and Williams, P and Petro, A and Ramsdell, JS},
Title = {Persistent neurobehavioral effects of early postnatal domoic
acid exposure in rats.},
Journal = {Neurotoxicol Teratol},
Volume = {28},
Number = {6},
Pages = {673-680},
Year = {2006},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17046199},
Abstract = {Domoic acid (DA) is a marine biotoxin, produced by the
diatom Pseudo-nitzchia spp., which has been shown to cause
cognitive impairment in adults who are exposed via
contaminated seafood. The neurobehavioral consequences of
developmental exposure are much less well understood. In a
previous study, we showed that a single prenatal exposure to
DA in rats at mid-gestation caused neurobehavioral changes
that persist into adulthood including increased
susceptibility to the benchmark amnestic drug scopolamine.
In the current study, we examined the lasting
neurobehavioral consequences of DA exposure on the first day
of postnatal life, a time in rats marking the completion of
the major phase of neuroproliferation and corresponding to
week 24 of human gestation. The effects of DA exposure at
doses from 0.025-0.1 mg/kg (s.c.) twice per day on each of
postnatal days 1 and 2 were compared with vehicle-treated
controls and rats treated by the same protocol with 1 mg/kg
of kainic acid. Following kainic acid exposure, a
sex-selective effect was seen with females but not males
showing a significant slowing of response latency in the
radial-arm maze. The high DA dose of 0.1 mg/kg was quite
toxic causing lethality in all of the offspring exposed and
this group was excluded from further analysis. When the
offspring in the 0.05 mg/kg DA dose group were tested,
significant hypoactivity in the Figure-8 maze was observed
during adolescence. No significant DA effects were seen in
response latency or choice accuracy on the radial-arm maze
during either acquisition or with challenge of the amnestic
drug scopolamine. Early postnatal DA exposure in the rat can
be lethal and sublethal exposure can cause neurobehavioral
effects manifest in modest hypoactivity during the
adolescent period. However, the sublethal persistent
neurobehavioral toxicity appears to be less pervasive than
reported effects following DA administered
mid-gestation.},
Doi = {10.1016/j.ntt.2006.08.005},
Key = {fds274235}
}
@article{fds274339,
Author = {Levin, ED},
Title = {The rationale for studying transmitter interactions to
understand the neural bases of cognitive
function.},
Journal = {EXS},
Volume = {98},
Pages = {1-3},
Year = {2006},
ISSN = {1023-294X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17019880},
Doi = {10.1007/978-3-7643-7772-4_1},
Key = {fds274339}
}
@article{fds274222,
Author = {Levin, E and Icenogle, L and Farzad, A},
Title = {Ketanserin attenuates nicotine-induced working memory
improvement in rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {82},
Number = {2},
Pages = {289-292},
Year = {2005},
Month = {October},
ISSN = {0091-3057},
url = {http://dx.doi.org/10.1016/j.pbb.2005.08.017},
Abstract = {Nicotinic systems have been shown in numerous studies to be
important for spatial working memory. Nicotinic systems are
certainly not acting alone in the basis of memory function,
but act in concert with a variety of other neural systems.
Important for these interactions is nicotinic induced
release of a variety of neurotransmitters involved in memory
function including serotonin (5-HT). We have found that the
5-HT2 receptor antagonist, ketanserin, effectively
attenuated nicotine-induced attentional improvement. The
current study explored the interaction between nicotinic and
serotonergic systems in the performance of a spatial working
memory task in the radial-arm maze. Female Sprague-Dawley
rats were trained on the win-shift working memory task on
the 8-arm radial maze. After 18 sessions of acquisition
training the rats were given acute doses of nicotine (0.2
and 0.4 mg/kg), ketanserin (0.5, 1 and 2 mg/kg) or
combinations of the two. The vehicle served as the control.
As seen in previous studies, nicotine caused a significant
improvement in working memory performance as indexed by the
number of correct arm entries before the first error
(entries to repeat). Ketanserin at the doses tested did not
cause a significant effect on choice accuracy, but it did
significantly attenuate the improvement caused by the 0.2
mg/kg nicotine dose. The higher 0.4 mg/kg nicotine dose was
nearly sufficient to overcome the ketanserin effect. This
study shows that, as with attentional function,
nicotine-induced working memory improvement is attenuated by
the 5-HT2 antagonist ketanserin. Given that many
antipsychotic drugs have substantial 5-HT2 antagonist
effects, these atypical antipsychotic drugs may reduce the
cognitive improvements caused by nicotinic
treatments.},
Doi = {10.1016/j.pbb.2005.08.017},
Key = {fds274222}
}
@article{fds274219,
Author = {Barron, S and White, A and Swartzwelder, HS and Bell, RL and Rodd, ZA and Slawecki, CJ and Ehlers, CL and Levin, ED and Rezvani, AH and Spear,
LP},
Title = {Adolescent vulnerabilities to chronic alcohol or nicotine
exposure: findings from rodent models.},
Journal = {Alcohol Clin Exp Res},
Volume = {29},
Number = {9},
Pages = {1720-1725},
Year = {2005},
Month = {September},
ISSN = {0145-6008},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16205372},
Abstract = {This article presents an overview of the proceedings from a
symposium entitled "Is adolescence special? Possible
age-related vulnerabilities to chronic alcohol or nicotine
exposure," organized by Susan Barron and Linda Spear and
held at the 2004 Research Society on Alcoholism Meeting in
Vancouver, British Columbia. This symposium, co-sponsored by
the Fetal Alcohol Syndrome Study Group and the
Neurobehavioral Teratology Society, focused on our current
knowledge regarding the long-term consequences of ethanol
and/or nicotine exposure during adolescence with the
emphasis on data from rodent models. The support from these
two societies represents the understanding by these research
groups that adolescence represents a unique developmental
stage for the effects of chronic drug exposure and also
marks an age in which many risky behaviors including alcohol
consumption and smoking typically begin. The speakers
included (1) Aaron White, who presented data on the effects
of adolescent ethanol exposure on subsequent motor or
cognitive response to an ethanol challenge in adulthood; (2)
Richard Bell, who presented data suggesting that genetic
differences could play a role in adolescent vulnerability to
ethanol; (3) Craig Slawecki, who presented data looking at
the effects of chronic exposure to alcohol or nicotine on
neurophysiologic and behavioral end points; and (4) Ed
Levin, who presented data on acute and long-term
consequences of adolescent nicotine exposure. Finally, Linda
Spear provided some summary points and recommendations
regarding unresolved issues and future directions.},
Doi = {10.1097/01.alc.0000179220.79356.e5},
Key = {fds274219}
}
@article{fds274220,
Author = {Levin, ED},
Title = {Marine and freshwater toxin impacts on neurobehavioral
function},
Journal = {Neurotoxicology and Teratology},
Volume = {27},
Number = {5},
Pages = {693},
Publisher = {Elsevier BV},
Year = {2005},
Month = {September},
ISSN = {0892-0362},
url = {http://dx.doi.org/10.1016/j.ntt.2005.06.011},
Doi = {10.1016/j.ntt.2005.06.011},
Key = {fds274220}
}
@article{fds274500,
Author = {Kreider, ML and Levin, ED and Seidler, FJ and Slotkin,
TA},
Title = {Gestational dexamethasone treatment elicits sex-dependent
alterations in locomotor activity, reward-based memory and
hippocampal cholinergic function in adolescent and adult
rats.},
Journal = {Neuropsychopharmacology},
Volume = {30},
Number = {9},
Pages = {1617-1623},
Year = {2005},
Month = {September},
ISSN = {0893-133X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15812569},
Keywords = {Acetylcholine • Age Factors • Analysis of Variance
• Animals • Animals, Newborn • Antineoplastic
Agents, Hormonal • Behavior, Animal • Cholinergic
Agents • Dexamethasone • Female •
Hemicholinium 3 • Hippocampus • Male • Maze
Learning • Memory • Motor Activity •
Pregnancy • Prenatal Exposure Delayed Effects* •
Protein Binding • Rats • Sex Characteristics*
• Tritium • adverse effects* • drug effects
• drug effects* • metabolism* •
pharmacokinetics},
Abstract = {Glucocorticoids are the consensus treatment for preventing
respiratory distress syndrome in preterm infants but there
is emerging evidence of subsequent neurobehavioral
abnormalities, independent of somatic growth effects.
Pregnant rats were given 0.2 mg/kg of dexamethasone, a dose
commensurate with clinical use, on gestational days 17-19
and behavioral evaluations were made on the offspring in
adolescence and adulthood. The dexamethasone groups had the
same body weights as the controls but nevertheless displayed
long-term, sex-selective alterations in locomotor and
cognitive behaviors. In the figure-8 activity apparatus,
dexamethasone treatment ablated the normal sex differences
in locomotor activity by reducing values in females to the
lower level typical of males; habituation of activity
similarly was impaired in females, reducing the profile to
match that of control males, while male rats in the
dexamethasone group showed a partially feminized pattern of
habituation. In the 8-arm radial maze, control rats
displayed typical sex differences, with male rats performing
more accurately than females. Dexamethasone treatment
eliminated this normal dichotomy, delaying learning in males
while improving performance in females to the level normally
seen in control males. Finally, we assessed hippocampal
[3H]hemicholinium-3 binding as a biomarker for cholinergic
synaptic activity, and again found loss of sex differences
in the dexamethasone group: values in males were increased
to the higher levels typical of females. These results
indicate that gestational treatment with dexamethasone
obtunds the normal sex differences in neurochemistry and
behavior that are typically seen in adolescence in
adulthood, thus producing sex-selective alterations in
activity, learning, and memory.},
Doi = {10.1038/sj.npp.1300716},
Key = {fds274500}
}
@article{fds274218,
Author = {Heindel, JJ and Levin, E},
Title = {Developmental origins and environmental influences--Introduction.
NIEHS symposium.},
Journal = {Birth Defects Res A Clin Mol Teratol},
Volume = {73},
Number = {7},
Pages = {469},
Year = {2005},
Month = {July},
url = {http://dx.doi.org/10.1002/bdra.20141},
Doi = {10.1002/bdra.20141},
Key = {fds274218}
}
@article{fds274342,
Author = {Levin, ED},
Title = {Fetal nicotinic overload, blunted sympathetic responsivity,
and obesity.},
Journal = {Birth Defects Res A Clin Mol Teratol},
Volume = {73},
Number = {7},
Pages = {481-484},
Year = {2005},
Month = {July},
ISSN = {1542-0752},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15959889},
Keywords = {Adipose Tissue • Animals • Central Nervous System
• Chlorpyrifos • Energy Metabolism • Female
• Nicotine • Obesity • Pregnancy •
Prenatal Exposure Delayed Effects* • Rats •
Sympathetic Nervous System • Time Factors • Weight
Gain • adverse effects • adverse effects* •
drug effects • drug effects* • etiology* •
metabolism • pharmacology},
Language = {eng},
Doi = {10.1002/bdra.20162},
Key = {fds274342}
}
@article{fds274465,
Author = {Levin, ED and Christopher, NC and Crapo, JD},
Title = {Memory decline of aging reduced by extracellular superoxide
dismutase overexpression.},
Journal = {Behav Genet},
Volume = {35},
Number = {4},
Pages = {447-453},
Year = {2005},
Month = {July},
ISSN = {0001-8244},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15971025},
Keywords = {Aging • Animals • Female • Gene Expression
Profiling • Genotype • Maze Learning • Memory
Disorders • Mice • Mice, Transgenic •
Oxidative Stress • Signal Transduction •
Superoxide Dismutase • biosynthesis* • enzymology
• genetics* • physiology* •
physiopathology*},
Abstract = {Extracellular superoxide dismutase (EC-SOD) plays an
important role in controlling oxidative stress as well as
intercellular signaling. In the current study, we tested the
effect of EC-SOD overexpression over the lifespan of a set
of mice and their wild-type controls to determine the time
scale over which EC-SOD overexpression might attenuate
aging-induced memory impairment. Mice with overexpression of
EC-SOD and wild-type controls were initially trained on the
radial-arm maze as young adults (3-5 months) and then
retrained during middle age (12-14 months) and retested in
old age at 27 and 30 months. There was little EC-SOD effect
during the young adult middle age periods. EC-SOD
overexpression prevented the decline in choice accuracy when
the mice were 27-30 months of age. The EC-SOD overexpressing
mice maintained their performance, while the wild-type mice
declined to naïve levels of performance by 30 months of
age. Enhancement of EC-SOD activity appears to improve
memory performance specifically in aging mice. EC-SOD
mimetic treatment during the course of aging may hold
promise for aging-induced cognitive impairment.},
Language = {eng},
Doi = {10.1007/s10519-004-1510-y},
Key = {fds274465}
}
@article{fds274439,
Author = {Addy, NA and Pocivavsek, A and Levin, ED},
Title = {Reversal of clozapine effects on working memory in rats with
fimbria-fornix lesions.},
Journal = {Neuropsychopharmacology},
Volume = {30},
Number = {6},
Pages = {1121-1127},
Year = {2005},
Month = {June},
ISSN = {0893-133X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15688087},
Keywords = {Animals • Antipsychotic Agents • Clozapine •
Female • Fornix, Brain • Hippocampus • Maze
Learning • Memory, Short-Term • Nicotine •
Nicotinic Agonists • Rats • Rats, Sprague-Dawley
• antagonists & inhibitors • drug effects •
drug effects* • pharmacology • pharmacology*
• physiology • physiology*},
Abstract = {Clozapine is an effective antipsychotic drug, but its
effects on cognitive function are unclear. Previously, we
found that clozapine caused a working memory deficit, which
was reversed by nicotine. Hippocampal systems are important
in determining clozapine effect on memory. In the current
study, the memory effects of clozapine and nicotine
administration were determined in rats with lesions of the
fimbria-fornix, a fiber bundle which carries cholinergic and
other projections between the septum and the hippocampus.
Female Sprague-Dawley rats were trained on a win-shift
procedure in the radial-arm maze, in which each arm entry
was rewarded once per session. Then, 13 rats received
bilateral knife-cut lesions of the fimbria-fornix, while 14
rats underwent sham surgery. The rats were tested after
subcutaneous injections with combinations of clozapine (0
and 1.25 mg/kg) and nicotine (0, 0.2, and 0.4 mg/kg). In
sham-operated rats, clozapine caused a significant (P<0.005)
working memory impairment. Fimbria-fornix lesions also
caused a significant (P<0.05) memory impairment.
Interestingly, clozapine had the opposite effect on working
memory in the lesioned vs sham-operated rats. In contrast to
its effects in controls, clozapine (1.25 mg/kg)
significantly (P<0.05) attenuated the working memory deficit
caused by fimbria-fornix lesions. Nicotine (0.2 mg/kg) did
not quite significantly improve memory in lesioned rats. The
effects of clozapine and nicotine were not additive in the
lesioned rats. This study demonstrates the efficacy of
clozapine in improving working memory in
fimbria-fornix-lesioned rats, whereas it causes impairments
in intact rats. Therapeutic treatment with clozapine in
people with malfunctions of the hippocampus such as seen in
schizophrenia may improve cognitive performance, whereas the
same doses of clozapine may impair memory in individuals
without hippocampal malfunction.},
Language = {eng},
Doi = {10.1038/sj.npp.1300669},
Key = {fds274439}
}
@article{fds274351,
Author = {Aldridge, JE and Levin, ED and Seidler, FJ and Slotkin,
TA},
Title = {Developmental exposure of rats to chlorpyrifos leads to
behavioral alterations in adulthood, involving serotonergic
mechanisms and resembling animal models of
depression.},
Journal = {Environ Health Perspect},
Volume = {113},
Number = {5},
Pages = {527-531},
Year = {2005},
Month = {May},
ISSN = {0091-6765},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15866758},
Keywords = {Animals • Animals, Newborn • Behavior, Animal
• Chlorpyrifos • Cognition Disorders •
Depression • Disease Models, Animal • Female
• Injections, Subcutaneous • Insecticides •
Male • Maze Learning • Memory • Memory
Disorders • Random Allocation • Rats • Rats,
Sprague-Dawley • Serotonin • administration &
dosage • chemically induced* • growth &
development • physiology • physiopathology •
toxicity*},
Abstract = {Developmental exposure to chlorpyrifos (CPF) causes
persistent changes in serotonergic (5HT) systems. We
administered 1 mg/kg/day CPF to rats on postnatal days 1-4,
a regimen below the threshold for systemic toxicity. When
tested in adulthood, CPF-exposed animals showed
abnormalities in behavioral tests that involve 5HT
mechanisms. In the elevated plus maze, males treated with
CPF spent more time in the open arms, an effect seen with
5HT deficiencies in animal models of depression. Similarly,
in an anhedonia test, the CPF-exposed group showed a
decreased preference for chocolate milk versus water.
Developmental CPF exposure also has lasting effects on
cognitive function. We replicated our earlier finding that
developmental CPF exposure ablates the normal sex
differences in 16-arm radial maze learning and memory:
during acquisition training, control male rats typically
perform more accurately than do control females, but CPF
treatment eliminated this normal sex difference. Females
exposed to CPF showed a reduction in working and reference
memory errors down to the rate of control males. Conversely,
CPF-exposed males exhibited an increase in working and
reference memory errors. After radial-arm acquisition
training, we assessed the role of 5HT by challenging the
animals with the 5HT2 receptor antagonist ketanserin.
Ketanserin did not affect performance in controls but
elicited dose-dependent increases in working and reference
memory errors in the CPF group, indicating an abnormal
dependence on 5HT systems. Our results indicate that
neonatal CPF exposures, classically thought to be subtoxic,
produce lasting changes in 5HT-related behaviors that
resemble animal models of depression.},
Doi = {10.1289/ehp.7867},
Key = {fds274351}
}
@article{fds274470,
Author = {Levin, ED and Petro, A and Caldwell, DP},
Title = {Nicotine and clozapine actions on pre-pulse inhibition
deficits caused by N-methyl-D-aspartate (NMDA) glutamatergic
receptor blockade.},
Journal = {Prog Neuropsychopharmacol Biol Psychiatry},
Volume = {29},
Number = {4},
Pages = {581-586},
Year = {2005},
Month = {May},
ISSN = {0278-5846},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15866361},
Keywords = {Animals • Antipsychotic Agents • Clozapine •
Dizocilpine Maleate • Dose-Response Relationship, Drug
• Drug Synergism • Excitatory Amino Acid
Antagonists • Female • Nicotine • Nicotinic
Agonists • Rats • Rats, Sprague-Dawley •
Receptors, N-Methyl-D-Aspartate • Startle Reaction
• antagonists & inhibitors • antagonists &
inhibitors* • drug effects* • pharmacology •
pharmacology*},
Abstract = {Pre-pulse inhibition (PPI) is a phenomenon of
neurobehavioral plasticity in which the motor response to a
startling stimulus is inhibited by a preceding stimulus of a
lower intensity. Most often this is tested in the auditory
mode. PPI is impaired in a variety of clinical states, most
notably schizophrenia. PPI is easily modeled in experimental
animals and serves as a useful basis for determining the
neural bases for behavioral plasticity. In the current study
we examined the interactions of N-methyl-D-aspartate (NMDA)
glutamate and nicotinic cholinergic receptor systems in the
expression of PPI. Female Sprague-Dawley rats were tested
for auditory PPI after s.c. injections of the NMDA
antagonist dizocilpine (also known as MK-801), the
prototypic nicotinic agonist nicotine or both. Vehicle
(saline) injections served as the control. Nicotine (0.2-0.8
mg/kg) by itself caused a modest but significant
dose-related improvement in PPI. Dizocilpine (25-100
microg/kg) caused a dramatic dose-related impairment in PPI.
Interestingly, the low to moderate doses of nicotine
potentiated the PPI impairment by dizocilpine. In a second
experiment nicotine and dizocilpine interactions with the
atypical antipsychotic drug clozapine were assessed. As in
the first experiment, nicotine potentiated the adverse
effects of dizocilpine on PPI. The combination of nicotine
with clozapine effectively attenuated the PPI impairment
caused by dizocilpine when neither alone was effective.
Inasmuch as PPI is impaired in schizophrenia, its reversal
by the antipsychotic drug clozapine may depend on
co-administration of nicotine by smoking in the patients.
Development of nicotinic-based co-treatments for
schizophrenia may achieve this benefit of nicotine without
the hazards of smoking. Sensory modulation deficit, which is
a syndrome of sensory over-responsiveness may also benefit
from such combination therapy.},
Doi = {10.1016/j.pnpbp.2005.01.012},
Key = {fds274470}
}
@article{fds274499,
Author = {Rezvani, AH and Caldwell, DP and Levin, ED},
Title = {Nicotinic-serotonergic drug interactions and attentional
performance in rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {179},
Number = {3},
Pages = {521-528},
Year = {2005},
Month = {May},
ISSN = {0033-3158},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15682310},
Keywords = {Animals • Attention • Dose-Response Relationship,
Drug • Drug Interactions • Female •
Ketanserin • Nicotine • Psychomotor Performance
• Rats • Rats, Sprague-Dawley • Receptor,
Serotonin, 5-HT2A • Serotonin Antagonists •
antagonists & inhibitors • drug effects* •
pharmacology • pharmacology* •
physiology},
Abstract = {RATIONALE: Both central serotonergic and nicotinic systems
play important roles in a variety of neurobehavioral
functions; however, the interactions of these two systems
have not been fully characterized. The current study served
to determine the impact of a relatively selective 5-HT2A
receptor antagonist, ketanserin, on attentional function in
rats and the interactions of ketanserin with nicotine
administration. METHODS: A standard operant visual signal
detection task was used to assess sustained attention. In
expt 1, adult female Sprague-Dawley rats (n = 39) were
injected subcutaneously (SC) with a dose range of ketanserin
(0, 0.25, 0.5 and 1 mg/kg). In expt 2, the interactions of
acute ketanserin (0, 1 and 2 mg/kg, SC) and acute nicotine
(0, 25 and 50 microg/kg, SC) were assessed. In expt 3, the
interaction of acute ketanserin (0, 1 and 2 mg/kg, SC) and
chronic nicotine (5 mg/kg per day, SC for 4 weeks via
osmotic pump) was characterized. Using an operant visual
signal detection task, three possible outcomes (dependent
variables) were measured in each trial: percent hit, percent
correct rejection, and response omissions. RESULTS:
Ketanserin, when given alone, did not have a significant
effect on either percent hit or percent correct rejection.
Acute administration of 25 microg/kg nicotine significantly
improved percent hit (i.e. improvement in choice accuracy),
an effect that was reversed by acute administration of 1
mg/kg ketanserin. Chronic nicotine infusion for 28
consecutive days significantly increased percent correct
rejection (i.e. improvement in choice accuracy) without
development of tolerance, an effect which was reversed by an
acute dose of 2 mg/kg ketanserin. CONCLUSIONS: These data
suggest a functional interaction between nicotine and 5-HT2A
receptor antagonist ketanserin.},
Doi = {10.1007/s00213-004-2060-y},
Key = {fds274499}
}
@article{fds274514,
Author = {Levin, ED and Tizabi, Y and Rezvani, AH and Caldwell, DP and Petro, A and Getachew, B},
Title = {Chronic nicotine and dizocilpine effects on regionally
specific nicotinic and NMDA glutamate receptor
binding.},
Journal = {Brain Res},
Volume = {1041},
Number = {2},
Pages = {132-142},
Year = {2005},
Month = {April},
ISSN = {0006-8993},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15829222},
Keywords = {Allosteric Regulation • Animals • Binding Sites
• Binding, Competitive • Brain •
Bungarotoxins • Cystine • Dizocilpine Maleate
• Drug Administration Schedule • Drug Interactions
• Drug Synergism • Excitatory Amino Acid
Antagonists • Female • Neural Inhibition •
Nicotine • Nicotinic Agonists • Protein Subunits
• Rats • Rats, Sprague-Dawley • Receptors,
N-Methyl-D-Aspartate • Receptors, Nicotinic •
Startle Reaction • drug effects • drug effects*
• metabolism • pharmacology • pharmacology*
• physiology},
Abstract = {Chronic nicotine administration has long been known to
increase the number of high-affinity alpha4beta2 nicotinic
receptors with lesser effects on low-affinity alpha7
nicotinic receptors. Nicotine has been shown to promote the
release of a variety of neurotransmitters including
glutamate. Nicotine may also interact directly with the
glutamatergic receptors. Nicotinic-glutamate interactions
may be critical to the long-term effects of nicotine.
Conversely, glutamatergic drugs may interact with the
nicotinic system. Such interactions have important
implications in interpretation of the mechanism of drug
actions, especially when the drugs are given together. The
current study examined the effects of chronic administration
of nicotine (5 mg of the nicotine base/kg/day for 28 days),
dizocilpine (MK-801) (0.3 mg/kg/day for 28 days), an NMDA
receptor antagonist, as well as the combination of the two
drugs on nicotinic and NMDA receptor densities in discrete
brain regions. The chronic dose of dizocilpine used was
behaviorally active causing a dramatic reduction in prepulse
inhibition (PPI) of acoustic startle response. The nicotine
dose used did not significantly affect PPI but previously we
have found it to be behaviorally active in improving working
memory function. High-affinity nicotinic receptor binding,
as has been seen previously, was significantly increased by
chronic nicotine in most areas. Chronic dizocilpine alone
did not affect high-affinity nicotinic receptor binding, but
it did modify the effects of chronic nicotine, attenuating
nicotine-induced increases in the frontal cortex and
striatum. Low-affinity nicotinic binding was significantly
increased by chronic nicotine in only one area, the
cerebellum. Chronic dizocilpine significantly increased
low-affinity nicotinic binding in several brain areas, the
colliculi, hippocampus, and the hypothalamus. The
combination of nicotine and dizocilpine attenuated the
effects of each with diminished nicotine-induced increased
nicotinic low-affinity binding in the cerebellum and
diminished dizocilpine-induced increased nicotinic
low-affinity binding in the hippocampus and hypothalamus. In
contrast, chronic nicotine and dizocilpine had a mutually
potentiating effect of increasing nicotinic low-affinity
binding in the frontal cortex. NMDA receptor binding was
affected only in the hippocampus, where both dizocilpine and
nicotine significantly increased binding. Chronic nicotine
effects on receptor regulation are significantly affected by
concurrent blockade of NMDA glutamate receptors.},
Language = {eng},
Doi = {10.1016/j.brainres.2005.01.104},
Key = {fds274514}
}
@article{fds274364,
Author = {Levin, ED},
Title = {Extracellular superoxide dismutase (EC-SOD) quenches free
radicals and attenuates age-related cognitive decline:
opportunities for novel drug development in
aging.},
Journal = {Curr Alzheimer Res},
Volume = {2},
Number = {2},
Pages = {191-196},
Year = {2005},
Month = {April},
ISSN = {1567-2050},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15974918},
Keywords = {Aging • Animals • Cognition Disorders • Free
Radicals • Humans • Maze Learning •
Superoxide Dismutase • Technology, Pharmaceutical
• biosynthesis* • drug effects • genetics
• metabolism* • methods* • physiology •
prevention & control • trends},
Abstract = {Superoxide dismutase (SOD) is one of the most effective
mechanisms in physiology for inactivating reactive oxygen
species. Elevated SOD activity can be therapeutically useful
by protecting against oxidative stress-induced
neurotoxicity. Acutely increased extracellular-SOD (EC-SOD)
activity protects against neurobehavioral impairment caused
by acute ischemia. Chronically increased EC-SOD activity may
also be therapeutically useful by protecting against chronic
oxidative stress-induced neurobehavioral damage that
accumulates during the aging process. We have found that
mice with genetic overexpression of EC-SOD do not show the
aging-induced decline in learning and memory that control,
wild type mice show. From 14-22 months of age, the EC-SOD
overexpressing mice have significantly better spatial
learning working memory function than that of controls. This
effect is specific to the aging period. Young adult EC-SOD
overexpressing mice do not have better learning and memory
function than controls. The beneficial effects of increased
EC-SOD activity with aging may be achieved without risk of
impairment during younger ages by chronically administering
EC-SOD mimetics from mature adulthood into the aging period.
Novel EC-SOD mimetics may be useful in attenuating
aging-induced cognitive impairments and other aspects of
physiological decline with aging.},
Doi = {10.2174/1567205053585710},
Key = {fds274364}
}
@article{fds136573,
Title = {Levin ED. Marine and freshwater toxin impacts on
neurobehavioral function. Neurotoxicol Teratol. 2005 Jul
27.},
Year = {2005},
Key = {fds136573}
}
@article{fds274221,
Author = {Slikker, W and Xu, ZA and Levin, ED and Slotkin, TA},
Title = {Mode of action: disruption of brain cell replication, second
messenger, and neurotransmitter systems during development
leading to cognitive dysfunction--developmental
neurotoxicity of nicotine.},
Journal = {Crit Rev Toxicol},
Volume = {35},
Number = {8-9},
Pages = {703-711},
Year = {2005},
ISSN = {1040-8444},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16417037},
Abstract = {Developmental exposure to nicotine in rats results in
neurobehavioral effects such as reduced locomotor and
cognitive function. Key events in the animal mode of action
(MOA) include binding to the nicotinic cholinergic receptor
during prenatal and/or early postnatal development. This
leads to premature onset of cell differentiation at the
expense of cell replication, which leads to brain cell death
or structural alterations in regional brain areas. Other
events include an initial increase followed by a decrease in
adenyl cyclase activity, as well as effects on the
noradrenergic, dopaminergic, and serotonergic
neurotransmitter systems. Because the nicotine receptor is
also present in the developing human brain and the
underlying biology for DNA synthesis and cell signaling is
comparable, this MOA is likely to be relevant for humans.
Although the effects of nicotine exposure in developing
humans is not well documented, nicotine exposure as a result
of cigarette smoking during pregnancy is associated with
several physiological and behavioral outcomes that are
reminiscent of the effects of nicotine alone in animal
models. As data become available with the advent of the use
of the nicotine patch in pregnant humans, the question as to
the relative importance of smoking per se versus nicotine
alone may be determined.},
Doi = {10.1080/10408440591007421},
Key = {fds274221}
}
@article{fds274440,
Author = {Levin, ED and Petro, A and Beatty, A},
Title = {Olanzapine interactions with nicotine and mecamylamine in
rats: effects on memory function.},
Journal = {Neurotoxicol Teratol},
Volume = {27},
Number = {3},
Pages = {459-464},
Year = {2005},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15939205},
Keywords = {Animals • Antipsychotic Agents • Benzodiazepines
• Dose-Response Relationship, Drug • Drug
Interactions • Female • Maze Learning •
Mecamylamine • Memory • Memory, Short-Term •
Nicotine • Nicotinic Agonists • Nicotinic
Antagonists • Rats • Rats, Sprague-Dawley •
drug effects • drug effects* •
pharmacology*},
Abstract = {Olanzapine is a widely used atypical antipsychotic drug. It
is quite effective in reducing psychotic symptoms. However,
the syndrome of schizophrenia encompasses more than
psychosis. There is a pronounced cognitive impairment among
other negative neurobehavioral symptoms. Classic
antipsychotic drugs such as haloperidol do not alleviate
cognitive impairment associated with schizophrenia and have
been shown to exacerbate the dysfunction. The atypical
antipsychotic drugs have a different profile of receptor
actions and may have a different array of actions on
cognitive function. The purpose of the current studies was
to determine the effects of olanzapine on working memory
function as measured by choice accuracy in the radial-arm
maze. In determining the cognitive effects of any
antipsychotic drug it is critical to determine its
interactions with nicotinic manipulations since the great
majority of people with schizophrenia smoke cigarettes and
alterations in nicotinic receptors have been found in people
with schizophrenia. Olanzapine caused a significant working
memory impairment. Nicotine attenuated olanzapine-induced
memory deficits. It may be the case that nicotinic
co-treatment will be useful in addressing the cognitive
impairment of schizophrenia.},
Doi = {10.1016/j.ntt.2005.01.011},
Key = {fds274440}
}
@article{fds274478,
Author = {Levin, ED and Pizarro, K and Pang, WG and Harrison, J and Ramsdell,
JS},
Title = {Persisting behavioral consequences of prenatal domoic acid
exposure in rats.},
Journal = {Neurotoxicol Teratol},
Volume = {27},
Number = {5},
Pages = {719-725},
Year = {2005},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16054336},
Keywords = {Animals • Behavior, Animal • Exploratory Behavior
• Female • Kainic Acid • Male • Maze
Learning • Memory • Motor Activity •
Muscarinic Antagonists • Neurotoxins • Pregnancy
• Prenatal Exposure Delayed Effects* • Rats •
Rats, Sprague-Dawley • Scopolamine Hydrobromide •
Sex Characteristics • analogs & derivatives* •
drug effects • drug effects* • pharmacology •
toxicity • toxicity*},
Abstract = {To investigate the behavioral effects of prenatal exposure
to the marine toxin domoic acid, pregnant female rats were
injected subcutaneously with 0, 0.3, 0.6, or 1.2 mg/kg of
domoic acid on gestational day 13. The offspring were then
run through a behavioral testing battery to determine the
developmental effects of the toxin on spontaneous
alternation in the T-maze, on locomotor activity in the
Figure-8 maze, and on working memory in the 8-arm radial
maze. In the T-maze, no significant domoic acid induced
differences were seen on spontaneous alternation, but there
were significant domoic acid effects on latency. Prenatal
domoic acid exposure caused a dose-related increase in
response latency in the second spontaneous alternation test.
There was also a significant domoic acid effect seen in the
1-h long Figure-8 maze test. Locomotor activity measured in
the Figure-8 maze detected a persisting effect of the 1.2
mg/kg domoic acid dose, which significantly increased the
rate of habituation over the activity test session. This was
characterized by higher initial activity followed by greater
decline in activity. In the radial-arm maze the control
vehicle treated rats showed the normal sex-related
difference in spatial learning and memory with males
outperforming females. Developmental domoic acid exposure
decreased this effect such that the normal sex difference in
spatial memory was not seen with the 1.2 mg/kg domoic acid
dose. The rats of both sexes with a history of prenatal
domoic acid exposure showed increased susceptibility to the
amnestic effects of the muscarinic acetylcholine
scopolamine, suggesting that they had less functional
reserve with which to solve the radial-arm maze memory task.
This study demonstrates persisting neurobehavioral effects
of acute prenatal exposure to domoic acid at doses that do
not cause overt clinical signs of toxicity.},
Language = {eng},
Doi = {10.1016/j.ntt.2005.06.017},
Key = {fds274478}
}
@article{fds274399,
Author = {Levin, ED and Weber, E and Icenogle, L},
Title = {Baclofen interactions with nicotine in rats: effects on
memory.},
Journal = {Pharmacol Biochem Behav},
Volume = {79},
Number = {2},
Pages = {343-348},
Year = {2004},
Month = {October},
ISSN = {0091-3057},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15501311},
Keywords = {Animals • Baclofen • Dose-Response Relationship,
Drug • Drug Interactions • Female • GABA
Agonists • Maze Learning • Memory • Nicotine
• Rats • Rats, Sprague-Dawley •
administration & dosage* • drug effects • drug
effects*},
Abstract = {Nicotine has been shown in numerous previous studies to
significantly improve memory on the radial-arm maze, yet the
critical mechanisms underlying this effect are not fully
characterized. Nicotine stimulates the release of a number
of neurotransmitters important for memory function including
(gamma-aminobutyric acid) GABA. The importance of
nicotinic-GABA interactions regarding memory is currently
unknown. The purpose of the current study was to determine
the interactive effects of nicotine and the GABA agonist
baclofen on working memory function as measured by choice
accuracy in the radial-arm maze. Female Sprague-Dawley rats
trained to asymptotic performance levels on a win-shift
eight-arm radial maze task were used for assessment of
nicotine-baclofen interactions. Low doses of baclofen
improved memory performance while higher doses impaired it.
Nicotine, as seen before, improved memory performance.
Nicotine also significantly reversed the higher dose
baclofen-induced deficit. These data show the importance of
both nicotinic and GABA systems in working memory function
and the interactions between these two transmitter receptor
systems. This not only provides information concerning the
neural bases of cognitive performance, it also lends insight
into new combination treatments for memory
impairment.},
Doi = {10.1016/j.pbb.2004.08.013},
Key = {fds274399}
}
@article{fds274217,
Author = {Rezvani, AH and Levin, ED},
Title = {Erratum: Nicotine-antipsychotic drug interactions and
attentional performance in female rats (European Journal of
Pharmacology (2004) 486 (175-182) DOI: 10.1016/j.ejphar.2003.12.021.)},
Journal = {European Journal of Pharmacology},
Volume = {489},
Number = {3},
Pages = {215},
Publisher = {Elsevier BV},
Year = {2004},
Month = {April},
url = {http://dx.doi.org/10.1016/j.ejphar.2004.03.009},
Doi = {10.1016/j.ejphar.2004.03.009},
Key = {fds274217}
}
@article{fds274395,
Author = {Rezvani, AH and Levin, ED},
Title = {Nicotine-antipsychotic drug interactions and attentional
performance in female rats.},
Journal = {Eur J Pharmacol},
Volume = {486},
Number = {2},
Pages = {175-182},
Year = {2004},
Month = {February},
ISSN = {0014-2999},
url = {http://www.ncbi.nlm.nih.gov/pubmed/14975706},
Keywords = {Animals • Antipsychotic Agents • Attention •
Central Nervous System Stimulants • Clozapine •
Dose-Response Relationship, Drug • Drug Interactions
• Female • Haloperidol • Nicotine •
Photic Stimulation • Psychomotor Performance •
Rats • Rats, Sprague-Dawley • Risperidone •
administration & dosage • drug effects* •
pharmacokinetics • pharmacology • pharmacology*
• physiology},
Abstract = {Schizophrenia is marked by pronounced cognitive impairments
in addition to the hallmark psychotic symptoms like
hallucinations. Antipsychotic drugs can effectively reduce
these hallucinations; however, the drugs have not resolved
the cognitive impairment. Interestingly, nicotine, a drug
commonly self-administered by people with schizophrenia, has
been shown to significantly improve cognitive function of
people with schizophrenia. The current study was conducted
to determine the effect of typical (haloperidol) and
atypical (clozapine and risperidone) antipsychotic drug
treatment on sustained attention in rats performing a visual
signal detection task. In addition, the interaction of
haloperidol with chronic nicotine administration was
assessed. Female Sprague-Dawley rats were injected
subcutaneously with clozapine (0, 0.6, 1.25 and 2.5 mg/kg),
risperidone (0, 0.025, 0.05 and 0.1 mg/kg) or haloperidol
(0, 0.01, 0.02 and 0.04 mg/kg). In the second part of the
study, the interaction of acute haloperidol (0, 0.005, 0.01
and 0.02 mg/kg) and chronic nicotine (5 mg/kg/day, for 4
weeks via osmotic minipump) was characterized. Clozapine,
risperidone and haloperidol all caused dose-related
impairments in percent hit performance. There was a
significant linear dose-related impairment in percent hit
caused by risperidone. All the doses of clozapine caused a
significant impairment in percent hit at the higher
luminance intensities in the visual signal detection task.
The 0.01 and 0.02 mg/kg haloperidol doses caused significant
decreases in percent hit. The 0.04 mg/kg haloperidol dose
impaired performance of the task to the point that reliable
choice accuracy measurements could not be made. Chronic
nicotine infusion significantly diminished the impairing
effects of haloperidol on performance during weeks 1-2. In
summary, both typical and atypical antipsychotic drugs
significantly impaired sustained attention in rats.
Haloperidol was more detrimental than clozapine and
risperidone. Chronic nicotine diminished the adverse effects
of haloperidol on performance. This study establishes a
paradigm to reliably determine the attentional impairment
caused by antipsychotic drugs.},
Language = {eng},
Doi = {10.1016/j.ejphar.2003.12.021},
Key = {fds274395}
}
@article{fds274370,
Author = {White, HK and Levin, ED},
Title = {Chronic transdermal nicotine patch treatment effects on
cognitive performance in age-associated memory
impairment.},
Journal = {Psychopharmacology (Berl)},
Volume = {171},
Number = {4},
Pages = {465-471},
Year = {2004},
Month = {February},
ISSN = {0033-3158},
url = {http://www.ncbi.nlm.nih.gov/pubmed/14534771},
Keywords = {Administration, Cutaneous • Aged • Aged, 80 and
over • Aging • Cognition • Cross-Over Studies
• Double-Blind Method • Drug Administration
Schedule • Female • Humans • Male •
Memory Disorders • Middle Aged • Nicotine •
Psychomotor Performance • Reaction Time •
administration & dosage* • drug effects* • drug
therapy* • physiology • psychology •
psychology*},
Abstract = {OBJECTIVES: Chronic transdermal nicotine has been found to
improve attentional performance in patients with Alzheimer's
disease (AD), but little is known about chronic nicotine
effects in age-associated memory impairment (AAMI), a milder
form of cognitive dysfunction. The current study was
performed to determine the clinical and neuropsychological
effects of chronic transdermal nicotine in AAMI subjects
over a 4-week period. DESIGN: The double-blind,
placebo-controlled, cross-over study consisted of two 4-week
periods separated by a 2-week washout period. SETTING: An
outpatient setting was used. PARTICIPANTS: The subjects (
n=11) met criteria for AAMI. INTERVENTIONS: The subjects
were given nicotine patches (Nicotrol) to wear for 16 h a
day at the following doses: 5 mg/day during week 1, 10
mg/day during week 2 and week 3 and 5 mg/day during week 4.
MEASUREMENTS: The effects of nicotine treatment were
determined with the clinical global impressions
questionnaire, Conners' Continuous Performance test, and the
automated neuropsychologic assessment metrics (ANAM)
computerized neuropsychology battery. RESULTS: Nicotine
significantly improved the clinical global impression score
as assessed by participants, as well as objective tests of
attentional function on the Connors' Continuous Performance
Test and decision reaction time on the neuropsychology test
battery. Nicotine did not improve performance on other tests
measuring motor and memory function. CONCLUSION: Chronic
transdermal nicotine treatment in AAMI subjects caused a
sustained improvement in clinical symptoms and objective
computerized tests of attention. These results support the
further investigation of nicotinic treatment as a promising
therapy for AAMI.},
Language = {eng},
Doi = {10.1007/s00213-003-1614-8},
Key = {fds274370}
}
@article{fds274352,
Author = {Levin, ED and Swain, HA and Donerly, S and Linney,
E},
Title = {Developmental chlorpyrifos effects on hatchling zebrafish
swimming behavior.},
Journal = {Neurotoxicol Teratol},
Volume = {26},
Number = {6},
Pages = {719-723},
Year = {2004},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15451035},
Keywords = {Animals • Behavior, Animal • Chlorpyrifos •
Cholinesterase Inhibitors • Disease Models, Animal
• Dose-Response Relationship, Drug • Embryo,
Nonmammalian • Habituation, Psychophysiologic •
Larva • Motor Activity • Physical Stimulation
• Reaction Time • Swimming • Zebrafish •
drug effects • drug effects* • embryology •
growth & development • methods • physiology •
physiology* • toxicity • toxicity*},
Abstract = {Chlorpyrifos (CPF), a widely used organophosphate
insecticide and potent acetylcholinesterase inhibitor,
interferes with neurobehavioral development. Rat models have
been key in demonstrating that developmental CPF exposure
causes learning deficits and locomotor activity alterations,
which persist into adulthood. Complementary nonmammalian
models can be useful in determining the neurodevelopmental
mechanisms underlying these persisting behavioral effects.
Zebrafish (Danio rerio) with their clear chorion and
extensive developmental information base provide an
excellent model for assessment of molecular processes of
toxicant-impacted neurodevelopment. We have developed
methods for assessing spatial discrimination learning in
adult zebrafish and have documented persisting effects of
developmental CPF exposure on swimming activity and learning
after low and high doses of CPF (10 and 100 ng/ml)
administered to zebrafish embryos on Days 1-5
postfertilization (pf). In the current study, we developed
methods for behavioral assessment of CPF exposure on
swimming activity in newly hatched zebrafish. An equal area
segmented annular grid (concentric circles divided into
quadrants through the diameter) was made in a 16-mm diameter
cylinder. The test area was placed on a heating device
secured to an Olympus SZH10 dissecting scope stage.
Zebrafish embryos were exposed to 10 ng/ml CPF, 100 ng/ml
CPF, or vehicle control (25 microl/ml DMSO)
(n=8-10/treatment group). Each treatment group was kept in a
total volume of 25 ml of egg water (60 mg/ml Instant Ocean)
including DMSO with or without CPF mixed to above dilutions
in an incubator set at 28.5 degrees C. CPF dilutions or
vehicle were changed daily with exposure ending on Day 5 pf.
Testing of larval zebrafish was performed on Days 6 and 9
pf. The fish were placed in the test cylinder with 1.5 ml of
egg H(2)O (28.5 degrees C). After a 2-min acclimation
period, the swimming activity of the fish was measured for a
3-min testing session. The 100 ng/ml CPF dose caused
significant slowing of swimming activity on Days 6 and 9 pf
and had persisting effects of impairing spatial
discrimination and decreasing response latency in adulthood.
Developmental exposure to 10 ng/ml of CPF did not cause a
significant change in locomotor activity during the period
soon after hatching. CPF exposure during early development
caused clear behavioral impairments detectable during the
posthatching period. In a previous study, we found that
early developmental CPF exposure caused behavioral
alterations in zebrafish, which lasted throughout adulthood.
The molecular mechanisms by which early developmental CPF
exposure produces these behavioral impairments expressed in
adulthood can now be studied in the zebrafish
model.},
Language = {eng},
Doi = {10.1016/j.ntt.2004.06.013},
Key = {fds274352}
}
@article{fds274388,
Author = {Levin, ED and Brunssen, S and Wolfe, GW and Harry,
GJ},
Title = {Neurobehavioral assessment of mice after developmental AZT
exposure.},
Journal = {Neurotoxicol Teratol},
Volume = {26},
Number = {1},
Pages = {65-71},
Year = {2004},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15001215},
Keywords = {Age Factors • Animals • Animals, Newborn •
Anti-HIV Agents • Dose-Response Relationship, Drug
• Eating • Female • Male • Maze Learning
• Mice • Motor Activity • Pregnancy •
Prenatal Exposure Delayed Effects* • Psychomotor
Performance • Reaction Time • Retention
(Psychology) • Sex Factors • Survival • Time
Factors • Zidovudine • drug effects • drug
effects* • toxicity • toxicity*},
Abstract = {Azidothymidine (AZT) is administered to pregnant women with
HIV to prevent the spread of infection to their fetuses.
Since gestation is a period of critical neurodevelopment, it
is important to determine the risk AZT exposure may pose to
neurobehavioral function of the offspring. The current study
focused on teratological risks of developmental AZT exposure
to neurocognitive function. Male and female Swiss mice were
administered AZT or vehicle (0, 100, or 200 mg/kg/day po
given twice daily in equal amounts for 32 weeks before and
during gestation). Adult male and female offspring (n =
10/sex/treatment group) underwent neurobehavioral testing
focused on determining learning and memory capabilities in
the radial-arm maze. AZT exposure did not cause significant
deficits during radial-arm maze acquisition. No impairment
was seen in asymptotic levels of choice accuracy indicative
of working memory function. Attempts to unmask subtle
learning impairments following developmental AZT by the
introduction of behavioral challenges such as reduction of
motivational state (food restriction either 4-6 h or 22-24
h) or imposition of intrasession delays of 1.5 min to 2.5 h
were unsuccessful. With a 4-week intersession delay, a
significant AZT Treatment x Delay effect was seen with a
significantly greater decline seen in the controls as
compared to the 100 mg/kg/day AZT group. Locomotor activity
on the radial-arm maze was significantly affected by AZT
treatment (100 mg/kg/day) during the acquisition phase, but
not during the other test phases. No behavioral alterations
were seen related to stress as measured by the elevated plus
maze. Vestibulomotor functioning on the balance beam
remained unaltered. Using an extended dosing regimen
including dosing of both sires and dams, as well as placing
a greater demand on reproductive system performance with
three continuous breedings, this study detected only subtle
neurobehavioral impairments in mice after prenatal AZT
exposure at clinically relevant doses.},
Doi = {10.1016/j.ntt.2003.10.001},
Key = {fds274388}
}
@article{fds274390,
Author = {Scalzo, FM and Levin, ED},
Title = {The use of zebrafish (Danio rerio) as a model system in
neurobehavioral toxicology.},
Journal = {Neurotoxicol Teratol},
Volume = {26},
Number = {6},
Pages = {707-708},
Year = {2004},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15451033},
Keywords = {Animals • Behavior, Animal • Central Nervous
System • Disease Models, Animal* • Neurotoxins
• Toxicology • Zebrafish • drug effects
• drug effects* • genetics • growth &
development • growth & development* • physiology
• standards* • toxicity •
trends},
Doi = {10.1016/j.ntt.2004.06.008},
Key = {fds274390}
}
@article{fds274425,
Author = {Levin, ED and Chen, E},
Title = {Nicotinic involvement in memory function in
zebrafish.},
Journal = {Neurotoxicol Teratol},
Volume = {26},
Number = {6},
Pages = {731-735},
Year = {2004},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15451037},
Keywords = {Acetylcholine • Animals • Brain •
Dose-Response Relationship, Drug • Memory • Memory
Disorders • Models, Animal • Nicotine •
Nicotinic Agonists • Receptors, Nicotinic •
Spatial Behavior • Zebrafish • chemically induced*
• drug effects • drug effects* • metabolism
• pharmacology • pharmacology* • physiology
• physiology* • physiopathology},
Abstract = {Zebrafish are an emerging model for the study of the
molecular mechanisms of brain function. To conduct studies
of the neural bases of behavior in zebrafish, we must
understand the behavioral function of zebrafish and how it
is altered by perturbations of brain function. This study
determined nicotine actions on memory function in zebrafish.
With the methods that we have developed to assess memory in
zebrafish using delayed spatial alternation (DSA), we
determined the dose effect function of acute nicotine on
memory function in zebrafish. As in rodents and primates,
low nicotine doses improve memory in zebrafish, while high
nicotine doses have diminished effect and can impair memory.
This study shows that nicotine affects memory function in
zebrafish much like in rats, mice, monkeys and humans. Now,
zebrafish can be used to help understand the molecular
mechanisms crucial to nicotine effects on
memory.},
Language = {eng},
Doi = {10.1016/j.ntt.2004.06.010},
Key = {fds274425}
}
@article{fds274486,
Author = {Icenogle, LM and Christopher, NC and Blackwelder, WP and Caldwell,
DP and Qiao, D and Seidler, FJ and Slotkin, TA and Levin,
ED},
Title = {Behavioral alterations in adolescent and adult rats caused
by a brief subtoxic exposure to chlorpyrifos during
neurulation.},
Journal = {Neurotoxicol Teratol},
Volume = {26},
Number = {1},
Pages = {95-101},
Year = {2004},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15001218},
Keywords = {Animals • Animals, Newborn • Behavior, Animal
• Behavioral Symptoms • Brain • Chlorpyrifos
• Dose-Response Relationship, Drug • Drug
Interactions • Female • Habituation,
Psychophysiologic • Inhibition (Psychology) •
Insecticides • Maze Learning • Memory, Short-Term
• Motor Activity • Muscarinic Antagonists •
Pregnancy • Prenatal Exposure Delayed Effects* •
Rats • Reaction Time • Scopolamine Hydrobromide
• chemically induced* • drug effects • drug
effects* • embryology • growth & development
• pharmacology • physiopathology •
toxicity*},
Abstract = {The widely used organophosphate insecticide, chlorpyrifos
(CPF), elicits neurobehavioral abnormalities after
apparently subtoxic neonatal exposures. In the current
study, we administered 1 or 5 mg/kg/day of CPF to pregnant
rats on gestational days 9-12, the embryonic phase spanning
formation and closure of the neural tube. Although there
were no effects on growth or viability, offspring showed
behavioral abnormalities when tested in adolescence and
adulthood. In the CPF-exposed groups, locomotor
hyperactivity was noted in early T-maze trials, and in the
elevated plus-maze; alterations in the rate of habituation
were also identified. Learning and memory were adversely
affected, as assessed using the 16-arm radial maze. Although
all CPF-exposed animals eventually learned the task,
reference and working memory were impaired in the early
training sessions. After training, rats in the CPF group did
not show the characteristic amnestic effect of scopolamine,
a muscarinic acetylcholine antagonist, suggesting that,
unlike the situation in the control group, muscarinic
pathways were not used to solve the maze. These results
indicate that apparently subtoxic CPF exposure during
neurulation adversely affects brain development, leading to
behavioral anomalies that selectively include impairment of
cholinergic circuits used in learning and memory. The
resemblance of these findings to those of late gestational
or neonatal CPF exposure indicates a prolonged window of
vulnerability of brain development to CPF.},
Language = {eng},
Doi = {10.1016/j.ntt.2003.09.001},
Key = {fds274486}
}
@article{fds274505,
Author = {Rezvani, AH and Levin, ED},
Title = {Adolescent and adult rats respond differently to nicotine
and alcohol: motor activity and body temperature.},
Journal = {Int J Dev Neurosci},
Volume = {22},
Number = {5-6},
Pages = {349-354},
Year = {2004},
ISSN = {0736-5748},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15380834},
Keywords = {Adaptation, Physiological • Age Factors • Aging
• Animals • Animals, Newborn • Dose-Response
Relationship, Drug • Drug Interactions • Ethanol
• Female • Injections, Intraperitoneal •
Injections, Subcutaneous • Locomotion • Nicotine
• Rats • Rats, Sprague-Dawley • Sex Factors
• administration & dosage* • drug effects •
drug effects* • physiology • physiology*},
Abstract = {Alcohol and nicotine are the most widely abused drugs in the
world. The use of these addictive drugs often begins in
adolescence, however, little is known about the different
impacts of nicotine and alcohol on adolescents versus
adults. This study examined both the individual and combined
effects of nicotine and alcohol on body temperature and
locomotor activity in adolescent and adults rats. Rats were
injected with saline (SC) + saline (IP), nicotine (SC) +
saline (IP), alcohol (IP) + saline (SC) or alcohol (IP) +
nicotine (SC). The dose selected for nicotine was 0.2 mg/kg
and for alcohol 2.5 g/kg (16% v/v). For each age/treatment,
10-13 animals were used, with each animal receiving only one
treatment. In regards to body temperature, both nicotine and
alcohol caused a significant age x drug interaction. The
combination of nicotine and alcohol caused greater drop in
body temperature in adolescent than in adult rats. Neither
of the two drugs, when given alone, caused differential
effects in adolescents or adult rats, though both resulted
in drop in body temperature. In terms of locomotor activity,
the treatment that produced a significantly different effect
between adolescents and adults was nicotine alone. Nicotine
significantly decreased locomotor activity in adolescent
compared to adult rats. These preliminary results suggest
that adolescent rats may have an increased sensitivity to
nicotine and alcohol, which may consequently impact their
initial addiction to these two drugs.},
Doi = {10.1016/j.ijdevneu.2004.03.007},
Key = {fds274505}
}
@article{fds274393,
Author = {Aldridge, JE and Gibbons, JA and Flaherty, MM and Kreider, ML and Romano, JA and Levin, ED},
Title = {Heterogeneity of toxicant response: sources of human
variability.},
Journal = {Toxicol Sci},
Volume = {76},
Number = {1},
Pages = {3-20},
Year = {2003},
Month = {November},
ISSN = {1096-6080},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12883075},
Keywords = {Age Factors • Cytochrome P-450 Enzyme System •
Drug Toxicity* • Environmental Pollutants •
Genetic Predisposition to Disease* • Humans • Risk
Assessment • Sex Factors • adverse effects* •
etiology • genetics • genetics* •
metabolism},
Abstract = {While risk assessment models attempt to predict human risk
to toxicant exposure, in many cases these models cannot
account for the wide variety of human responses. This review
addresses several primary sources of heterogeneity that may
affect individual responses to drug or toxicant exposure.
Consideration was given to genetic polymorphisms,
age-related factors during development and senescence,
gender differences associated with hormonal function, and
preexisting diseases influenced by toxicant exposure. These
selected examples demonstrate the need for additional steps
in risk assessment that are needed to more accurately
predict human responses to toxicants and
drugs.},
Doi = {10.1093/toxsci/kfg204},
Key = {fds274393}
}
@article{fds274404,
Author = {Levin, ED and Sledge, D and Baruah, A and Addy, NA},
Title = {Ventral hippocampal NMDA blockade and nicotinic effects on
memory function.},
Journal = {Brain Res Bull},
Volume = {61},
Number = {5},
Pages = {489-495},
Year = {2003},
Month = {September},
ISSN = {0361-9230},
url = {http://www.ncbi.nlm.nih.gov/pubmed/13679247},
Keywords = {Animals • Dizocilpine Maleate • Drug Interactions
• Excitatory Amino Acid Antagonists • Female
• Hippocampus • Maze Learning • Memory •
Memory Disorders • Neural Pathways • Neurons
• Nicotine • Rats • Rats, Sprague-Dawley
• Reaction Time • Receptors, N-Methyl-D-Aspartate
• Receptors, Nicotinic • Synaptic Transmission
• chemically induced • cytology • drug
effects • drug effects* • metabolism •
pharmacology • physiology • physiopathology},
Abstract = {Nicotinic acetylcholine and NMDA glutamate receptors play
critical roles in memory function. The brain areas involved
in their interaction are still under investigation. One
likely area is the hippocampus. Ventral hippocampal
administration of nicotinic antagonists impair memory.
Hippocampal administration of NMDA antagonists also cause
memory impairments. We evaluated the importance of ventral
hippocampal NMDA receptors for nicotinic actions on memory
by testing the impact of systemic nicotine on memory with
and without administration of the NMDA antagonist
dizocilpine into the ventral hippocampus. Sprague-Dawley
rats (N=11) trained on the 16-arm radial maze were
bilaterally implanted with local infusion cannulae in the
ventral hippocampus. The effects on memory function of
ventral hippocampal infusions of 0, 2, 6 and 18 microg per
side of dizocilpine were examined with and without acute
systemic nicotine administration (0 or 0.4 mg/kg). The
dizocilpine doses tested did not cause memory deficits by
themselves but only did so when given in combination with
systemic nicotine. Blocking NMDA ventral hippocampal actions
revealed an impairing action of nicotine on memory. Nicotine
effects on other non-NMDA hippocampal receptor systems or
extra-hippocampal systems may have been left unchecked by
the diminished nicotinic effect on ventral hippocampal NMDA
receptors.},
Doi = {10.1016/s0361-9230(03)00183-7},
Key = {fds274404}
}
@article{fds274441,
Author = {Levin, ED and Rezvani, AH and Montoya, D and Rose, JE and Swartzwelder,
HS},
Title = {Adolescent-onset nicotine self-administration modeled in
female rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {169},
Number = {2},
Pages = {141-149},
Year = {2003},
Month = {September},
ISSN = {0033-3158},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12764575},
Keywords = {Adolescent • Age Factors • Age of Onset* •
Animals • Disease Models, Animal • Dose-Response
Relationship, Drug • Female • Humans •
Hypothermia • Infusions, Intravenous • Injections,
Subcutaneous • Motor Activity • Nicotine •
Rats • Rats, Sprague-Dawley • Self Administration*
• Time Factors • administration & dosage* •
adverse effects • chemically induced • drug
effects • pharmacokinetics* • physiology*},
Abstract = {RATIONALE: Although the great majority of tobacco addiction
begins during adolescence, little is known about
differential nicotine effects in adolescents versus adults.
OBJECTIVES: A rat model was used to determine the impact of
the age of onset on nicotine self-administration. METHODS:
In expt 1, nicotine self-administration of female
Sprague-Dawley rats over a range of acute doses (0.01-0.08
mg/kg per infusion) was determined in adolescent (beginning
at 54-62 days) versus adult (beginning at 84-90 days). In
expt 2, chronic nicotine self-administration over 4 weeks
from adolescence into adulthood was compared with the
chronic self-administration beginning in adulthood. In expt
3, adolescent-adult differences in nicotine effects on body
temperature and locomotor responses were determined.
RESULTS: Adolescent-onset rats showed a significant main
effect of increased nicotine intake compared with
adult-onset rats in an eight-fold range of acute unit
doses/infusion. Significant age differences were also seen
in the chronic level of nicotine self-administration. Over 4
weeks, the adolescent-onset group had nearly double the rate
of nicotine self-administration of the benchmark nicotine
dose (0.03 mg/kg per infusion) compared to the adult-onset
group. This increased nicotine intake persisted into
adulthood. Adolescent rats had significantly greater
response than adults to the hypothermic effects of nicotine,
but had significantly less response than adults to the
reduction in locomotor activity seen after nicotine.
CONCLUSIONS: Adolescent-onset nicotine self-administration
in female rats was associated with significantly higher
levels of nicotine self-administration versus rats, which
began nicotine self-administration in adulthood. This
greater self-administration persists into adulthood and may
underlie greater propensity of adolescents to nicotine
addiction.},
Doi = {10.1007/s00213-003-1486-y},
Key = {fds274441}
}
@article{fds274397,
Author = {Rezvani, AH and Levin, ED},
Title = {Nicotine-alcohol interactions and attentional performance on
an operant visual signal detection task in female
rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {76},
Number = {1},
Pages = {75-83},
Year = {2003},
Month = {August},
ISSN = {0091-3057},
url = {http://www.ncbi.nlm.nih.gov/pubmed/13679219},
Keywords = {Animals • Attention • Conditioning, Operant •
Dose-Response Relationship, Drug • Drug Interactions
• Ethanol • Female • Nicotine • Photic
Stimulation • Psychomotor Performance • Rats
• Rats, Sprague-Dawley • antagonists & inhibitors
• drug effects* • methods • pharmacology*
• physiology},
Abstract = {Nicotine and alcohol are very often co-used and co-abused.
Thus, it is important to understand their interactions. In
many ways, nicotine and alcohol have opposing effects. This
can be clearly seen in terms of their effects on cognitive
function. Nicotine effectively improves attention while
alcohol impairs it. The current study was conducted to
determine in a rat model the interaction of nicotine and
alcohol on attention using an operant visual signal
detection task. It is hypothesized that nicotine would
reverse the alcohol-induced impairment in accuracy of
performance in this task. Female Sprague-Dawley rats (N=35)
were trained on a visual operant signal detection task for
food reinforcement with 300 trials/session in three equal
time blocks. The rats were divided into poor and good
performers according to their predrug baseline performance
accuracy. The first experiment examined the dose-effect
function of alcohol (0, 0.375, and 0.75 g/kg i.p.) on this
task. The lower alcohol dose significantly impaired percent
correct rejection in the high-performing rats but not the
low-performing rats. The higher alcohol dose significantly
impaired percent hit performance during the first two thirds
of the session in both high- and low-performing groups. The
second experiment examined alcohol (0.75 g/kg i.p.)
interactions with nicotine (0, 12.5, 25, and 50 microg/kg
s.c.) on attentional performance. The 25 and 50 microg/kg
nicotine doses caused a significant (P<.05) improvement in
hit accuracy. Alcohol blocked this nicotine-induced
improvement, even though at this later time it no longer had
an effect of its own. In the high baseline group, the 25
microg/kg nicotine dose also caused a significant (P<.025)
improvement in hit accuracy. As in Experiment 1, the high
baseline group was not significantly impaired by 0.75 g/kg
of alcohol. However, this alcohol dose did eliminate the
nicotine-induced improvement. These results suggest that
alcohol, when given alone, impairs sustained attention and
blocks nicotine-induced attentional improvements even when
it does not cause impairments on its own.},
Doi = {10.1016/s0091-3057(03)00193-x},
Key = {fds274397}
}
@article{fds274469,
Author = {Levin, ED and Christopher, CN},
Title = {Lobeline-induced learning improvement of rats in the
radial-arm maze.},
Journal = {Pharmacol Biochem Behav},
Volume = {76},
Number = {1},
Pages = {133-139},
Year = {2003},
Month = {August},
ISSN = {0091-3057},
url = {http://www.ncbi.nlm.nih.gov/pubmed/13679226},
Keywords = {Animals • Dose-Response Relationship, Drug •
Female • Lobeline • Maze Learning • Rats
• Rats, Sprague-Dawley • drug effects* •
pharmacology* • physiology},
Abstract = {Lobeline is a nicotinic ligand with some nicotine-like
effects, but with some atypical effects as well, including
actions as a nicotinic antagonist. Lobeline, like nicotine,
has been found to significantly improve memory function as
well as provide anxiolytic-like effects in the elevated plus
maze. Lobeline effects on learning remain to be fully
characterized. Nicotine has been found to improve learning
of shock avoidance tasks. Other nicotinic agonists also have
been shown to improve learning performance. However, this
effect is limited. In some tasks, nicotine has been found to
cause deficits. In the current study, effects of lobeline
and nicotine injections were assessed in a repeated
acquisition procedure in the radial-arm maze for 3 weeks of
drug administration. Lobeline (0.3 and 0.9 mg/kg) improved
learning on the radial-arm maze. Neither nicotine dose (0.1
and 0.3 mg/kg) improved learning. This nicotine dose range
was previously found to improve post-acquisition working
memory performance in the radial-arm maze. The atypical
effects of lobeline may underlie its greater efficacy than
nicotine for improving repeated acquisition. The effect of
lobeline improving learning may be useful in the development
of novel treatments for learning deficits.},
Doi = {10.1016/s0091-3057(03)00216-8},
Key = {fds274469}
}
@article{fds274363,
Author = {May-Simera, H and Levin, ED},
Title = {NMDA systems in the amygdala and piriform cortex and
nicotinic effects on memory function.},
Journal = {Brain Res Cogn Brain Res},
Volume = {17},
Number = {2},
Pages = {475-483},
Year = {2003},
Month = {July},
ISSN = {0926-6410},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12880917},
Keywords = {Amygdala • Animals • Cerebral Cortex •
Dizocilpine Maleate • Dose-Response Relationship, Drug
• Excitatory Amino Acid Antagonists • Female
• Memory • Nicotine • Rats • Rats,
Sprague-Dawley • Receptors, N-Methyl-D-Aspartate •
antagonists & inhibitors* • drug effects* •
pharmacology • pharmacology* •
physiology},
Abstract = {Both nicotinic cholinergic and NMDA glutaminergic systems
are important for memory function. Nicotine has been found
repeatedly to significantly improve working memory
performance in the radial-arm maze. The NMDA antagonist
dizocilpine has been found to impair working memory
performance. There is neuropharmacological evidence that
these two systems are functionally related. Nicotine is
potent at releasing many transmitters including glutamate.
The current study was conducted to examine the interaction
of nicotinic and NMDA systems within the amygdala with
regard to working and reference memory. Rats were trained on
a working/reference procedure on a 16-arm radial maze. After
acquisition, local infusion cannulae were implanted
bilaterally into the amygdala and piriform cortex using
stereotaxic techniques. Then 20 min prior to running the
rats on the radial-arm maze, they were injected
subcutaneously with (-) nicotine ditartrate at doses of 0
and 0.4 mg/kg. Following this, the rats received local
infusions of (+) dizocilpine maleate (MK-801) at doses of 0,
2, 6 and 18 microg per side into the lateral amygdala or
piriform cortex 10 min prior to running on the radial-arm
maze. Each of the eight nicotine and dizocilpine
combinations was administered to each rat in a
counterbalanced order. After completion of the drug sessions
the rats were sacrificed, and using histological methods the
cannulae placements were verified. Acute amygdalar infusions
of the NMDA glutamate receptor antagonist dizocilpine
induced dose-related working and reference memory deficits
in the radial-arm maze. Systemic nicotine was not seen to
reverse these effects. Dizocilpine infusions into the
adjacent piriform cortex did not impair memory function,
supporting the specificity of dizocilpine effects in the
amygdala. Latency effects were seen with both drugs in both
areas. Latencies were decreased with both systemic nicotine
and dizocilpine in both the lateral amygdala and the
piriform cortex. This study demonstrated the importance of
NMDA glutamate systems in the amygdala for
appetitively-motivated spatial memory performance.},
Doi = {10.1016/s0926-6410(03)00163-0},
Key = {fds274363}
}
@article{fds274368,
Author = {Rezvani, AH and Levin, ED},
Title = {Nicotinic-glutamatergic interactions and attentional
performance on an operant visual signal detection task in
female rats.},
Journal = {Eur J Pharmacol},
Volume = {465},
Number = {1-2},
Pages = {83-90},
Year = {2003},
Month = {March},
ISSN = {0014-2999},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12650836},
Keywords = {Animals • Attention • Behavior, Animal •
Conditioning, Operant • Dizocilpine Maleate •
Dose-Response Relationship, Drug • Drug Interactions
• Excitatory Amino Acid Antagonists • Male •
Nicotine • Nicotinic Agonists • Psychomotor
Performance • Rats • Rats, Sprague-Dawley •
Signal Detection (Psychology) • drug effects •
drug effects* • pharmacology*},
Abstract = {Nicotinic systems have been shown to be critically involved
in cognitive function including attention. Nicotine has been
shown to improve performance on attentional tasks in humans
with Alzheimer's disease, schizophrenia and attention
deficit hyperactivity disorder. Nicotine has mixed effects
on attentional accuracy in unimpaired rats with findings of
increased, reduced or unaltered accuracy under different
conditions. Nicotine effects on attentional function in rats
might be more clearly seen in reversing impaired
performance. The current study determined nicotine effects
on attentional accuracy reduced by the NMDA receptor
antagonist dizocilpine (MK-801). Sprague-Dawley rats (N=35)
were trained on a food-motivated two-lever operant task with
one lever correct after a brief visual signal (0.027-1.22
lx) for hits and the other lever correct after the absence
of a signal for correct rejections. First, a dose response
study of dizocilpine was conducted to determine the
threshold for impairment. The rats were administered acute
doses of dizocilpine (0, 12.5, 25 and 50 microg/kg, sc). The
50 microg/kg dose caused significant (p<0.0005) reduction in
percent hit at the four highest signal intensities. Percent
correct rejection was also significantly lowered by this
dose (p<0.005). No effect was seen with 12.5 microg/kg and
only minimal effect seen with 25 microg/kg. Then,
nicotine-dizocilpine interactions were investigated. The
rats were administered acute doses of dizocilpine (0, 37.5
and 50 microg/kg, sc) and nicotine (0, 25 and 50 microg/kg,
sc), alone or in combination. Percent hit was affected by
nicotine and dizocilpine in a complex fashion with only the
nicotinexdizocilpinexsignal intensity interaction being
significant (p<0.05). Percent correct rejection showed a
more straightforward effect. Percent correct rejection was
significantly reduced by 50 microg/kg dizocilpine (p<0.025).
The addition of 25 microg/kg of nicotine significantly
(p<0.025) reversed the dizocilpine-induced reduction of
correct rejection. This study shows that dizocilpine reduces
signal detection accuracy in a dose-dependent fashion.
Nicotine can partially counteract an aspect of this
reduction by reversing the dizocilpine-induced reduction of
correct rejection.},
Doi = {10.1016/s0014-2999(03)01439-0},
Key = {fds274368}
}
@article{fds274347,
Author = {Yang, YK and McEvoy, JP and Wilson, WH and Levin, ED and Rose,
JE},
Title = {Reliabilities and intercorrelations of reported and
objective measures of smoking in patients with
schizophrenia.},
Journal = {Schizophr Res},
Volume = {60},
Number = {1},
Pages = {9-12},
Year = {2003},
Month = {March},
ISSN = {0920-9964},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12505133},
Keywords = {Adult • Antipsychotic Agents • Carbon Dioxide
• Female • Haloperidol • Humans • Male
• Matched-Pair Analysis • Middle Aged •
Psychiatric Status Rating Scales • Questionnaires
• Reproducibility of Results • Schizophrenia
• Smoking • Statistics • Tobacco Use Disorder
• adverse effects • complications* •
diagnosis • drug therapy • epidemiology •
metabolism • metabolism* • methods •
therapeutic use},
Abstract = {We examined the test-retest reliabilities of reported and
objective measures of smoking, and the intercorrelations
among these measures, in acutely psychotic patients with
schizophrenia to determine whether severe psychiatric
illness affects the utility of these variables. All measures
demonstrated good test-retest reliability. Objective
measures of smoking were consistently intercorrelated and
should be the preferred outcome measures in studies testing
strategies to reduce smoking.},
Doi = {10.1016/s0920-9964(02)00208-6},
Key = {fds274347}
}
@article{fds274461,
Author = {Addy, NA and Nakijama, A and Levin, ED},
Title = {Nicotinic mechanisms of memory: effects of acute local
DHbetaE and MLA infusions in the basolateral
amygdala.},
Journal = {Brain Res Cogn Brain Res},
Volume = {16},
Number = {1},
Pages = {51-57},
Year = {2003},
Month = {March},
ISSN = {0926-6410},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12589888},
Keywords = {Aconitine • Amygdala • Animals •
Dihydro-beta-Erythroidine • Dose-Response Relationship,
Drug • Female • Maze Learning • Memory •
Nicotinic Antagonists • Rats • Rats,
Sprague-Dawley • Reaction Time • Receptors,
Nicotinic • administration & dosage • analogs &
derivatives* • anatomy & histology •
classification • drug effects • drug effects*
• pharmacology* • physiology},
Abstract = {Nicotine has been shown to improve working memory. The
neural mechanisms underlying this effect are still being
determined. The ventral hippocampus is critical for
nicotinic effects on memory. Local ventral hippocampal
infusions of either the nicotinic alpha7 nicotinic receptor
antagonist methyllycaconitine (MLA) or the alpha4beta2
nicotinic receptor antagonist dihydro-beta-erythroidine
(DHbetaE) caused working memory impairments, but no additive
effects were seen. Other areas, such as the amygdala, also
likely play important roles in nicotinic effects on memory.
Amygdalar lesions cause memory impairment and there is a
dense concentration of nicotinic receptors in the
basolateral amygdala. The current study used local
basolateral amygdalar infusions of the nicotinic antagonists
MLA and DHbetaE to determine the involvement of alpha7 and
alpha4beta2 nicotinic receptors in spatial working and
reference memory. Rats (n=8) were trained in the 16-arm
radial maze and were implanted with bilateral infusion
cannulae into the basolateral amygdala. Acute infusions of
MLA (6.75 micro g/side, P<0.0005) or DHbetaE (3.38 micro
g/side, P<0.025) caused significant working memory
impairments. When given together MLA and DHbetaE did not
produce an additive effect. In fact, the 6.75 micro g/kg
dose of DHbetaE produced a significant (P<0.0005)
attenuation of the MLA-induced working memory impairment.
Significant effects were not seen with reference memory or
response latency. Nicotinic systems in the basolateral
amygdala, as in the ventral hippocampus, are important for
spatial working memory. In both the basolateral amygdala and
the ventral hippocampus, MLA and DHbetaE individually caused
working memory impairments. The lowest effective dose of
DHbetaE was lower in the basolateral amygdala than in the
ventral hippocampus. In both the basolateral amygdala and
the ventral hippocampus, combined MLA and DHbetaE treatment
did not produce additive working memory deficits. Unlike in
the ventral hippocampus, the addition of DHbetaE to MLA in
the basolateral amygdala significantly reduced the
MLA-induced working memory deficit.},
Doi = {10.1016/s0926-6410(02)00209-4},
Key = {fds274461}
}
@article{fds274215,
Author = {Levin, ED},
Title = {Behavioral Toxicology Society 2002 annual meeting
report},
Journal = {Neurotoxicology and Teratology},
Volume = {25},
Number = {1},
Pages = {77-80},
Publisher = {Elsevier BV},
Year = {2003},
Month = {January},
url = {http://dx.doi.org/10.1016/S0892-0362(02)00355-0},
Doi = {10.1016/S0892-0362(02)00355-0},
Key = {fds274215}
}
@article{fds274216,
Author = {Levin, ED and Chrysanthis, E and Yacisin, K and Linney,
E},
Title = {Erratum: Chlorpyrifos exposure of developing zebrafish:
Effects on survival and long-term effects on response
latency and spatial discrimination (Neurotoxicology and
Teratology (2003) 25 (51-57))},
Journal = {Neurotoxicology and Teratology},
Volume = {25},
Number = {5},
Pages = {639},
Publisher = {Elsevier BV},
Year = {2003},
Month = {January},
url = {http://dx.doi.org/10.1016/S0892-0362(03)00077-1},
Doi = {10.1016/S0892-0362(03)00077-1},
Key = {fds274216}
}
@article{fds274350,
Author = {Levin, ED and Blackwelder, WP and Glasgow, HB and Burkholder, JM and Moeller, PDR and Ramsdell, JS},
Title = {Learning impairment caused by a toxin produced by Pfiesteria
piscicida infused into the hippocampus of
rats.},
Journal = {Neurotoxicol Teratol},
Volume = {25},
Number = {4},
Pages = {419-426},
Year = {2003},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12798959},
Keywords = {Animals • Behavior, Animal • Female •
Hippocampus • Learning Disorders • Maze Learning
• Neurotoxins • Pfiesteria piscicida •
Protozoan Infections, Animal • Rats • Rats,
Sprague-Dawley • Reaction Time • Time Factors
• drug effects • etiology* • metabolism*
• microbiology* • physiopathology* •
toxicity*},
Abstract = {Pfiesteria piscicida, an estuarine dinoflagellate, which has
been shown to kill fish, has also been associated with
neurocognitive deficits in humans. With a rat model, we have
demonstrated the cause-and-effect relationship between
Pfiesteria exposure and learning impairment. In several
studies, we have replicated the finding in Sprague-Dawley
rats that exposure to fixed acute doses of Pfiesteria cells
or filtrates caused radial-arm maze learning impairment.
Recently, this finding of Pfiesteria-induced learning
impairment in rats has been independently replicated in
another laboratory as well. We have demonstrated significant
Pfiesteria-induced learning impairment in both the win-shift
and repeated-acquisition tasks in the radial-arm maze and in
reversal learning in a visual operant signal detection task.
These learning impairments have been seen as long as 10
weeks after a single acute exposure to Pfiesteria. In the
current study, we used a hydrophilic toxin isolated from
clonal P. piscicida cultures (PfTx) and tested its effect
when applied locally to the ventral hippocampus on repeated
acquisition of rats in the radial-arm maze. Toxin exposure
impaired choice accuracy in the radial-arm maze repeated
acquisition procedure. The PfTx-induced impairment was seen
at the beginning of the session and the early learning
deficit was persistent across 6 weeks of testing after a
single administration of the toxin. Eventually, with enough
practice, in each session, the PfTx-exposed rats did learn
that session's problem as did control rats. This model has
demonstrated the cause-and-effect relationship between
exposure to a hydrophilic toxin produced by P. piscicida and
learning impairment, and specifically that the ventral
hippocampus was critically involved.},
Doi = {10.1016/s0892-0362(03)00011-4},
Key = {fds274350}
}
@article{fds274430,
Author = {Levin, ED and Chrysanthis, E and Yacisin, K and Linney,
E},
Title = {Chlorpyrifos exposure of developing zebrafish: effects on
survival and long-term effects on response latency and
spatial discrimination.},
Journal = {Neurotoxicol Teratol},
Volume = {25},
Number = {1},
Pages = {51-57},
Year = {2003},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12633736},
Keywords = {Animals • Behavior, Animal • Central Nervous
System • Chlorpyrifos • Discrimination Learning
• Disease Models, Animal • Dose-Response
Relationship, Drug • Embryo, Nonmammalian •
Embryonic Development • Female • Humans •
Insecticides • Larva • Pregnancy • Prenatal
Exposure Delayed Effects* • Reaction Time • Space
Perception • Survival Rate • Zebrafish • drug
effects • drug effects* • embryology •
embryology* • growth & development • growth &
development* • physiology • physiopathology •
toxicity*},
Abstract = {Chlorpyrifos (CPF) is a widely used insecticide, which has
been shown to interfere with neurobehavioral development.
Rat models have been key in demonstrating that prenatal CPF
exposure causes choice accuracy deficits and motor
alterations, which persist into adulthood. Complementary
nonmammalian models can be useful in determining the
molecular mechanisms underlying the persisting behavioral
effects of developmental CPF exposure. Zebrafish with their
clear chorion and extensive developmental information base
provide an excellent model for assessment of molecular
processes of toxicant impacted neurodevelopment. To
facilitate the use of the zebrafish model and to compare it
to the more typical rodent models, the behavioral phenotype
of CPF toxicity in zebrafish must be well characterized. Our
laboratory has developed methods for assessing spatial
discrimination learning in zebrafish, which can
differentiate response latency from choice accuracy in a
three chambered fish tank. Low and high doses of CPF (10 and
100 ng/ml on days 1-5 postfertilization) both had
significant persisting effects on both spatial
discrimination and response latency over 18 weeks of
testing. The high, but not the low dose, significantly
accelerated mortality rates of the fish during the study
from 20-38 weeks of age. Developmental exposure to either 10
or 100 ng/ml of CPF caused significant spatial
discrimination impairments in zebrafish when they were
adults. The impairment caused by 10 ng/ml was seen during
early but not later testing, while the impairment caused by
100 ng/ml became more pronounced with continued testing. The
higher dose caused a more pervasive impairment. The 10 and
100 ng/ml doses had opposite effects on response latency.
The low 10 ng/ml dose significantly slowed response latency,
while the high 100 ng/ml dose significant increased response
latency. Both of these effects diminished with continued
testing. CPF exposure during early development caused clear
behavioral impairments, which lasted throughout adulthood in
zebrafish. The molecular mechanisms by which early
developmental CPF exposure produces these behavioral
impairments expressed in adulthood can now be studied in the
zebrafish model.},
Doi = {10.1016/s0892-0362(02)00322-7},
Key = {fds274430}
}
@article{fds274349,
Author = {Levin, ED},
Title = {Nicotinic receptor subtypes and cognitive
function.},
Journal = {J Neurobiol},
Volume = {53},
Number = {4},
Pages = {633-640},
Year = {2002},
Month = {December},
ISSN = {0022-3034},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12436426},
Keywords = {Amygdala • Animals • Cognition • Hippocampus
• Humans • Memory • Nicotine • Nicotinic
Agonists • Nicotinic Antagonists • Receptors,
Nicotinic • drug effects • drug effects* •
genetics • metabolism • pharmacology •
pharmacology* • physiology},
Abstract = {Nicotinic receptor systems are involved in a wide variety of
behavioral functions including cognitive function. Nicotinic
medications may provide beneficial treatment for cognitive
dysfunction such as Alzheimer's disease, schizophrenia, and
attention deficit hyperactivity disorder (ADHD). Nicotine
has been shown to improve attentional performance in all of
these disorders. Better efficacy with fewer side effects
might be achieved with novel nicotinic ligands selective for
particular nicotinic subtypes. To develop these novel
selective nicotinic ligands it is important to use animal
models to determine the critical neurobehavioral bases for
nicotinic involvement in cognitive function.
Nicotine-induced cognitive improvement in rats is most
consistently seen in working memory tasks. We have found
that both acute and chronic nicotine administration
significantly improves working memory performance of rats in
the radial-arm maze. The pharmacologic and anatomic
mechanisms for this effect have been examined in our
laboratory in a series of local drug infusion studies. Both
alpha 4 beta 2 and alpha 7 nicotinic receptors in the
ventral hippocampus and basolateral amygdala are involved in
working memory function. Working memory impairments were
caused by local infusion of either alpha 4 beta 2 or alpha 7
antagonists. Ventral hippocampal alpha 4 beta 2
blockade-induced working memory deficits are reversed by
chronic systemic nicotine treatment, while ventral
hippocampal alpha 7 blockade-induced working memory deficits
were not found to be reversed by the same nicotine regimen.
Interestingly, alpha 4 beta 2 and alpha 7 induced deficits
were not found to be additive in either the ventral
hippocampus or the basolateral amygdala. In fact, in the
amygdala, alpha 7 antagonist cotreatment actually reversed
the working memory impairment caused by alpha 4 beta 2
antagonist administration. These studies of the neural
nicotinic mechanisms underlying cognitive function are key
for opening avenues for development of safe and effective
nicotinic treatments for cognitive dysfunction.},
Doi = {10.1002/neu.10151},
Key = {fds274349}
}
@article{fds274382,
Author = {Rezvani, AH and Bushnell, PJ and Levin, ED},
Title = {Effects of nicotine and mecamylamine on choice accuracy in
an operant visual signal detection task in female
rats.},
Journal = {Psychopharmacology (Berl)},
Volume = {164},
Number = {4},
Pages = {369-375},
Year = {2002},
Month = {December},
ISSN = {0033-3158},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12457266},
Keywords = {Animals • Attention • Choice Behavior •
Conditioning, Operant • Contrast Sensitivity •
Dose-Response Relationship, Drug • Female •
Mecamylamine • Nicotine • Nicotinic Antagonists
• Rats • Rats, Sprague-Dawley • Reaction Time
• Signal Detection (Psychology) • drug effects
• drug effects* • pharmacology*},
Abstract = {RATIONALE: During the past decade, central nicotinic systems
have been shown in both experimental animals and humans to
play an important role in cognitive function. However, the
way in which specific aspects of cognitive function are
affected by nicotinic systems has remained unclear. In
humans, the most pronounced action of nicotine is to improve
attention, but in rats, memory improvement is more easily
seen. This may be due to differences in methods for
assessing attention in rats and humans or to species
differences in the roles of nicotinic systems in cognitive
function. In the current study, we explored the effects of
nicotine and mecamylamine using an operant visual signal
detection task designed to model sustained attention
processes common to rats and humans. METHODS: Adult female
rats ( n=35) were trained to perform the signal detection
task to a stable baseline of about 75% accuracy. The rats
were then assigned to two subgroups of high and low accuracy
based on overall accuracy (hits and correct rejections) at
the end of training. All rats were then injected (SC, 10 min
before testing) with saline or different doses of nicotine
(0.0125, 0.025, 0.05, 0.1, 0.2 and 0.4 mg/kg) or the
nicotinic antagonist mecamylamine (1, 2 and 4 mg/kg).
RESULTS: A low dose range of nicotine (0.0125, 0.025, and
0.05 mg/kg) caused a dose-related increase in percent
correct rejection. This dose range did not affect correct
detections of the signal (percent hit). Higher doses of
nicotine (0.1, 0.2 and 0.4 mg/kg) did not affect percent
correct rejection, but did have a time-dependent effect on
percent hit. Early in the session, the higher doses of
nicotine reduced percent hit, whereas during the later part
of the session higher doses of nicotine increased percent
hit. Effects of nicotine did not differ between the high-
and low-accuracy rats. Mecamylamine decreased choice
accuracy, reducing both percent hit and percent correct
rejection. Mecamylamine reduced percent hit in the
low-accuracy rats at a lower drug dose than in the
high-accuracy rats. CONCLUSIONS: These results support the
involvement of nicotinic systems in attention in rats, as
has been shown in humans. This rat model of sustained
attention may provide a good approach to studying neural
mechanisms underlying the effects of nicotinic cholinergic
receptors on attention and a means to evaluate the potential
of novel nicotinic agonists to counteract attentional
dysfunction.},
Doi = {10.1007/s00213-002-1221-0},
Key = {fds274382}
}
@article{fds274411,
Author = {Addy, N and Levin, ED},
Title = {Nicotine interactions with haloperidol, clozapine and
risperidone and working memory function in
rats.},
Journal = {Neuropsychopharmacology},
Volume = {27},
Number = {4},
Pages = {534-541},
Year = {2002},
Month = {October},
ISSN = {0893-133X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12377390},
Keywords = {Animals • Antipsychotic Agents • Brain •
Clozapine • Dopamine • Dose-Response Relationship,
Drug • Drug Interactions • Female •
Haloperidol • Maze Learning • Memory, Short-Term
• Neural Pathways • Nicotine • Rats •
Rats, Sprague-Dawley • Reaction Time • Receptors,
Dopamine • Risperidone • Schizophrenia •
adverse effects • antagonists & inhibitors • drug
effects • drug effects* • drug therapy •
metabolism • metabolism* • pharmacology* •
physiology • physiopathology},
Abstract = {Nicotine has been shown in a variety of studies to improve
memory performance. The cognitive effects of nicotine are
particularly important with regard to schizophrenia. In the
current studies nicotine interactions with three different
antipsychotic drugs, haloperidol, clozapine and risperidone,
were assessed with regard to memory function. Female
Sprague-Dawley rats were trained on the radial-arm maze to
asymptotic levels of choice accuracy. They were then
administered nicotine alone or in combination with
haloperidol, clozapine or risperidone. Acute haloperidol
(0.04 mg/kg) did not by itself affect memory performance.
Co-administration of haloperidol with nicotine, however,
decreased memory performance compared with nicotine
administration in isolation. Acute clozapine (1.25 and 2.5
mg/kg) caused a significant memory impairment, an effect
reversed by acute nicotine co-treatment. Risperidone (0.05
mg/kg), like haloperidol, did not by itself affect memory
performance. Risperidone co-administration with nicotine,
however, did significantly attenuate the improvement caused
by nicotine administration in isolation. The similar
interaction of haloperidol and risperidone with nicotine may
be due to their common action of blocking D(2) receptors, a
mechanism of action not shared by clozapine. In contrast to
the interaction of nicotine with haloperidol or risperidone,
nicotine effectively reversed clozapine-induced memory
impairment. These studies demonstrate interactions between
nicotine and antipsychotic drugs in terms of memory, which
may have important impacts on the treatment of
schizophrenia.},
Doi = {10.1016/S0893-133X(02)00327-5},
Key = {fds274411}
}
@article{fds274438,
Author = {Levin, ED and Rezvani, AH},
Title = {Nicotinic treatment for cognitive dysfunction.},
Journal = {Curr Drug Targets CNS Neurol Disord},
Volume = {1},
Number = {4},
Pages = {423-431},
Year = {2002},
Month = {August},
ISSN = {1568-007X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12769614},
Keywords = {Alzheimer Disease • Animals • Attention Deficit
Disorder with Hyperactivity • Cognition Disorders
• Humans • Nicotinic Agonists • Nicotinic
Antagonists • Schizophrenia • drug therapy •
drug therapy* • psychology • therapeutic
use*},
Abstract = {Nicotinic medications may provide beneficial therapeutic
treatment for cognitive dysfunction such as Alzheimer's
disease, schizophrenia and attention deficit hyperactivity
disorder (ADHD). For development of nicotinic treatments we
are fortunate to have a well characterized lead compound,
nicotine. Transdermal nicotine patches offer a way to
deliver measured doses of nicotine in a considerably safer
fashion than the more traditional means of administration,
tobacco smoking. We have found that transdermal nicotine
significantly improves attentional function in people with
Alzheimer's disease, schizophrenia or ADHD as well as normal
nonsmoking adults. To follow-up on this proof of principal
that nicotinic treatment of cognitive dysfunction holds
promise, it is important to use animal models to determine
the critical neurobehavioral bases for nicotinic involvement
in cognitive function so that more selective nicotinic
analogues that improve cognitive function with fewer side
effects can be developed. We have found with local infusion
in rat studies that the hippocampus and amygdala are
important substrates for nicotinic effects on working memory
function. Both alpha7 and alpha4beta2 nicotinic receptors
are involved in working memory. Nicotinic interactions with
dopaminergic and glutaminergic systems are also important in
the basis of cognitive function. Studies of the neural
nicotinic mechanisms underlying cognitive function are key
for opening avenues for development of safe and effective
nicotinic treatments for cognitive dysfunction.},
Doi = {10.2174/1568007023339102},
Key = {fds274438}
}
@article{fds274367,
Author = {Rezvani, AH and Levin, ED},
Title = {Nicotine-alcohol interactions and cognitive function in
rats.},
Journal = {Pharmacol Biochem Behav},
Volume = {72},
Number = {4},
Pages = {865-872},
Year = {2002},
Month = {July},
ISSN = {0091-3057},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12062576},
Keywords = {Animals • Body Temperature • Central Nervous
System Depressants • Cognition • Dose-Response
Relationship, Drug • Ethanol • Female •
Injections, Intraperitoneal • Injections, Subcutaneous
• Maze Learning • Memory, Short-Term •
Nicotine • Nicotinic Agonists • Rats • Rats,
Sprague-Dawley • drug effects • drug effects*
• pharmacology*},
Abstract = {Nicotine and ethanol are the most widely abused drugs in the
world. They are very often used and abused together.
However, little is known about the functional interaction of
nicotine and ethanol. The current project studied the
interactive effects of nicotine and ethanol on working
memory in the eight-arm radial maze. Adult female rats were
trained on a radial arm maze for 18 sessions to reach
asymptotic levels of choice accuracy. During the maintenance
phase of radial arm maze testing, which indexed working
memory function, the rats were injected with nicotine (0,
0.15, 0.3, 0.6, and 1.2 mg/kg sc, 20 min before testing)
with and without ethanol pretreatment (0 or 1.5 g/kg, 16%
v/v ip, 30 min before testing). All animals received the
treatments in a counterbalanced order with at least 1 week
between treatments. Higher doses of nicotine had a
significant interaction with ethanol in terms of radial arm
maze choice accuracy. Nicotine plus ethanol coadministration
precipitated a significant choice accuracy impairment at
doses that when given alone had no effect on performance. At
the lower dose range of nicotine, ethanol coadministration
eliminated the nicotine-induced memory improvement. No
significant effects were seen with either nicotine or
ethanol treatment or their interaction on response latency
in the radial arm maze. The nicotine-ethanol interactive
effects on memory were compared with the interaction of
their well-characterized hypothermic effects. Nicotine and
alcohol, when injected separately or in combination, induced
hypothermia with no significant interactive effect. This
study found that ethanol blocked low-dose nicotine-induced
memory improvement and precipitated memory impairment with
high-dose nicotine treatment. This interaction may be an
important consideration for nicotine and ethanol coabuse and
the possible therapeutic use of nicotinic drugs for memory
dysfunction.},
Doi = {10.1016/s0091-3057(02)00762-1},
Key = {fds274367}
}
@article{fds316109,
Author = {Qiao, D and Seidler, FJ and Levin, ED and Padilla, S and Slotkin,
TA},
Title = {Developmental neurotoxicity of chlorpyrifos: Defining the
vulnerable period},
Journal = {FASEB JOURNAL},
Volume = {16},
Number = {5},
Pages = {A949-A949},
Publisher = {FEDERATION AMER SOC EXP BIOL},
Year = {2002},
Month = {March},
ISSN = {0892-6638},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000174593901244&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316109}
}
@article{fds274454,
Author = {Levin, ED and Christopher, NC and Lateef, S and Elamir, BM and Patel, M and Liang, L-P and Crapo, JD},
Title = {Extracellular superoxide dismutase overexpression protects
against aging-induced cognitive impairment in
mice.},
Journal = {Behav Genet},
Volume = {32},
Number = {2},
Pages = {119-125},
Year = {2002},
Month = {March},
ISSN = {0001-8244},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12036109},
Keywords = {Aging • Animals • Extracellular Space •
Female • Gene Expression Regulation, Enzymologic •
Genotype • Humans • Maze Learning • Mice
• Mice, Transgenic • Oxidative Stress •
Retention (Psychology) • Signal Transduction •
Superoxide Dismutase • enzymology* • genetics
• genetics* • physiology •
physiology*},
Abstract = {Extracellular superoxide dismutase (EC-SOD) controls the
availability of extracellular superoxide and appears to play
a role in controlling oxidative stress and intercellular
signaling. Whether EC-SOD overexpression would help or
hinder neurobehavioral function appears to depend on the age
of the individual. In young adult mice, we have found that
EC-SOD overexpression can interfere with learning on the
radial-arm maze, possibly by reducing control over nitric
oxide neurotransmission. In aged mice, we found, in the
current study, that EC-SOD overexpression greatly improves
learning on the radial-arm maze. Control (N = 17) and EC-SOD
overexpressing mice (N = 13) acquired the 8-arm radial maze
over 21 sessions of training. The EC-SOD overexpressing mice
had significantly better choice accuracy than the control
mice (p < 0.005). The EC-SOD overexpressing mice averaged
6.34+/-0.22 correct arm entries before an error (entries to
repeat) during the acquisition phase, while the control mice
averaged 5.18+/-0.22 entries to repeat. EC-SOD genotype did
not cause a main effect on response latency. The advantage
held by the EC-SOD overexpressing mice persisted during the
eight-session post-acquisition phase of testing (p < 0.01).
When there was a shift from high to low levels of motivation
by reducing the period of food restriction before testing,
the EC-SOD overexpression-induced improvement was reduced
slightly, but it was still significant compared with the
wild-type controls (p < 0.025). Then, after 4 months of no
testing, the mice were tested for retention and
reacquisition of performance on the radial-arm maze. The
EC-SOD overexpressing mice maintained their significantly
better choice accuracy (p < 0.05). Enhancement of EC-SOD
activity appears to improve learning and memory performance,
specifically in aging mice. EC-SOD mimetic treatment during
the course of aging may hold promise for aging-induced
cognitive impairment.},
Doi = {10.1023/a:1015201823417},
Key = {fds274454}
}
@article{fds274481,
Author = {Arthur, D and Levin, ED},
Title = {Chronic inhibition of alpha4beta2 nicotinic receptors in the
ventral hippocampus of rats: impacts on memory and nicotine
response.},
Journal = {Psychopharmacology (Berl)},
Volume = {160},
Number = {2},
Pages = {140-145},
Year = {2002},
Month = {March},
ISSN = {0033-3158},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11875631},
Keywords = {Alzheimer Disease • Animals • Cognition Disorders
• Dihydro-beta-Erythroidine • Female •
Hippocampus • Memory • Nicotine • Nicotinic
Antagonists • Rats • Rats, Sprague-Dawley •
Receptors, Nicotinic • Time Factors • antagonists
& inhibitors • drug effects* • drug therapy •
metabolism • pharmacology*},
Abstract = {RATIONALE: Acute and chronic systemic nicotine
administration has been shown to cause significant spatial
memory improvement. The critical nicotinic receptor subtypes
for this effect and their location are still being
determined. Nicotinic receptors in the ventral hippocampus
have been found to be critically involved in memory. Acute
ventral hippocampal infusions of dihydro-beta-erythroidine
(DHbetaE), an alpha4beta2 nicotinic receptor antagonist,
impaired spatial memory of rats in the radial-arm maze.
OBJECTIVES: The current study used chronic ventral
hippocampal infusion of DHbetaE as a model of nicotinic
receptor loss such as that which occurs in Alzheimer's
disease. The therapeutic effect of systemic nicotine
treatment in reversing the DHbetaE-induced memory impairment
was determined. METHODS: Rats were pretrained to asymptotic
levels of performance on the eight-arm radial maze. Then,
they were implanted with bilateral infusion cannulae in the
ventral hippocampus, through which 0, 33.3, or 100
microg/side/day of DHbetaE was continuously infused for 4
weeks. The rats were retested on the eight-arm maze
throughout infusion period and after withdrawal, and the
interaction of acute systemic nicotine injections on memory
was tested. RESULTS: The higher (100 microg/side/day) but
not the lower (33.3 microg/side/day) DHbetaE dose caused a
significant spatial memory impairment. Acute systemic
nicotine injections (0, 0.1, 0.2, and 0.4 mg/kg,
subcutaneous) attenuated the memory impairing effects of 100
microg/side/day of DHbetaE. There was no significant effect
on response latency with the chronic DHbetaE infusion. Acute
systemic nicotine infusions did significantly speed
responding, an effect which was reversed by chronic
hippocampal infusions of DHbetaE. After withdrawal there
were no significant lasting effects on choice accuracy or
response latency. Wet-dog shakes were significantly elevated
during chronic hippocampal DHbetaE administration with no
effect during the withdrawal period. CONCLUSIONS: These
results indicate that chronic inhibition of a subset of
nicotinic receptors in the hippocampus results in a
significant impairment in the spatial memory choice
accuracy. The ability of nicotine to attenuate the
impairment supports the development of nicotinic agonist
therapy of syndromes, such as Alzheimer's disease, that
involve a chronic decrease in the activity of the
alpha4beta2 nicotinic receptors and memory
impairment.},
Doi = {10.1007/s00213-001-0961-6},
Key = {fds274481}
}
@article{fds316103,
Author = {Rossler, IB and Johnson, RC and Krystal, AD and Weiner, RD and Levin,
ED and Logue, P and Coffey, CE and Edwards, CL},
Title = {A naturalistic study of the effects of smoking on the
cognitive side effects of ECT.},
Journal = {JOURNAL OF ECT},
Volume = {18},
Number = {1},
Pages = {64-64},
Publisher = {LIPPINCOTT WILLIAMS & WILKINS},
Year = {2002},
Month = {March},
ISSN = {1095-0680},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000174804700030&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316103}
}
@article{fds274338,
Author = {Esposito, E and Cortesi, R and Porta, R and Trento, F and Nastruzzi,
C},
Title = {Effect of long-term stabilization of cationic liposomes as
defibrotide delivery system for antithrombotic
activity},
Journal = {Drug Development Research},
Volume = {55},
Number = {2},
Pages = {127-138},
Publisher = {WILEY},
Year = {2002},
Month = {January},
ISSN = {0272-4391},
url = {http://dx.doi.org/10.1002/ddr.10041},
Abstract = {The general goal of this study was to produce cationic
liposome formulations suitable for the in vivo
administration of defibrotide (DFT) (a DNA-based drug) and
to investigate in vitro and in vivo the stability of such a
formulation. This article describes the freeze-drying of
cationic liposomes using as cryoprotectants different
carbohydrates, such as sorbitol, mannitol, and sucrose.
Liposome characteristics before and after freeze-drying,
such as size, morphology, and ability in complexing a
DNA-based drug, have been investigated. The in vitro studies
indicate that cationic liposomes sufficiently maintain the
initial characteristics after lyophilization and rehydration
including the ability to complex DFT. The in vivo data show
that lyophilized cationic liposome formulations can be
safely stored for at least 3 months. Before in vivo use,
liposomes can be rehydrated with DFT solutions, resulting in
the formation of stable complexes retaining an in vivo
activity comparable to that of the freshly prepared
formulation. © 2002 Wiley-Liss, Inc.},
Doi = {10.1002/ddr.10041},
Key = {fds274338}
}
@article{fds316085,
Author = {Levin, ED and Christopher, NC},
Title = {Persistence of nicotinic agonist RJR 2403-induced working
memory improvement in rats},
Journal = {Drug Development Research},
Volume = {55},
Number = {2},
Pages = {97-103},
Publisher = {WILEY},
Year = {2002},
Month = {January},
ISSN = {0272-4391},
url = {http://dx.doi.org/10.1002/ddr.10024},
Abstract = {Nicotinic systems are involved in the neural basis of memory
function and nicotinic agonists have shown promise for the
treatment of cognitive dysfunction. Both acute and chronic
nicotinic treatment has been shown to improve memory
performance. There is some evidence for the persistence of
nicotine-induced memory improvements lasting longer than the
pharmacokinetic presence of nicotine. Novel nicotinic
agonists may produce the beneficial effects of nicotine on
cognitive function with fewer side effects. RJR 2403
(metanicotine or (E)-N-methyl-4-(3-pyridinyl)-3-butene-1-amine)
a preferential α4β2 nicotinic agonist has been shown in
previous studies to improve memory function. The present
study examined the persistence of oral RJR 2403 on memory
performance in young adult Sprague-Dawley rats (3-5 months
old) 30 min, 1 h, and 6 h post-administration (PO). In the
first experiment, the typical inverted U-shaped dose
response curve for cognitive enhancing drugs was seen with
RJR 2403 30 min after administration. The lower dose of 1
mg/kg (3.6 μmol/kg), but not higher doses of 3 or 10 mg/kg
(10.8 or 36 μmol/kg), of RJR 2403 significantly (P < 0.05)
improved working memory on the radial-arm maze relative to
placebo-treated controls. In the second experiment, young
adult rats were administered RJR 2403 (0, 0.3, or 1.0 mg/kg)
and tested 1 h or 6 h following administration in separate
treatment groups. The 0.3 mg/kg RJR 2403 dose (1.08
αmol/kg) caused a significant (P < 0.05) memory improvement
1 h after oral administration. Interestingly, both the 0.3
and 1.0 mg/kg RJR 2403 doses (1.08 and 3.6 μmol/kg)
significantly (P < 0.05) improved memory six hours after
administration. These data demonstrate the efficacy of oral
RJR 2403 in improving cognitive performance and the long
duration of action of RJR 2403 in young adult rats. In
contrast, no significant memory improvement was seen in aged
rats aged (24-26 months old) after RJR 2403 administration.
The inability of RJR 2403 to enhanced cognitive functions in
aged rats might be related to the decrease in the number of
α4β2 nicotinic receptors, which occurs with age. A similar
decreased responsiveness in aged rats has been seen with
nicotine. The persistence of action of RJR 2403 provides
additional promise for its potential as a treatment for
cognitive dysfunction. However, the decreased responsiveness
in subjects in populations with decreased nicotinic receptor
number may limit the effectiveness of nicotinic therapies.
© 2002 Wiley-Liss, Inc.},
Doi = {10.1002/ddr.10024},
Key = {fds316085}
}
@article{fds274344,
Author = {Levin, ED and Bradley, A and Addy, N and Sigurani,
N},
Title = {Hippocampal alpha 7 and alpha 4 beta 2 nicotinic receptors
and working memory.},
Journal = {Neuroscience},
Volume = {109},
Number = {4},
Pages = {757-765},
Year = {2002},
ISSN = {0306-4522},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11927157},
Keywords = {Acetylcholine • Animals • Dihydro-beta-Erythroidine
• Dose-Response Relationship, Drug • Female •
Grooming • Hippocampus • Maze Learning •
Mecamylamine • Memory, Short-Term • Neurons •
Nicotinic Antagonists • Rats • Rats,
Sprague-Dawley • Receptors, Nicotinic • Synaptic
Transmission • cytology • drug effects •
metabolism • metabolism* • pharmacology •
pharmacology* • physiology • physiology*},
Abstract = {Nicotine and other nicotinic receptor agonists have been
found in a variety of studies to improve memory, while
nicotinic receptor blockade can impair memory. The critical
neural mechanisms for nicotinic involvement with memory are
still under investigation. Initial evidence supports the
involvement of the ventral hippocampus. Lesions in this area
block nicotine-induced memory improvement and
mecamylamine-induced impairment. Local ventral hippocampal
application of the nicotinic channel blocker mecamylamine
impairs memory in the 8-arm radial maze. Both alpha 4 beta 2
and alpha 7 nicotinic receptors seem to be involved. Ventral
hippocampal infusions of high doses of the alpha 4 beta 2
nicotinic antagonist dihydro-beta-erythrodine (DH beta E)
and the alpha 7 nicotinic antagonist methyllycaconitine
(MLA) impair memory performance on the 8-arm radial maze.
However, high doses of these drugs may limit specificity and
they cause preconvulsant effects, which in themselves may
affect memory. The current study used the more challenging
16-arm radial maze to determine the effects of lower doses
of these drugs on memory and to differentiate effects on
working and reference memory. Adult female Sprague-Dawley
rats were trained on a working and reference memory task in
the 16-arm radial maze and then were implanted with
bilateral chronic guide cannulae directed to the ventral
hippocampus. After recovery from surgery, the rats received
acute intrahippocampal infusions of dose combinations of DH
beta E and MLA. In the first study, DH beta E (0 and 6.75
microg/side) and MLA (0, 6.75, 13.5 and 27 microg/side) were
administered in a counter-balanced order. In the second
study, lower doses of DH beta E (0, 1.6375, 3.275 and 6.75
microg/side) were administered alone or with MLA (0 and 6.75
microg/side) in a counter-balanced order. In the first
study, DH beta E caused a significant increase in both
working and reference memory errors. MLA at a dose of 27
microg/side caused a significant increase in working memory
errors, but this dose had no significant effect on reference
memory errors. Interestingly, no additive effects were seen
with combined administration of DH beta E and MLA in this
study, and at the doses used, no effects were seen on
response latency. In the second study, lower doses of DH
beta E did not cause a significant deficit in working memory
performance. Co-administration of MLA with these
subthreshold doses did precipitate a memory impairment. The
current results confirm the specificity of the memory
deficits caused by these drugs. These results support the
involvement of alpha 4 beta 2 and alpha 7 nicotinic
receptors in the ventral hippocampus as being critical for
memory function.},
Doi = {10.1016/s0306-4522(01)00538-3},
Key = {fds274344}
}
@article{fds274473,
Author = {Levin, ED and Addy, N and Baruah, A and Elias, A and Christopher, NC and Seidler, FJ and Slotkin, TA},
Title = {Prenatal chlorpyrifos exposure in rats causes persistent
behavioral alterations.},
Journal = {Neurotoxicol Teratol},
Volume = {24},
Number = {6},
Pages = {733-741},
Year = {2002},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12460655},
Keywords = {Animals • Animals, Newborn • Brain •
Chlorpyrifos • Cholinergic Fibers • Cholinesterase
Inhibitors • Cognition Disorders • Dose-Response
Relationship, Drug • Female • Male • Maze
Learning • Memory, Short-Term • Mental Disorders
• Motor Activity • Muscarinic Antagonists •
Pregnancy • Prenatal Exposure Delayed Effects* •
Rats • Rats, Sprague-Dawley • Reaction Time •
Receptors, Muscarinic • Scopolamine • Sex
Characteristics • chemically induced* • drug
effects • drug effects* • metabolism •
pharmacology • physiology • physiopathology •
toxicity*},
Abstract = {Use of chlorpyrifos (CPF) has been curtailed due to its
developmental neurotoxicity. In rats, postnatal CPF
administration produces lasting changes in cognitive
performance, but less information is available about the
effects of prenatal exposure. We administered CPF to
pregnant rats on gestational days (GD) 17-20, a peak period
of neurogenesis, using doses (1 or 5 mg/kg/day) below the
threshold for fetal growth impairment. We then evaluated
performance in the T-maze, Figure-8 apparatus and 16-arm
radial maze, beginning in adolescence and continuing into
adulthood. CPF elicited initial locomotor hyperactivity in
the T-maze. Females showed slower habituation in the Fig. 8
maze; no effects were seen in males. In the radial-arm maze,
females showed impaired choice accuracy for both working and
reference memory and again, males were unaffected. Despite
the deficits, all animals eventually learned the maze with
continued training. At that point, we challenged them with
the muscarinic antagonist, scopolamine, to determine the
dependence of behavioral performance on cholinergic
function. Whereas control females showed impairment with
scopolamine, CPF-exposed females did not, implying that the
delayed acquisition of the task had been accomplished
through alternative mechanisms. The differences were
specific to muscarinic circuits, as control and CPF groups
responded similarly to the nicotinic antagonist,
mecamylamine. Surprisingly, adverse effects of CPF were
greater in the group receiving 1 mg/kg as compared to 5
mg/kg. Promotional effects of acetylcholine (ACh) on cell
differentiation may thus help to offset CPF-induced
developmental damage that occurs through other
noncholinergic mechanisms. Our results indicate that late
prenatal exposure to CPF induces long-term changes in
cognitive performance that are distinctly gender-selective.
Additional defects may be revealed by similar strategies
that subject the animals to acute challenges, thus,
uncovering the adaptive mechanisms that maintain basal
performance.},
Doi = {10.1016/s0892-0362(02)00272-6},
Key = {fds274473}
}
@article{fds274408,
Author = {Bettany, JH and Levin, ED},
Title = {Ventral hippocampal alpha 7 nicotinic receptor blockade and
chronic nicotine effects on memory performance in the
radial-arm maze.},
Journal = {Pharmacol Biochem Behav},
Volume = {70},
Number = {4},
Pages = {467-474},
Year = {2001},
Month = {December},
ISSN = {0091-3057},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11796146},
Keywords = {Aconitine • Animals • Dose-Response Relationship,
Drug • Female • Hippocampus • Insecticides
• Maze Learning • Memory • Nicotine •
Nicotinic Agonists • Nicotinic Antagonists • Rats
• Rats, Sprague-Dawley • Receptors, Nicotinic
• administration & dosage* • analogs &
derivatives* • drug effects* • pharmacology •
pharmacology* • physiology • physiology*},
Abstract = {Chronic nicotine administration has been shown to
significantly improve working memory. Nicotinic involvement
in memory function critically involves the ventral
hippocampus. Local ventral hippocampal infusions of the
nicotinic antagonists mecamylamine, dihydro-beta-erythroidine
(DH beta E) and methyllycaconitine (MLA) significantly
impair working memory. The impairment caused by hippocampal
infusion of the alpha 4 beta 2 antagonist DH beta E is
reversed by chronic systemic nicotine. This study determined
the interaction of chronic systemic nicotine with acute
ventral hippocampal infusions of the alpha 7 antagonist MLA.
Adult female Sprague-Dawley rats were trained on an 8-arm
radial maze working memory task. Then they underwent ventral
hippocampal cannulation and received sc implants of
minipumps delivering nicotine (0 or 5 mg/kg/day for 28
days). Acute ventral hippocampal infusions of MLA (0, 4.88,
14.64 and 43.92 microg/side) were given during 3-4 weeks of
chronic nicotine. MLA caused a significant dose-related
memory impairment. In the rats not receiving nicotine, the
14.64 and 43.92 microg/side MLA doses caused significant
memory impairment. Chronic systemic nicotine exposure did
not block the MLA-induced memory impairment. Comparing the
current results with MLA with previous results with DH beta
E, equimolar ventral hippocampal DH beta E more effectively
impaired memory than MLA, but the DH beta E-induced
impairment was more effectively reversed by chronic systemic
nicotine administration.},
Doi = {10.1016/s0091-3057(01)00643-8},
Key = {fds274408}
}
@article{fds274421,
Author = {Levin, ED},
Title = {A rat model of the cognitive impairment from Pfiesteria
piscicida exposure.},
Journal = {Environ Health Perspect},
Volume = {109 Suppl 5},
Number = {Suppl 5},
Pages = {757-763},
Year = {2001},
Month = {October},
ISSN = {0091-6765},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11677185},
Keywords = {Animals • Cognition Disorders • Disease Models,
Animal • Environmental Exposure* • Female •
Maze Learning • Pfiesteria piscicida • Protozoan
Infections • Rats • Rats, Sprague-Dawley •
complications* • etiology* • pathogenicity*},
Abstract = {Pfiesteria piscicida Steidinger & Burkholder, an estuarine
dinoflagellate known to kill fish, has also been associated
with neurocognitive deficits in humans. We have developed a
rat model to determine the cause-and-effect relationship
between exposure to Pfiesteria-containing water and
cognitive impairment and to determine the neurobehavioral
mechanisms underlying the Pfiesteria effect. The rat model
of Pfiesteria toxicity can also provide important
information concerning the toxin or toxins responsible for
neurocognitive deficits resulting from Pfiesteria exposure.
With the rat model we have repeatedly documented a
Pfiesteria-induced choice accuracy impairment during
radial-arm maze learning. The Pfiesteria-induced impairment
was relatively specific to the acquisition phase of
training. When rats were pretrained, Pfiesteria treatment
did not affect performance. However, when these same rats
were retrained on another task, the Pfiesteria-induced
impairment became evident. Pfiesteria-induced effects were
also seen in a locomotor activity test in the figure-8
apparatus and selected components of the functional
observational battery. Pfiesteria effects on choice accuracy
in the radial-arm maze in rats constitute a critical
component of the model of Pfiesteria toxicity, as the
hallmark of Pfiesteria toxicity in humans is cognitive
dysfunction. Our finding that analysis of the first six
sessions of radial-arm maze testing is sufficient for
determining the effect means that this test will be useful
as a rapid screen for identifying the critical neurotoxin(s)
of Pfiesteria in future studies.},
Doi = {10.1289/ehp.01109s5757},
Key = {fds274421}
}
@article{fds274511,
Author = {Levin, ED and Addy, N and Nakajima, A and Christopher, NC and Seidler,
FJ and Slotkin, TA},
Title = {Persistent behavioral consequences of neonatal chlorpyrifos
exposure in rats.},
Journal = {Brain Res Dev Brain Res},
Volume = {130},
Number = {1},
Pages = {83-89},
Year = {2001},
Month = {September},
ISSN = {0165-3806},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11557096},
Keywords = {Animals • Animals, Newborn • Behavior, Animal
• Chlorpyrifos • Female • Insecticides •
Male • Maze Learning • Mecamylamine • Memory
• Motor Activity • Muscarinic Antagonists •
Nicotinic Antagonists • Pregnancy • Rats •
Rats, Sprague-Dawley • Scopolamine • drug effects
• drug effects* • pharmacology •
pharmacology*},
Abstract = {Chlorpyrifos (CPF) is a widely used insecticides which has
been shown to alter brain cell development. The current
project was conducted to determine whether there are
persistent behavioral effects of early [1 mg/kg/day
postnatal days (PNDs) 1-4] or late (5 mg/kg/day PNDs 11-14)
postnatal CPF exposure in rats. We tested spontaneous
alternation in a T-maze, locomotor activity in the Figure-8
apparatus and learning in the 16-arm radial maze, throughout
adolescence and into adulthood. Exposure during either
neonatal period elicited significant long-term effects on
cognitive behavior. In the radial-arm maze, as has been seen
previously, control male performed more accurately than
control females. Early postnatal CPF exposure reversed this
effect. With exposure on PNDs 1-4, females in the CPF group
showed a reduction in working and reference memory errors in
the radial maze, reducing their error rate to that seen in
control males; in contrast, CPF-exposed males exhibited an
increase in errors during the initial stages of training.
When animals were exposed on PNDs 11-14 and then tested in
adolescence and adulthood, males showed a significant
slowing of response latency in the T-maze and the rate of
habituation in the Figure-8 apparatus was slowed in both
sexes. When females were challenged acutely with the
muscarinic antagonist, scopolamine, they did not show
reference memory impairment, whereas controls did; these
results suggest that adaptations occur after CPF exposure
that lead to loss of muscarinic cholinergic control of
reference memory. No such changes were seen with a nicotinic
cholinergic antagonist (mecamylamine). These results
indicate that early neonatal exposure to CPF induces
long-term changes in cognitive performance that, in keeping
with the neurochemical changes seen previously, are
distinctly gender-selective. Additional defects may be
revealed by similar strategies that subject the animals to
acute challenges, thus uncovering the adaptive mechanisms
that maintain basal performance.},
Doi = {10.1016/s0165-3806(01)00215-2},
Key = {fds274511}
}
@article{fds274482,
Author = {Levin, ED and Conners, CK and Silva, D and Canu, W and March,
J},
Title = {Effects of chronic nicotine and methylphenidate in adults
with attention deficit/hyperactivity disorder.},
Journal = {Exp Clin Psychopharmacol},
Volume = {9},
Number = {1},
Pages = {83-90},
Year = {2001},
Month = {February},
ISSN = {1064-1297},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11519638},
Keywords = {Adult • Attention • Attention Deficit Disorder
with Hyperactivity • Central Nervous System Stimulants
• Depressive Disorder • Female • Humans
• Male • Memory • Methylphenidate •
Middle Aged • Nicotine • Nicotinic Agonists •
Psychiatric Status Rating Scales • Psychomotor
Performance • drug effects • drug therapy* •
psychology • therapeutic use*},
Abstract = {Acute nicotine treatment has been found to reduce symptoms
of attention deficit/hyperactivity disorder in adults (E. D.
Levin, C. K. Conners, et al., 1996). In this study, chronic
nicotine effects were compared with placebo and
methylphenidate. Acute and chronic nicotine treatment
significantly attenuated the rise in hit reaction time
standard error over session blocks on the Conners Continuous
Performance Test (C. K. Conners et al., 1996). Acute
nicotine significantly reduced severity of clinical symptoms
on the Clinical Global Impressions scale (National Institute
of Mental Health, 1985). Nicotine caused a significant
decrease in self-report of depressive mood as measured by
the Profile of Mood States test (D. M. McNair, M. Lorr, & L.
F. Droppleman, 1981). This small study (40 participants)
provided evidence that nicotine treatment can reduce
severity of attentional deficit symptoms and produce
improvement on an objective computerized attention
task.},
Doi = {10.1037/1064-1297.9.1.83},
Key = {fds274482}
}
@article{fds274485,
Author = {Rezvani, AH and Levin, ED},
Title = {Cognitive effects of nicotine.},
Journal = {Biol Psychiatry},
Volume = {49},
Number = {3},
Pages = {258-267},
Year = {2001},
Month = {February},
ISSN = {0006-3223},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11230877},
Keywords = {Adult • Aged • Alzheimer Disease • Animals
• Cognition Disorders • Hippocampus • Humans
• Neuropsychological Tests* • Nicotine •
Receptors, Nicotinic • Treatment Outcome • drug
effects • drug therapy* • therapeutic
use*},
Abstract = {Nicotine and other nicotinic agonists have been found to
improve performance on attention and memory tasks. Clinical
studies using nicotine skin patches have demonstrated the
efficacy of nicotine in treating cognitive impairments
associated with Alzheimer's disease, schizophrenia, and
attention-deficit/hyperactivity disorder. Experimental
animal studies have demonstrated the persistence of
nicotine-induced working memory improvement with chronic
exposure, in addition to the efficacy of a variety of
nicotinic agonists. Mechanistic studies have found that
alpha7 and alpha4beta2 nicotinic receptors in the
hippocampus are critical for nicotinic involvement in
cognitive function. Clinical and experimental animal studies
provide mutually supporting information for the development
of novel nicotinic therapies for cognitive
dysfunction.},
Doi = {10.1016/s0006-3223(00)01094-5},
Key = {fds274485}
}
@article{fds136383,
Title = {Rezvani AH and ED Levin. Cognitive effects of nicotine.
Biological Psychiatry. 49:258-267, 2001.},
Year = {2001},
Key = {fds136383}
}
@article{fds136384,
Title = {Arthur D and ED Levin. Spatial and non-spatial
discrimination learning in zebrafish (Danio rerio) Animal
Cognition, 4:125-131, 2001.},
Year = {2001},
Key = {fds136384}
}
@article{fds136385,
Title = {Levin ED, A Bradley N Addy and N Sigurani. Hippocampal (7
and (4(2 nicotinic receptors and working memory.
Neuroscience. In press.},
Year = {2001},
Key = {fds136385}
}
@article{fds136386,
Title = {Levin ED and NC Christopher. Persistence of nicotinic
agonist RJR 2403 induced working memory improvement in rats.
Drug Development Research, In press.},
Year = {2001},
Key = {fds136386}
}
@article{fds136387,
Title = {Levin ED and AH Rezvani. Nicotinic Involvement in Memory
Function of Rats. In: Nicotinic Receptors in the Nervous
System. ED Levin (ed.), CRC Press, New York, 167-178
2001.},
Year = {2001},
Key = {fds136387}
}
@article{fds136388,
Title = {Levin ED. Nicotine Effects on Attention Deficit
Hyperactivity Disorder. In: Nicotinic Receptors in the
Nervous System. ED Levin (ed.), CRC Press, New York,
251-260, 2001.},
Year = {2001},
Key = {fds136388}
}
@article{fds136389,
Title = {Book Nicotinic Receptors in the Nervous System. ED Levin
(ed.), CRC Press, New York, 2001.},
Year = {2001},
Key = {fds136389}
}
@article{fds136401,
Title = {Levin ED, N Addy, A Nakajima, NC Christopher, FJ Seidler and
TA Slotkin Persistent behavioral consequences of neonatal
chlorpyrifos exposure in rats. Developmental Brain Research,
130:83-89, 2001.},
Year = {2001},
Key = {fds136401}
}
@article{fds136402,
Title = {Levin ED, A rat model of the cognitive impairment from
Pfiesteria piscicida exposure. Environmental Health
Perspectives, 109(Suppl. 5):757-763, 2001.},
Year = {2001},
Key = {fds136402}
}
@article{fds136403,
Title = {Rezvani AH, PJ Bushnell, JM Burkholder, HB Glasgow, Jr. and
ED Levin. Specificity of cognitive impairment from
Pfiesteria piscicida exposure in rats: Attention and visual
function vs. behavioral plasticity. Neurotoxicology and
Teratology. 23:609-616, 2001.},
Year = {2001},
Key = {fds136403}
}
@article{fds136404,
Title = {Levin ED. Nicotinic Systems: An Integrated Approach. In:
Nicotinic Receptors in the Nervous System. ED Levin (ed.),
CRC Press, New York, 281-282, 2001.},
Year = {2001},
Key = {fds136404}
}
@article{fds274340,
Author = {Arthur, D and Levin, ED},
Title = {Spatial and non-spatial discrimination learning in zebrafish
(Danio rerio)},
Journal = {Animal Cognition},
Volume = {4},
Number = {2},
Pages = {125-131},
Publisher = {Springer Nature},
Year = {2001},
url = {http://dx.doi.org/10.1007/s100710100111},
Abstract = {Zebrafish (Danio rerio) provide an excellent model for
assessment of molecular processes of neurodevelopment. To
determine the functional importance of molecular events
during neurodevelopment, we have developed methods for
assessing learning in zebrafish in a three-chambered fish
tank. In the first study, simple escape response was
assessed. Zebrafish tested with a moving net learned to
escape to another chamber more rapidly over the six sessions
of training than the fish with the still net which did not
learn. Upon reversal of the contingencies, the fish switched
to the inactive net rapidly learned to suppress the escape
response and fish formerly in the inactive net condition
learned to avoid the moving net. In the second study,
spatial discrimination learning was assessed. Zebrafish were
trained on a right-left position discrimination to avoid the
active net. Zebrafish showed significant improvement in
escape responses over six sessions of training with three
trials per session. In the third study, red-blue non-spatial
discrimination learning was assessed. There was a
significant improvement over the first six training
sessions. With the reversal of contingencies, there was a
significant decline of performance. With continued training,
the fish again significantly improved avoidance. These
studies found an effective motivational stimulus and
procedure for studying escape behavior in zebrafish; a
procedure whereby zebrafish would learn both spatial and
non-spatial discrimination. These methods are being
developed to help determine the functional importance of
molecular events during zebrafish neurodevelopment. ©
Springer-Verlag 2001.},
Doi = {10.1007/s100710100111},
Key = {fds274340}
}
@article{fds274433,
Author = {Rezvani, AH and Bushnell, PJ and Burkholder, JM and Glasgow, HB and Levin, ED},
Title = {Specificity of cognitive impairment from Pfiesteria
piscicida exposure in rats: attention and visual function
versus behavioral plasticity.},
Journal = {Neurotoxicol Teratol},
Volume = {23},
Number = {6},
Pages = {609-616},
Year = {2001},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11792529},
Keywords = {Animals • Attention • Discrimination Learning
• Female • Injections, Subcutaneous • Maze
Learning • Pfiesteria piscicida • Photic
Stimulation • Rats • Rats, Sprague-Dawley •
drug effects* • pathogenicity*},
Abstract = {Pfiesteria piscicida is a toxic dinoflagellate that has
caused massive fish kills in estuaries along the East Coast
of the United States, and exposure of humans to toxic
Pfiesteria has been associated with cognitive impairment. A
visual signal detection task was used to determine the
possible importance of attentional and visual processes in
Pfiesteria effects on cognitive function. Adult female rats
were trained to perform the signal detection task. After
training, the rats were injected subcutaneously with fish
culture water containing toxic Pfiesteria (35,600 or 106,800
cells of Pfiesteria/kg of rat body weight) or with (control)
fish culture water containing no Pfiesteria. Effects of
toxic Pfiesteria on maintenance of signal detection behavior
were assessed for 2 weeks after treatment. Then, the
signal-response contingencies were reversed. After the
discrimination was reestablished on the reversed levers, the
rats received a second dose of toxic Pfiesteria. The rats
were again tested for 2 weeks, after which a second reversal
was imposed. Pfiesteria did not affect behavior in the
signal detection task during 2 weeks of prereversal testing
after either exposure. However, a significant
Pfiesteria-induced deficit emerged when the signal-response
contingencies were reversed. These findings suggest that
Pfiesteria-induced deficits emerge during periods of
behavioral transition and not during performance of
previously learned tasks.},
Doi = {10.1016/s0892-0362(01)00169-6},
Key = {fds274433}
}
@article{fds274467,
Author = {Levin, ED and Mead, T and Rezvani, AH and Rose, JE and Gallivan, C and Gross, R},
Title = {The nicotinic antagonist mecamylamine preferentially
inhibits cocaine vs. food self-administration in
rats.},
Journal = {Physiol Behav},
Volume = {71},
Number = {5},
Pages = {565-570},
Year = {2000},
Month = {December},
ISSN = {0031-9384},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11239676},
Keywords = {Animals • Cocaine • Conditioning, Operant •
Dopamine Uptake Inhibitors • Eating • Female
• Food • Mecamylamine • Nicotinic Antagonists
• Rats • Rats, Sprague-Dawley • Reinforcement
(Psychology) • Self Administration •
administration & dosage • drug effects • drug
effects* • pharmacology*},
Abstract = {Nicotinic acetylcholine systems play important roles in
addiction, and nicotinic receptor stimulation stimulates
dopamine release while the nicotinic antagonist mecamylamine
reduces it. Reid et al. [Neuropsychopharmacology 20 (1999)
297.] recently found in human cocaine addicts that
mecamylamine reduced cue-elicited cocaine craving. The
current study assessed the impact of mecamylamine on cocaine
self-administration in rats. Female Sprague-Dawley rats
(N=7) were implanted with intravenous (iv) catheters and
trained to lever press for cocaine (0.32 mg/kg/infusion FR-1
with a 60-s timeout) in 45-min sessions. After 2 weeks of
training, the rats were injected with saline or mecamylamine
(1, 2, or 4 mg/kg sc) 10 min before the session. They
received the same dose for 1 week with 1 week of uninjected
testing between doses. Mecamylamine, compared to saline,
significantly (P<.05) reduced the number of cocaine
infusions per session with each of these doses. This effect
did not appear to be due to a generalized reduction in
behavioral activity. Another set of female Sprague-Dawley
rats (N=8) were trained to lever press for food
reinforcement. In these rats, the 1 and 2-mg/kg mecamylamine
doses had no effect on food self-administration. Significant
reductions in food self-administration were not seen unless
the high dose of 4-mg/kg mecamylamine was used. Nicotinic
antagonist treatment reduces cocaine self-administration in
rats at doses that do not cause generalized effects on
food-reinforced responding. Nicotinic antagonistic treatment
may be a useful new approach to treat cocaine
addiction.},
Doi = {10.1016/s0031-9384(00)00382-6},
Key = {fds274467}
}
@article{fds274414,
Author = {Bancroft, A and Levin, ED},
Title = {Ventral hippocampal alpha4beta2 nicotinic receptors and
chronic nicotine effects on memory.},
Journal = {Neuropharmacology},
Volume = {39},
Number = {13},
Pages = {2770-2778},
Year = {2000},
Month = {October},
ISSN = {0028-3908},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11044746},
Keywords = {Animals • Behavior, Animal • Dihydro-beta-Erythroidine
• Female • Hippocampus • Maze Learning •
Memory • Memory, Short-Term • Nicotine •
Nicotinic Agonists • Nicotinic Antagonists • Rats
• Rats, Sprague-Dawley • Receptors, Nicotinic
• drug effects • drug effects* • metabolism
• pharmacology • pharmacology*},
Abstract = {Chronic nicotine administration has been repeatedly shown to
facilitate working memory function in rats on the radial-arm
maze. The critical neural mechanisms for this effect are
still being discovered. The nicotinic nature of the chronic
nicotine induced memory improvement is supported by the
finding that it is blocked by chronic mecamylamine
co-infusion. The hippocampus also appears to be critically
important. Hippocampal ibotenic acid lesions block the
effect. Within the hippocampus, we have found that the
alpha4beta2 nicotinic receptor subtype is involved in memory
functioning. Acute ventral hippocampal infusions of the
alpha4beta2 nicotinic antagonist dihydro-beta-erythroidine
(DHbetaE) significantly decreased working memory performance
in the radial-arm maze. The aim of the current study was to
determine the importance of alpha4beta2 receptors within the
ventral hippocampus for the memory enhancing effects of
chronic nicotine treatment. Adult female Sprague-Dawley rats
were trained on the 8-arm radial maze and were cannulated
bilaterally in the ventral hippocampus. Osmotic minipumps
administering chronic nicotine at a rate of 5 mg per kg per
day were also implanted in the nicotine treatment rats.
Control rats received saline-only minipumps. For a period of
4 weeks after surgery, each rat received bilateral
hippocampal infusions of 0, 2, 6 and 18 microg per side of
DHbetaE and tested for memory performance on the radial-arm
maze. Radial-arm maze choice accuracy was impaired by acute
hippocampal DHbetaE infusion in a dose-related fashion. This
acute hippocampal DHbetaE-induced choice accuracy impairment
was eliminated by chronic systemic nicotine infusion.
Chronic nicotine in combination with acute vehicle
hippocampal infusion was not seen to alter choice accuracy.
Response latency was not found to be altered by acute
hippocampal DHbetaE in the absence of chronic nicotine
administration, but it did attenuate the response latency
reduction induced by chronic nicotine infusion. Wet dog
shakes were not found to be affected by hippocampal DHbetaE
when given without chronic nicotine. Wet dog shakes were
significantly increased by chronic nicotine infusion.
Intra-hippocampal DHbetaE significantly potentiated this
effect. The results from the current study reinforce the
hypothesis that ventral hippocampal alpha4beta2 nicotinic
receptors are important for memory function. These receptors
may also have a role to play in the development of other
aspects of behavior associated with chronic nicotine
treatment.},
Doi = {10.1016/s0028-3908(00)00099-x},
Key = {fds274414}
}
@article{fds274504,
Author = {Narahashi, T and Fenster, CP and Quick, MW and Lester, RA and Marszalec,
W and Aistrup, GL and Sattelle, DB and Martin, BR and Levin,
ED},
Title = {Symposium overview: mechanism of action of nicotine on
neuronal acetylcholine receptors, from molecule to
behavior.},
Journal = {Toxicol Sci},
Volume = {57},
Number = {2},
Pages = {193-202},
Year = {2000},
Month = {October},
ISSN = {1096-6080},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11006350},
Keywords = {Animals • Anthelmintics • Dose-Response
Relationship, Drug • Drug Interactions • Ethanol
• Hippocampus • Humans • Insecticides •
Memory • Neurons • Nicotine • Receptors,
Nicotinic • Up-Regulation • drug effects •
drug effects* • genetics • metabolism •
metabolism* • pharmacology • pharmacology*},
Abstract = {Nicotine has long been known to interact with nicotinic
acetylcholine (ACh) receptors since Langley used it
extensively to chart sympathetic ganglia a century ago. It
has also been used as an effective insecticide. However, it
was not until the 1990s that the significance of nicotine
was increasingly recognized from the toxicological,
pharmacological, and environmental points of view. This is
partly because studies of neuronal nicotinic ACh receptors
are rapidly emerging from orphan status, fueled by several
lines of research. Since Alzheimer's disease is known to be
associated with down-regulation of cholinergic activity in
the brain, a variety of nicotine derivatives are being
tested and developed for treatment of the disease. Public
awareness of the adverse effects of nicotine has reached the
highest level recently. Since insect resistance to
insecticides is one of the most serious issues in the
pest-control arena, it is an urgent requirement to develop
new insecticides that act on target sites not shared by the
existing insecticides. The neuronal nicotinic ACh receptor
is one of them, and new nicotinoids are being developed.
Thus, the time is ripe to discuss the mechanism of action of
nicotine from a variety of angles, including the molecular,
physiological, and behavioral points of view. This Symposium
covered a wide area of nicotine studies: genetic, genomic,
and functional aspects of nicotinic ACh receptors were
studied, as related to anthelmintics and insecticides;
interactions between ethanol and nicotine out the ACh
receptor were analyzed, in an attempt to explain the
well-known heavy drinker-heavy smoker correlation; the
mechanisms that underlie the desensitization of ACh
receptors were studied as related to nicotine action;
selective pharmacological profiles of nicotine, and
descriptions of some derivatives were described; and chronic
nicotine infusion effects on memory were examined using
animal models.},
Doi = {10.1093/toxsci/57.2.193},
Key = {fds274504}
}
@article{fds274360,
Author = {Rusted, JM and Newhouse, PA and Levin, ED},
Title = {Nicotinic treatment for degenerative neuropsychiatric
disorders such as Alzheimer's disease and Parkinson's
disease.},
Journal = {Behav Brain Res},
Volume = {113},
Number = {1-2},
Pages = {121-129},
Year = {2000},
Month = {August},
ISSN = {0166-4328},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10942039},
Keywords = {Alzheimer Disease • Animals • Brain • Humans
• Nicotinic Agonists • Parkinson Disease •
Receptors, Nicotinic • Treatment Outcome • adverse
effects • drug effects • drug therapy* •
therapeutic use*},
Abstract = {Nicotinic systems play an important role in the neural basis
of working memory and attention. Recent progress in
understanding of the structure, function, and distribution
of central nervous system (CNS) nicotinic receptors and
their pharmacology has opened up new possibilities for novel
CNS therapeutics with nicotinic agents. In this paper, we
review the theoretical justification and the experimental
evidence supporting these developments. We focus on the
applications of nicotinic agonists in CNS disorders that are
degenerative in nature, namely Parkinson's disease and
Alzheimer's disease. We suggest that there is considerable
potential for therapeutic applications in the near future.
Clinically, two major issues remain: (a) the selectivity of
effects, that is, developing compounds which are selective
in producing improvement in cognition, motor function,
attention, or pain without significant side-effects; and (b)
the realistic likelihood of long-term improvements in
everyday functioning in people who have degenerative
diseases.},
Doi = {10.1016/s0166-4328(00)00207-2},
Key = {fds274360}
}
@article{fds274509,
Author = {White, AM and Ghia, AJ and Levin, ED and Swartzwelder,
HS},
Title = {Binge pattern ethanol exposure in adolescent and adult rats:
differential impact on subsequent responsiveness to
ethanol.},
Journal = {Alcohol Clin Exp Res},
Volume = {24},
Number = {8},
Pages = {1251-1256},
Year = {2000},
Month = {August},
ISSN = {0145-6008},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10968665},
Keywords = {Aging* • Animals • Behavior, Animal • Body
Weight • Ethanol • Male • Memory • Rats
• Rats, Sprague-Dawley • administration & dosage*
• drug effects • pharmacology},
Abstract = {BACKGROUND: Recent evidence indicates that adolescent
animals are more sensitive than adults to the disruptive
effects of acute ethanol exposure on spatial learning. It is
not yet known whether adolescent animals are also more
sensitive than adults to the enduring neurobehavioral
effects of repeated ethanol exposure. In this study, animals
were exposed to ethanol in a binge-pattern during either
adolescence or adulthood. At a time when all subjects were
adults, spatial working memory was examined in the absence
and presence of an acute ethanol challenge. METHODS: Rats
were exposed to ethanol (5.0 g/kg intraperitoneally) or
isovolumetric saline at 48 hr intervals over 20 days.
Exposure began on either postnatal day 30 (adolescent group)
or 70 (adult group). Twenty days after the final injection,
a time at which all animals were adults, the subjects were
tested on an elevated plus maze and then were trained to
perform a spatial working memory task on an eight-arm radial
maze. At the beginning of each session of training on the
working memory task, subjects retrieved food rewards on four
of the eight arms. After a delay, subjects were placed on
the maze and allowed to retrieve food from the remaining
four arms. RESULTS: Prior exposure to ethanol did not
influence behavior on the plus maze. Performance of the
groups did not differ during acquisition of the spatial
working memory task with a 5 min delay or during subsequent
testing with a 1 hr delay. However, animals treated with
ethanol during adolescence exhibited larger working memory
impairments during an ethanol challenge (1.5 g/kg
intraperitoneally) than subjects in the other three groups.
CONCLUSIONS: The findings indicate that binge pattern
exposure to ethanol during adolescence enhances
responsiveness to the memory-impairing effects of ethanol in
adulthood.},
Doi = {10.1097/00000374-200008000-00017},
Key = {fds274509}
}
@article{fds274436,
Author = {Grilly, DM and Simon, BB and Levin, ED},
Title = {Nicotine enhances stimulus detection performance of middle-
and old-aged rats: a longitudinal study.},
Journal = {Pharmacol Biochem Behav},
Volume = {65},
Number = {4},
Pages = {665-670},
Year = {2000},
Month = {April},
ISSN = {0091-3057},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10764920},
Keywords = {Aging • Animals • Cognition • Conditioning,
Operant • Cues • Dose-Response Relationship, Drug
• Longitudinal Studies • Male • Nicotine
• Nicotinic Agonists • Photic Stimulation •
Psychomotor Performance • Rats • Rats, Inbred F344
• drug effects • drug effects* •
pharmacology* • psychology*},
Abstract = {The effects of nicotine on sustained attention were tested
in F344xBN male rats when they were chronologically middle
and old aged. The rats (n = 11) were trained in a
two-choice, stimulus detection task in which a press of one
of two levers was reinforced with food, with the correct
lever indicated by the position of a briefly illuminated
light. They were tested when they were 24-25 and 34-35
months of age (i.e., at 60-68% and 85-95%, respectively of
their expected median life span) after saline or 0.1-0.5
mg/kg doses of nicotine (SC). A significant dose-related
improvement in percent correct choices and decrease in
choice response times was found at both ages, and there was
no significant main effect of age or an age by dose
interaction. These results support the position that
nicotine can enhance attentional processes in rats
throughout their life span. Nicotine and other nicotinic
agonists may have efficacy in the treatment of disorders
such as Alzheimer's disease.},
Doi = {10.1016/s0091-3057(99)00259-2},
Key = {fds274436}
}
@article{fds274457,
Author = {Levin, ED and Rezvani, AH},
Title = {Development of nicotinic drug therapy for cognitive
disorders.},
Journal = {Eur J Pharmacol},
Volume = {393},
Number = {1-3},
Pages = {141-146},
Year = {2000},
Month = {March},
ISSN = {0014-2999},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10771007},
Keywords = {Adult • Alzheimer Disease • Animals •
Attention • Attention Deficit Disorder with
Hyperactivity • Cognition Disorders • Disease
Models, Animal • Drug Design • Humans •
Learning • Memory • Nicotine • Nicotinic
Agonists • Rats • Schizophrenia • Smoking
• drug effects • drug therapy • drug therapy*
• pharmacology • therapeutic use*},
Abstract = {Nicotine, as well as other nicotinic drugs, may provide
useful therapeutic treatment for a variety of cognitive
impairments including those found in Alzheimer's disease,
schizophrenia and attention deficit hyperactivity disorder
(ADHD). We have found that nicotine skin patches
significantly improve attentional performance in people with
these disease states as well as normal nonsmoking adults.
Animal models are critical for determining the
neurobehavioral bases for nicotinic effects on cognitive
function. We have found in lesion and local infusion studies
with rats that the hippocampus is an important substrate for
nicotinic effects on working memory function. Both alpha7
and alpha4beta2 nicotinic receptors in the hippocampus are
involved. Further work has investigated the relationship of
nicotinic systems with dopaminergic and glutaminergic
systems in the basis of cognitive function. Nicotine has
proven to be a useful prototypic compound for the family of
nicotinic compounds. It produces cognitive improvements in
both animal models and clinical populations. Recent work
with more selective nicotinic receptor agonists and
antagonists in animal models is providing important
information concerning the neural mechanisms for nicotinic
involvement in cognitive function and opening avenues for
development of safe and effective nicotinic treatments for
clinical use.},
Doi = {10.1016/s0014-2999(99)00885-7},
Key = {fds274457}
}
@article{fds274447,
Author = {Levin, ED and Brucato, FH and Crapo, JD},
Title = {Molecular overexpression of extracellular superoxide
dismutase increases the dependency of learning and memory
performance on motivational state.},
Journal = {Behav Genet},
Volume = {30},
Number = {2},
Pages = {95-100},
Year = {2000},
Month = {March},
ISSN = {0001-8244},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10979599},
Keywords = {Animals • Appetitive Behavior • Extracellular
Space • Female • Food Deprivation • Gene
Expression Regulation, Enzymologic • Maze Learning
• Mental Recall • Mice • Motivation* •
Superoxide Dismutase • enzymology • genetics*
• physiology • physiology*},
Abstract = {Extracellular superoxide dismutase (EC-SOD) controls the
availability of extracellular superoxide and appears to play
a role in controlling intercellular signaling. In this role
EC-SOD can have potent effects on neurobehavioral function.
In previous studies, we have found that either over- or
under-expression of EC-SOD in mice significantly impairs
spatial learning on the radial-arm maze. In the current
study, the neurobehavioral nature of the EC-SOD role in
cognitive function was determined. EC-SOD overexpression
altered the relationship between both learning and memory
with motivational state. Mice were tested in the radial-arm
maze under a high motivational state (22-24 hours of food
restriction) or a low motivational state (4-6 hours of food
restriction). Under a high motivational state, the EC-SOD
overexpressing mice were able to learn in the radial-arm
maze, albeit at a slightly lower rate than wild-type
controls. This contrasts with the failure to learn by EC-SOD
overexpressing mice in our previous study conducted with the
low motivational state. The change in motivational state did
not significantly alter the learning rate of controls.
Similarly, during postacquisition memory phase of testing,
the EC-SOD overexpressing mice were significantly worse than
controls when tested in a low motivational state but not
under a high motivation state. As with learning,
motivational state did not significantly affect memory
performance in controls. This study shows that mice with
EC-SOD overexpression are not incapable of learning and
memory in the radial-arm maze, but that the mechanisms which
allow control animals to perform this task well under low
motivational states are deficient in the mice with EC-SOD
overexpression.},
Doi = {10.1023/a:1001947003299},
Key = {fds274447}
}
@article{fds274361,
Author = {Bushnell, PJ and Levin, ED and Marrocco, RT and Sarter, MF and Strupp,
BJ and Warburton, DM},
Title = {Attention as a target of intoxication: insights and methods
from studies of drug abuse.},
Journal = {Neurotoxicol Teratol},
Volume = {22},
Number = {4},
Pages = {487-502},
Year = {2000},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10974587},
Keywords = {Animals • Attention • Cocaine • Humans •
Mental Disorders • Nicotine • Pharmaceutical
Preparations • Substance-Related Disorders •
adverse effects • adverse effects* • drug effects*
• physiology • physiopathology},
Abstract = {A symposium was convened to discuss recent developments in
the assessment of attention and the effects of drugs and
toxic chemicals on attention at the 17th annual meeting of
the Behavioral Toxicology Society on May 1, 1999, in
Research Triangle Park, NC. Speakers addressed issues
including the methodology of assessing cognitive function,
the neurobiology of specific aspects of attention, the dual
roles of attention as a target of intoxication and as a
mediating variable in the development of addiction to
psychoactive drugs, the changes in attention that accompany
neuropsychological disorders of schizophrenia, senile
dementia of the Alzheimer type and attention deficit
hyperactivity disorder, and potential therapies for these
disorders. This article provides an overview of the
objectives of the symposium, followed by summaries of each
of the talks given.},
Doi = {10.1016/s0892-0362(00)00077-5},
Key = {fds274361}
}
@article{fds274474,
Author = {Levin, ED and Rezvani, AH and Christopher, NC and Glasgow, HB and Deamer-Melia, NJ and Burkholder, JM and Moser, VC and Jensen,
K},
Title = {Rapid neurobehavioral analysis of Pfiesteria piscicida
effects in juvenile and adult rats.},
Journal = {Neurotoxicol Teratol},
Volume = {22},
Number = {4},
Pages = {533-540},
Year = {2000},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10974591},
Keywords = {Aging • Animals • Behavior, Animal • Female
• Male • Maze Learning • Motor Activity
• Pfiesteria piscicida* • Protozoan Infections,
Animal • Rats • Rats, Sprague-Dawley •
physiology • physiology* • physiopathology*},
Abstract = {The estuarine dinoflagellate Pfiesteria piscicida is known
to kill fish and has been associated with neurocognitive
deficits in humans. We have developed a rat model to
demonstrate that exposure to Pfiesteria causes significant
learning impairments. This has been repeatedly seen as a
choice accuracy impairment during radial-arm maze learning.
Pfiesteria-induced effects were also seen in a locomotor
activity test in the figure-8 apparatus. The current studies
used the short-term radial-arm maze acquisition, the
figure-8 activity test, and the functional observational
battery (FOB) to assess Pfiesteria-induced neurobehavioral
effects in adult and juvenile rats. In study 1, the
neurobehavioral potency of three different Pfiesteria
cultures (Pf 113, Pf 728, and Pf Vandermere) was assessed.
Ninety-six (12 per group) adult female Sprague-Dawley rats
were injected subcutaneously with a single dose of
Pfiesteria taken from aquarium-cultured Pfiesteria (35,600
or 106,800 Pfiesteria cells per kilogram of rat body
weight). One control group (N = 12) was injected with saline
and one (N = 12) with aquarium water not containing
Pfiesteria. All three of the Pfiesteria samples (p < 0.05)
impaired choice accuracy over the first six sessions of
training. At the time of the radial-arm maze choice accuracy
impairment, no overt Pfiesteria-related effects were seen
using an FOB, indicating that the Pfiesteria-induced choice
accuracy deficit was not due to generalized debilitation. In
the figure-8 apparatus, Pfiesteria treatment caused a
significant decrease in mean locomotor activity. In study 2,
the neurobehavioral effects of the Pf 728 sample type were
assessed in juvenile rats. Twenty-four day-old male and
female rats were injected with 35,600 or 106,800 Pf-728
Pfiesteria cells per kilogram of rat body weight. As with
adult females, the juvenile rats showed a significant
impairment in radial-arm maze choice accuracy. No changes in
locomotor activity or the FOB were detected in the juvenile
rats. Furthermore, there were no differences between male
and female rats in the Pfiesteria-induced choice accuracy
impairment. Pfiesteria effects on choice accuracy in the
radial-arm maze in rats constitute a critical component of
the model of Pfiesteria toxicity, because the hallmark of
Pfiesteria toxicity in humans is cognitive dysfunction. Our
finding that analysis of the first six sessions of
radial-arm maze testing is sufficient for determining the
effect means that this test will be useful as a rapid screen
for identifying the critical neurotoxin(s) of Pfiesteria in
future studies.},
Doi = {10.1016/s0892-0362(00)00080-5},
Key = {fds274474}
}
@article{fds274214,
Author = {Keller, JM and Meyer, JN and Mattie, M and Augspurger, T and Rau, M and Dong, J and Levin, ED},
Title = {Assessment of immunotoxicology in wild populations: Review
and recommendations},
Journal = {Reviews in Toxicology},
Volume = {3},
Number = {1-4},
Pages = {167-212},
Year = {1999},
Month = {December},
Abstract = {A heightened recognition of the immunotoxicity of many
xenobiotics has sparked increased interest in studying
immune system effects in wildlife. Immunotoxicological
endpoints have been directly informative in assessing the
health of wildlife populations themselves, and wildlife
could also potentially be used as indicators of human and
ecosystem health. However, the lack of standard methods and
information regarding normal ranges of immune system
parameters makes field assessments of wildlife immunological
status difficult. Compounding this difficulty is the
unfamiliarity of most wildlife toxicologists with the
complex immune system and the wide array of methods
available to study immunotoxicity. This restricts the number
of studies carried out and further limits the growth of a
wildlife immunological database. The purpose of this review
is to facilitate the study of immunological endpoints by
wildlife toxicologists by presenting 1) an overview of
immunotoxicology from a biomedical perspective with an
emphasis on the fundamentals of the immune system and the
tools/assays available for measuring its function; 2) a
limited review of applied immunotoxicity studies in wild
fish, birds, and mammals; and 3) recommendations for
expanding immunological assessments in wildlife.},
Key = {fds274214}
}
@article{fds274507,
Author = {Levin, ED and Bettegowda, C and Blosser, J and Gordon,
J},
Title = {AR-R17779, and alpha7 nicotinic agonist, improves learning
and memory in rats.},
Journal = {Behav Pharmacol},
Volume = {10},
Number = {6-7},
Pages = {675-680},
Year = {1999},
Month = {November},
ISSN = {0955-8810},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10780509},
Keywords = {Animals • Bridged Compounds • Female •
Learning • Maze Learning • Memory • Memory,
Short-Term • Nicotinic Agonists • Rats •
Rats, Sprague-Dawley • Receptors, Nicotinic •
Spiro Compounds • drug effects • drug effects*
• pharmacology*},
Abstract = {Nicotinic acetylcholine systems have been found to be
important for learning and memory function. The prototypic
nicotinic agonist nicotine has been shown in a variety of
studies to improve aspects of cognitive function. The
specific involvement of nicotinic receptor subtypes is now
being investigated. The involvement of alpha7 nicotinic
receptors was assessed in this project using a novel alpha7
nicotinic agonist, AR-R 17779. Repeated doses (subcutaneous
injection 20 min before testing) of the racemic mixture AR-R
13489 and its active isomer AR-R 17779 were assessed in
adult female Sprague-Dawley rats using the eight-arm radial
maze. AR-R 13489 (2 mg/kg) caused a significant improvement
of long-term win-shift acquisition after 3 weeks of training
(n = 10 per group). The same dose of AR-R 17779 also caused
a significant improvement in repeated acquisition within
each daily session in the radial-arm maze. In another study,
the active isomer AR-R 17779 significantly improved
radial-arm maze working memory function in rats with lesions
to the septohippocampal projection. Fimbria-fornix lesions
significantly impaired working memory performance and AR-R
17779 significantly reversed that impairment. These studies
showed that alpha7 nicotinic agonist treatment improved
learning in two radial-arm maze tasks and reversed working
memory impairment caused by fimbria-fornix sections,
providing evidence for alpha7 involvement in learning and
memory, and the potential therapeutic use of AR-R
17779.},
Doi = {10.1097/00008877-199911000-00014},
Key = {fds274507}
}
@article{fds274212,
Author = {Levin, ED and Lippiello, P},
Title = {Mutually potentiating effects of mecamylamine and
haloperidol in producing catalepsy in rats},
Journal = {Drug Development Research},
Volume = {47},
Number = {2},
Pages = {90-96},
Publisher = {WILEY},
Year = {1999},
Month = {August},
ISSN = {0272-4391},
url = {http://dx.doi.org/10.1002/(SICI)1098-2299(199906)47:2<90::AID-DDR4>3.0.CO;2-5},
Abstract = {Haloperidol and other dopaminergic (DA) blockers have long
been known to induce catalepsy. Recently, it has been
reported that nicotine potentiates the cataleptic effect of
haloperidol. However, this presents a quandary in terms of
neural interactions between nicotinic and DA systems.
Nicotine promotes the release of DA in the striatum, which
should attenuate haloperidol-induced catalepsy. To resolve
this quandary, we assessed haloperidol interactions with
nicotine and its antagonist mecamylamine in five studies.
With low to moderate doses, we did not find that nicotine
potentiated haloperidol-induced catalepsy. However, in two
different studies we found that mecamylamine, a nicotinic
antagonist, significantly potentiated the
haloperidol-induced catalepsy. This effect was seen with a
dose of mecamylamine which, by itself, did not have any
cataleptic effect. These results demonstrate that nicotinic
receptor blockade effectively potentiates catalepsy caused
by DA blockade. This suggests that previously seen nicotine-
induced potentiation of catalepsy may have been due to its
desensitizing effect. Perhaps the use of nicotinic
antagonists such as mecamylamine or nicotine + mecamylamine
combinations would provide a useful adjunct to DA antagonist
therapy in motor disorders such as Tourette's
syndrome.},
Doi = {10.1002/(SICI)1098-2299(199906)47:2<90::AID-DDR4>3.0.CO;2-5},
Key = {fds274212}
}
@article{fds274213,
Author = {Levin, ED and Imad Damaj and M and Glassco, W and May, EL and Martin,
BR},
Title = {Bridged nicotine, isonicotine, and norisonicotine effects on
working memory performance of rats in the radial-arm
maze},
Journal = {Drug Development Research},
Volume = {46},
Number = {2},
Pages = {107-111},
Publisher = {WILEY},
Year = {1999},
Month = {May},
ISSN = {0272-4391},
url = {http://dx.doi.org/10.1002/(SICI)1098-2299(199902)46:2<107::AID-DDR3>3.0.CO;2-C},
Abstract = {Nicotine and other nicotinic agonists have been found tO
improve performance in a variety of tasks, including the
radial-arm maze to improve memory. There has been an active
effort to develop novel nicotinic agonists for the treatment
of cognitive dysfunction such as is seen in Alzheimer's
disease. These novel ligands can also serve as tools with
which to increase our knowledge concerning the involvement
of nicotinic systems with cognitive function. The current
studies were conducted to assess the actions of three new
nicotinic agonists, i.e., bridged nicotine, isonicotine, and
norisonicotine, on choice accuracy in the radial-arm maze.
Rats were trained on a win-shift working memory task in the
eight-arm radial maze. In Experiment 1, the rats were
administered (subcutaneously) saline and three doses of
bridged nicotine, isonicotine, and norisonicotine (0.5, 1.5,
and 4.5 mg/kg). Bridged nicotine did not cause any
significant effects on memory performance, although it did
significantly increase latency and at the high dose caused
severe slowing and nonperformance. Both isonicotine and
norisonicotine caused a significant linear dose-related
improvement in choice accuracy, indicative of improved
working memory function. In Experiment 2, another set of
rats received the effective doses of 4.5 mg/kg of
isonicotine and norisonicotine as well as higher doses of
13.5 mg/kg of each compound. These doses were administered
alone or in combination with 5 mg/kg of the nicotinic
antagonist mecamylamine to determine the nicotinic nature of
the effects. As in Experiment 1 the 4.5 mg/kg of isonicotine
caused a significant memory improvement. The 4.5 mg/kg dose
of norisonicotine caused a more modest rise in performance,
which was not significantly different from control in this
experiment. When both experiments were considered together,
the 4.5 mg/kg doses of both isonicotine and norisonicotine
were the most effective in improving working memory
performance. Significant improvements in working memory were
seen with both drugs (P < 0.025). The higher doses of 13.5
mg/kg of both isonicotine and norisonicotine resulted in
nearly control-level performance. Thus, the typical inverted
U-shaped dose-effect function was evident for both
isonicotine and norisonicotine. Mecamylamine brought
performance improved by the 4.5 mg/kg dose back to control
levels, providing evidence for the nicotinic nature of the
effect. Both isonicotine and norisonicotine show promise for
development as memory-improving nicotinic agonist
drugs.},
Doi = {10.1002/(SICI)1098-2299(199902)46:2<107::AID-DDR3>3.0.CO;2-C},
Key = {fds274213}
}
@article{fds274343,
Author = {White, HK and Levin, ED},
Title = {Four-week nicotine skin patch treatment effects on cognitive
performance in Alzheimer's disease.},
Journal = {Psychopharmacology (Berl)},
Volume = {143},
Number = {2},
Pages = {158-165},
Year = {1999},
Month = {April},
ISSN = {0033-3158},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10326778},
Keywords = {Administration, Cutaneous • Aged • Aged, 80 and
over • Alzheimer Disease • Attention •
Cognition • Female • Humans • Male •
Memory • Middle Aged • Nicotine • Nicotinic
Agonists • Psychomotor Performance • Treatment
Outcome • administration & dosage • drug effects
• drug effects* • drug therapy* • psychology*
• therapeutic use*},
Abstract = {RATIONALE: Acute nicotine injections have been found to
improve attentional performance in patients with Alzheimer's
disease (AD), but little is known about chronic nicotine
effects. OBJECTIVE: The present study was undertaken to
evaluate the clinical and neuropsychological effects of
chronic transdermal nicotine in Alzheimer's disease subjects
over a 4-week period. METHODS: The double-blind, placebo
controlled, cross-over study consisted of two 4-week periods
separated by a 2-week washout period. Patients wore the
nicotine patch (Nicotrol) for 16 h a day at the following
doses: 5 mg/day during week 1, 10 mg/day during weeks 2 and
3 and 5 mg/day during week 4. The eight subjects had mild to
moderate AD and were otherwise healthy. RESULTS: Nicotine
significantly improved attentional performance as measured
by the Conners' continuous performance test (CPT). There was
a significant reduction in errors of omission on the CPT
which continued throughout the period of chronic nicotine
administration. The variability of hit reaction time
(reaction time for correct responses) on the CPT was also
significantly reduced by chronic nicotine. Nicotine did not
improve performance on other tests measuring motor and
memory function. CONCLUSIONS: The sustained improvement in
attention found in this study with nicotine dermal patches
is encouraging. However, the lack of detected effects of
nicotine treatment on other cognitive and behavioral domains
in this study leaves questions concerning the clinical
impact of nicotinic treatment in Alzheimer's disease. The
modest size of this study limited statistical power which
may have been needed to detect more subtle but clinically
significant cognitive effects. Higher doses of nicotine,
other nicotinic ligands or combination treatment of nicotine
with other therapies may be efficacious for producing
broader therapeutic effects.},
Doi = {10.1007/s002130050931},
Key = {fds274343}
}
@article{fds316084,
Author = {Gingras, JL and Leatherman, NE and Cutler, AR and Levin,
ED},
Title = {Nicotine and/or cocaine alters postnatal ventilatory control
in the rat pup gestationally exposed},
Journal = {PEDIATRIC RESEARCH},
Volume = {45},
Number = {4},
Pages = {51A-51A},
Publisher = {INT PEDIATRIC RESEARCH FOUNDATION, INC},
Year = {1999},
Month = {April},
ISSN = {0031-3998},
url = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000079476700294&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=47d3190e77e5a3a53558812f597b0b92},
Key = {fds316084}
}
@article{fds274443,
Author = {Wilkerson, A and Levin, ED},
Title = {Ventral hippocampal dopamine D1 and D2 systems and spatial
working memory in rats.},
Journal = {Neuroscience},
Volume = {89},
Number = {3},
Pages = {743-749},
Year = {1999},
Month = {March},
ISSN = {0306-4522},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10199609},
Keywords = {(R)-2,3,4,5-Tetrahydro-8-chloro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol
• Animals • Dopamine • Dopamine Agonists
• Dopamine Antagonists • Dose-Response
Relationship, Drug • Female • Hippocampus •
Maze Learning • Memory • Phenanthridines •
Quinpirole • Raclopride • Rats • Rats,
Sprague-Dawley • Receptors, Dopamine D1 •
Receptors, Dopamine D2 • Salicylamides • Spatial
Behavior • agonists • antagonists & inhibitors
• drug effects • drug effects* • pharmacology
• physiology*},
Abstract = {The hippocampus has long been known to be important for
memory function. However, the involvement of hippocampal
dopamine systems with memory has received little attention.
In the current study, dopamine D1 and D2 hippocampal
receptor system involvement with memory was assessed in
female Sprague-Dawley rats by local infusion of D1 and D2
agonists and antagonists into the ventral hippocampus.
Working memory performance was assessed on the radial-arm
maze. Neither the D1 agonist dihydrexidine (1.1-10
microg/side) nor the D1 antagonist SCH 23390 (0.19-1.67
microg/side) was effective in significantly altering
radial-arm maze choice accuracy. In contrast, there were
significant and opposite effects of D2 agonist and
antagonist treatments. The D2 agonist quinpirole caused a
significant (P<0.05) dose-related improvement in choice
accuracy over a dose range of 1.1-10 microg/side. In a
complementary fashion, the D2 antagonist raclopride caused a
significant (P<0.05) dose-related choice accuracy deficit
over a range of 0.19-1.67 microg/side. This study provides
clear evidence that hippocampal D2 activity is positively
related to working memory performance, while evidence for D1
systems is less compelling. Dopamine D2 receptors in the
ventral hippocampus were shown to have important influences
on spatial working memory. In a consistent pattern of
effects ventral hippocampal infusion of the D2 agonist
quinpirole improved working memory performance in the
radial-arm maze, while ventral hippocampal infusion of the
D2 antagonist raclopride impaired performance.},
Doi = {10.1016/s0306-4522(98)00346-7},
Key = {fds274443}
}
@article{fds274480,
Author = {Gainetdinov, RR and Wetsel, WC and Jones, SR and Levin, ED and Jaber, M and Caron, MG},
Title = {Role of serotonin in the paradoxical calming effect of
psychostimulants on hyperactivity.},
Journal = {Science},
Volume = {283},
Number = {5400},
Pages = {397-401},
Year = {1999},
Month = {January},
ISSN = {0036-8075},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9888856},
Keywords = {Animals • Attention Deficit Disorder with Hyperactivity
• Behavior, Animal • Carrier Proteins •
Central Nervous System Stimulants • Corpus Striatum
• Dopamine • Dopamine Plasma Membrane Transport
Proteins • Fluoxetine • Humans • Hyperkinesis
• Maze Learning • Membrane Glycoproteins •
Membrane Transport Proteins* • Mice • Mice, Inbred
C57BL • Mice, Knockout • Motor Activity •
Nerve Tissue Proteins* • Norepinephrine Plasma Membrane
Transport Proteins • Serotonin • Serotonin Plasma
Membrane Transport Proteins • Serotonin Uptake
Inhibitors • Symporters* • Synaptic Transmission*
• antagonists & inhibitors • drug effects •
drug therapy • drug therapy* • genetics •
metabolism • metabolism* • pharmacology •
pharmacology* • physiology • physiology* •
physiopathology • psychology},
Abstract = {The mechanism by which psychostimulants act as calming
agents in humans with attention-deficit hyperactivity
disorder (ADHD) or hyperkinetic disorder is currently
unknown. Mice lacking the gene encoding the plasma membrane
dopamine transporter (DAT) have elevated dopaminergic tone
and are hyperactive. This activity was exacerbated by
exposure to a novel environment. Additionally, these mice
were impaired in spatial cognitive function, and they showed
a decrease in locomotion in response to psychostimulants.
This paradoxical calming effect of psychostimulants depended
on serotonergic neurotransmission. The parallels between the
DAT knockout mice and individuals with ADHD suggest that
common mechanisms may underlie some of their behaviors and
responses to psychostimulants.},
Doi = {10.1126/science.283.5400.397},
Key = {fds274480}
}
@article{fds274501,
Author = {Levin, ED and Christopher, NC and Weaver, T and Moore, J and Brucato,
F},
Title = {Ventral hippocampal ibotenic acid lesions block chronic
nicotine-induced spatial working memory improvement in
rats.},
Journal = {Brain Res Cogn Brain Res},
Volume = {7},
Number = {3},
Pages = {405-410},
Year = {1999},
Month = {January},
ISSN = {0926-6410},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9838204},
Keywords = {Animals • Conditioning (Psychology) • Drug
Interactions • Excitatory Amino Acid Agonists •
Female • Hippocampus • Ibotenic Acid • Maze
Learning • Memory, Short-Term • Nicotine •
Nicotinic Agonists • Rats • Rats, Sprague-Dawley
• Reaction Time • drug effects • drug
effects* • pharmacology* • physiology},
Abstract = {Chronic nicotine infusions have been found to significantly
improve working memory performance in the radial-arm maze.
This effect is blocked by co-infusions of the nicotinic
antagonist mecamylamine. Acute nicotine injections also
improve working memory performance in the radial-arm maze.
This effect is also blocked by mecamylamine
co-administration. Recent local infusions studies have
demonstrated the importance of the ventral hippocampus for
nicotinic involvement in memory. Local infusions of
mecamylamine, DHbetaE or MLA impair working memory
performance on the radial-arm maze. The current study was
conducted to determine the importance of the ventral
hippocampus for the chronic effects of nicotine. Rats were
trained on the working memory task in an eight-arm radial
maze. After acquisition they underwent either infusions of
ibotenic acid lesions or vehicle infusions and received
subcutaneous implants of osmotic minipumps that delivered
either nicotine at a dose of 5 mg kg-1 day-1 or vehicle in a
2x2 design. The rats then were given 2 days of recovery and
were tested on the radial-arm maze three times per week for
the next 4 weeks. As seen in previous studies, in the sham
lesioned group nicotine infusions caused a significant
improvement in choice accuracy. In contrast no
nicotine-induced improvement was seen in the rats after
ibotenic acid lesions of the ventral hippocampus. The effect
of nicotine was blocked even though this lesion did not
cause a deficit in performance. Previous work showed that
chronic nicotine infusion still caused a significant
improvement in working memory performance in the radial-arm
maze after knife-cut lesions of the fimbria-fornix carrying
the septo-hippocampal cholinergic innervation. Thus it
appears that it is the postsynaptic nicotinic receptors in
the ventral hippocampus which are critically important for
the expression of the chronic nicotine induced working
memory improvement.},
Doi = {10.1016/s0926-6410(98)00044-5},
Key = {fds274501}
}
@article{fds136400,
Title = {Gainetinov RR, WW Wetsel, SR Jones, ED Levin, M Jaber and MG
Caron. Role of serotonin in the paradoxical calming effect
of psychostimulants on hyperactivity. Science, 283:397-401,
1999.},
Year = {1999},
Key = {fds136400}
}
@article{fds274496,
Author = {Levin, ED and Simon, BB and Schmechel, DE and Glasgow, HB and Deamer-Melia, NJ and Burkholder, JM and Moser, VC and Jensen, K and Harry, GJ},
Title = {Pfiesteria toxin and learning performance.},
Journal = {Neurotoxicol Teratol},
Volume = {21},
Number = {3},
Pages = {215-221},
Year = {1999},
ISSN = {0892-0362},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10386824},
Keywords = {Animals • Female • Humans • Maze Learning
• Motor Activity • Pfiesteria piscicida •
Protozoan Infections • Rats • Rats, Sprague-Dawley
• Time Factors • pathogenicity* • physiology*
• physiopathology • psychology},
Abstract = {Pfiesteria piscicida is an estuarine dinoflagellate involved
with fish kills along the east coast of the United States.
We previously documented a radial-arm maze learning deficit
in rats exposed to Pfiesteria that may be related to
cognitive deficits seen in humans after accidental
Pfiesteria exposure. The current study elucidated important
behavioral parameters of this deficit. There were six dose
groups. Forty (10/group) adult female Sprague-Dawley rats
were injected (s.c.) with a single dose of Pfiesteria taken
from aquarium-cultured Pfiesteria (35,600, 106,800, or
320,400 Pfiesteria cells/kg of rat body weight or a
cell-free filtrate of the 106,800 cells/kg dose). One
control group (N = 10) was injected with saline and one (N =
10) with aquarium water not containing Pfiesteria. Half of
the rats in each group were tested on an 8-arm radial maze
in a standard test room, and the other half were tested on
the radial maze in a sound-attenuating chamber. In the
standard maze room, there was a significant effect of
Pfiesteria (p < 0.05) impairing choice accuracy improvement
over the first six sessions of training among rats
administered 106,800, 320,400, and the 106,800 cells/kg
filtered sample. In contrast, there was no indication of an
effect of Pfiesteria when the rats were tested on the same
configuration radial maze in the sound-attenuating chamber.
After 18 sessions of training in one room, the rats were
switched for six sessions of testing in the other room and
finally were switched back to their original room for three
sessions. There was a significant Pfiesteria-induced deficit
when the rats were tested in the standard test room but not
when they were tested in the sound-attenuating chamber. When
the Pfiesteria-exposed rats were initially switched from the
sound-attenuating chamber to the standard test room they
performed significantly worse than controls, whereas
Pfiesteria-treated rats switched from the standard test room
to the sound-attenuating chamber did not perform differently
from controls. These results suggest that the
Pfiesteria-induced learning impairment may result from the
negative impact of distracting stimuli. At the time of the
learning impairment, no overt Pfiesteria-related effects
were seen using a functional observational battery and no
overall response latency effects were seen, indicating that
the Pfiesteria-induced choice accuracy deficit was not due
to generalized debilitation. In the initial use of the
figure-8 maze in this line of research, the rats in the same
Pfiesteria treatment groups that showed significant deficits
in the radial-arm maze showed greater declines in activity
rates in a 1-h figure-8 locomotor activity test. Both the
106,800 and 320,400 Pfiesteria cells/kg groups showed
significantly greater linear trends of activity decline
relative to tank water-treated controls. This reflected an
initial slight hyperactivity in the Pfiesteria-treated
animals followed by a decrease to control levels. Pfiesteria
effects in the figure-8 maze and in early radial-arm maze
training may be useful in a rapid screen for identifying the
critical toxin(s) of Pfiesteria in future
studies.},
Doi = {10.1016/s0892-0362(98)00041-5},
Key = {fds274496}
}
@article{fds274398,
Author = {Levin, ED and Bettegowda, C and Weaver, T and Christopher,
NC},
Title = {Nicotine-dizocilpine interactions and working and reference
memory performance of rats in the radial-arm
maze.},
Journal = {Pharmacol Biochem Behav},
Volume = {61},
Number = {3},
Pages = {335-340},
Year = {1998},
Month = {November},
ISSN = {0091-3057},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9768569},
Keywords = {Animals • Dizocilpine Maleate • Drug Interactions
• Excitatory Amino Acid Antagonists • Female
• Maze Learning • Memory • Memory Disorders
• Nicotine • Nicotinic Agonists • Psychomotor
Performance • Rats • Rats, Sprague-Dawley •
administration & dosage • drug effects • drug
effects* • drug therapy • pharmacology •
pharmacology* • therapeutic use},
Abstract = {Both nicotinic cholinergic and NMDA glutaminergic systems
are important for memory function. Nicotine has been found
repeatedly to significantly improve working memory
performance in the radial-arm maze. The NMDA antagonist
dizocilpine has been found to impair working memory
performance. There is neuropharmacological evidence that
these two systems are functionally related. Nicotine is
potent at releasing many transmitters including glutamate.
The current study was conducted to examine the interaction
of nicotinic and NMDA systems with regard to working and
reference memory. Rats were trained on a working/reference
procedure on a 16-arm radial maze. After acquisition, they
were administered nicotine (0, 0.2, and 0.4 mg/kg) and
dizocilpine (0, 100, and 200 microg/kg) alone or in
combination in a repeated measures, counterbalanced design.
As seen previously, nicotine at a dose of 0.2 mg/kg caused a
significant improvement in working but not reference memory
performance in the radial-arm maze. The 200 microg/kg dose
of dizocilpine made the rats nonresponsive on the maze so
that choice accuracy could not be assessed. The 100
microg/kg dose of dizocilpine caused significant impairments
in both working and reference memory. The 0.4 mg/kg dose of
nicotine significantly attenuated the dizocilpine-induced
deficit in both working and reference memory. NMDA blockade
impairs working and reference memory and blocks the
expression of the working memory improvement caused by 0.2
mg/kg of nicotine. However, a higher dose of 0.4 mg/kg of
nicotine is effective at attenuating the dizocilpine-induced
deficit, even though this dose alone is not effective in
improving performance. A second study examined the effects
of a lower dose range of dizocilpine. Comensurately smaller
memory impairments were seen with lower doses of dizocilpine
down to 12.5 microg/kg, which did not produce any
significant effects on memory performance or response
latency. Nicotine had a more modest effect in attenuating
the smaller deficits caused by these lower doses of
dizocilpine. These studies provide evidence for important
interactions between nicotinic and NMDA systems with regard
to memory function.},
Doi = {10.1016/s0091-3057(98)00109-9},
Key = {fds274398}
}
@article{fds274484,
Author = {Levin, ED and Conners, CK and Silva, D and Hinton, SC and Meck, WH and March, J and Rose, JE},
Title = {Transdermal nicotine effects on attention.},
Journal = {Psychopharmacology (Berl)},
Volume = {140},
Number = {2},
Pages = {135-141},
Year = {1998},
Month = {November},
ISSN = {0033-3158},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9860103},
Keywords = {Administration, Cutaneous • Adolescent • Adult
• Attention • Attention Deficit Disorder with
Hyperactivity • Double-Blind Method • Female
• Humans • Male • Nicotine •
administration & dosage* • drug effects* • drug
therapy • pharmacology},
Abstract = {Nicotine has been shown to improve attentiveness in smokers
and attenuate attentional deficits in Alzheimer's disease
patients, schizophrenics and adults with
attention-deficit/hyperactivity disorder (ADHD). The current
study was conducted to determine whether nicotine
administered via transdermal patches would improve
attentiveness in non-smoking adults without attentional
deficits. The subjects underwent the nicotine and placebo
exposure in a counterbalanced double-blind manner. Measures
of treatment effect included the Profile of Mood States
(POMS), Conners' computerized Continuous Performance Test
(CPT) of attentiveness and a computerized interval-timing
task. The subjects were administered a 7 mg/day nicotine
transdermal patch for 4.5 h during a morning session.
Nicotine significantly increased self-perceived vigor as
measured by the POMS test. On the CPT, nicotine
significantly decreased the number of errors of omission
without causing increases in either errors of commission or
correct hit reaction time. Nicotine also significantly
decreased the variance of hit reaction time and the
composite measure of attentiveness. This study shows that,
in addition to reducing attentional impairment, nicotine
administered via transdermal patches can improve
attentiveness in normal adult non-smokers.},
Doi = {10.1007/s002130050750},
Key = {fds274484}
}
@article{fds274448,
Author = {Levin, ED and Brady, TC and Hochrein, EC and Oury, TD and Jonsson, LM and Marklund, SL and Crapo, JD},
Title = {Molecular manipulations of extracellular superoxide
dismutase: functional importance for learning.},
Journal = {Behav Genet},
Volume = {28},
Number = {5},
Pages = {381-390},
Year = {1998},
Month = {September},
ISSN = {0001-8244},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9926619},
Keywords = {Animals • Brain • Extracellular Space •
Female • Gene Expression Regulation, Enzymologic •
Genotype* • Humans • Male • Maze Learning
• Mental Recall • Mice • Mice, Knockout
• Mice, Transgenic • Nitric Oxide Synthase •
Pregnancy • Retention (Psychology) • Superoxide
Dismutase • enzymology • enzymology* •
genetics* • physiology • physiology*},
Abstract = {Extracellular superoxide dismutase (EC-SOD) controls the
availability of extracellular superoxide (O2.-), which is
important for a variety of physiological pathways, including
the primary means of inactivating nitric oxide (NO). The
role of EC-SOD in neurobehavioral function has been until
now unexplored. In the current studies, the phenotypic
expression of genotypic alterations of EC-SOD production in
mice were characterized for spatial learning and memory.
Dramatic impairments in spatial learning in the win-shift
8-arm radial maze were seen in both EC-SOD knockout mice and
EC-SOD overexpressing mice. The EC-SOD overexpressing mice
were further characterized as having significant deficits in
a repeated acquisition task in the radial-arm maze, which
permitted the dissociation of long and short-term learning.
Long-term learning was significantly impared by EC-SOD
overexpression, whereas short-term learning was not
significantly affected by EC-SOD overexpression. No systems
have been shown to be importantly involved in learning and
memory. This may be important in the current studies because
EC-SOD has primary control over the inactivation of NO. We
found that EC-SOD overexpressing mice were resistant to the
cognitive effects of L-NAME (NG-nitro-L-arginine methyl
ester hydrochloride), an NO synthase inhibitor. Decreased NO
catabolism in these mice may have served to counter the
effects of NOS inhibition by L-NAME. The current finding
that EC-SOD levels that were either higher or lower than
controls impaired learning demonstrates that the proper
control of brain extracellular O2.- may be more vital than
merely reduction of brain extracellular O2.- in maintaining
adequate learning function.},
Doi = {10.1023/a:1021673703129},
Key = {fds274448}
}
@article{fds274492,
Author = {Levin, ED and Simon, BB},
Title = {Nicotinic acetylcholine involvement in cognitive function in
animals.},
Journal = {Psychopharmacology (Berl)},
Volume = {138},
Number = {3-4},
Pages = {217-230},
Year = {1998},
Month = {August},
ISSN = {0033-3158},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9725745},
Keywords = {Acetylcholine • Animals • Attention •
Cognition • Humans • Memory • Nicotinic
Agonists • Receptors, Neurotransmitter •
Receptors, Nicotinic • drug effects • metabolism*
• pharmacology • physiology* • therapeutic
use},
Abstract = {Nicotinic cholinergic systems are involved with several
important aspects of cognitive function including attention,
learning and memory. Nicotinic cholinergic receptors are
located in many regions of the brain, including areas
important for cognitive function such as the hippocampus and
frontal cortex. Nicotinic agonists have been found in rodent
and non-human primate studies to improve performance on a
variety of memory tasks. In a complementary fashion,
nicotinic antagonists such as mecamylamine impair working
memory function. In humans, similar effects have been seen.
Nicotinic agonist treatment can improve attention, learning
and memory and nicotinic antagonist treatment can cause
deficits. To define the neural substrates of nicotinic
involvement in cognitive function, three areas of
investigation are underway. 1) Critical neuroanatomic loci
for nicotinic effects are beginning to be determined. The
hippocampus, frontal cortex and midbrain dopaminergic nuclei
have been found to be important sites of action for
nicotinic involvement in memory function. 2) Nicotinic
receptor subtype involvement in cognitive function is being
studied. There has been considerable recent work identifying
nicotinic receptor subunit conformation including alpha and
beta subunits. Nicotinic receptor subtypes appear to be
associated with different functional systems; however, much
remains to be done to determine the precise role each
subtype plays in terms of cognitive function. 3) Nicotinic
interactions with other transmitter systems are being
assessed. Nicotine receptors interact in important ways with
other systems to affect cognitive functioning, including
muscarinic ACh, dopamine, norepinepherine, serotonin,
glutamate, and other systems. Nicotinic function in clinical
populations and potential for therapeutics has been
investigated for Alzheimer's disease, Parkinson's disease,
schizophrenia and attention deficit/hyperactivity disorder.
Areas which need to receive greater attention are the exact
anatomical location and the specific receptor subtypes
critically involved in nicotine's effects. In addition, more
work needs to be done to develop and determine the efficacy
and safety of novel nicotinic ligands for use in the
long-term treatment of human cognitive disorders.},
Doi = {10.1007/s002130050667},
Key = {fds274492}
}
@article{fds274442,
Author = {Kelly, KA and Havrilla, CM and Brady, TC and Abramo, KH and Levin,
ED},
Title = {Oxidative stress in toxicology: established mammalian and
emerging piscine model systems.},
Journal = {Environ Health Perspect},
Volume = {106},
Number = {7},
Pages = {375-384},
Year = {1998},
Month = {July},
ISSN = {0091-6765},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9637794},
Keywords = {Animals • Antioxidants • Fishes • Humans
• Mammals • Models, Biological • Oxidative
Stress • Reactive Oxygen Species • Toxicology
• drug effects* • metabolism • metabolism*
• methods* • pharmacology},
Abstract = {Interest in the toxicological aspects of oxidative stress
has grown in recent years, and research has become
increasingly focused on the mechanistic aspects of oxidative
damage and cellular responses in biological systems. Toxic
consequences of oxidative stress at the subcellular level
include lipid peroxidation and oxidative damage to DNA and
proteins. These effects are often used as end points in the
study of oxidative stress. Typically, mammalian species have
been used as models to study oxidative stress and to
elucidate the mechanisms underlying cellular damage and
response, largely because of the interest in human health
issues surrounding oxidative stress. However, it is becoming
apparent that oxidative stress also affects aquatic
organisms exposed to environmental pollutants. Research in
fish has demonstrated that mammalian and piscine systems
exhibit similar toxicological and adaptive responses to
oxidative stress. This suggests that piscine models, in
addition to traditional mammalian models, may be useful for
further understanding the mechanisms underlying the
oxidative stress response.},
Doi = {10.1289/ehp.98106375},
Key = {fds274442}
}
@article{fds274391,
Author = {Schwartz-Bloom, RD and McDonough, KJ and Chase, PJ and Chadwick, LE and Inglefield, JR and Levin, ED},
Title = {Long-term neuroprotection by benzodiazepine full versus
partial agonists after transient cerebral ischemia in the
gerbil [corrected].},
Journal = {J Cereb Blood Flow Metab},
Volume = {18},
Number = {5},
Pages = {548-558},
Year = {1998},
Month = {May},
ISSN = {0271-678X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9591847},
Keywords = {Animals • Benzodiazepines • Cell Death • GABA
Modulators • Gerbillinae • Hypothermia, Induced
• Imidazoles • Injections, Intraperitoneal •
Ischemic Attack, Transient • Male • Time Factors
• administration & dosage* • adverse effects
• drug effects • drug therapy* •
pathology*},
Abstract = {The ability of diazepam, a benzodiazepine full agonist, and
imidazenil, a benzodiazepine partial agonist, to protect
hippocampal area CA1 neurons from death for at least 35 days
after cerebral ischemia was investigated. Diazepam (10
mg/kg) administered to gerbils 30 and 90 minutes after
forebrain ischemia produced significant protection of
hippocampal area CA1 pyramidal neurons 7 days later. In
gerbils surviving for 35 days, diazepam produced the same
degree of neuroprotection (70% +/- 30%) in the hippocampus
compared with 7 days after ischemia. The therapeutic window
for diazepam was short; there was no significant
neuroprotection when the administration of diazepam was
delayed to 4 hours after ischemia. The neuroprotective dose
of diazepam also produced hypothermia (approximately 32
degrees C) for several hours after injection. To assess the
role of hypothermia in neuroprotection by diazepam,
hypothermia depth and duration was simulated using a
cold-water spray in separate gerbils. Seven days after
ischemia, neuroprotection by hypothermia was similar to that
produced by diazepam. However, 35 days after ischemia, there
was no significant protection by hypothermia, suggesting
that hypothermia does not play a significant role in
long-term diazepam neuroprotection. Imidazenil (3 mg/kg),
which produced only minimal hypothermia, protected area CA1
of hippocampus to the same degree as that by diazepam 7 days
after ischemia. At 35 days after ischemia, significant
protection remained, but it was considerably reduced
compared with 7 days. Like diazepam, the therapeutic window
for imidazenil was short. Imidazenil neuroprotection was
lost when the drug was administered as early as 2 hours
after ischemia. The ability of ischemia to produce deficits
in working memory and of benzodiazepines to prevent the
deficits also was investigated. Gerbils trained on an
eight-arm radial maze before ischemia demonstrated a
significant increase in the number of working errors 1 month
after ischemia. The ischemia-induced deficits in working
memory were completely prevented by diazepam but not by
imidazenil. There was a significant, but weak, negative
correlation between the degree of CA1 pyramidal cell
survival and the number of working errors in both the
diazepam and imidazenil groups. Thus, if given early enough
during reperfusion, both benzodiazepine full and partial
agonists are neuroprotective for at least 35 days, but the
lack of sedating side effects of imidazenil must be weighed
against its reduced efficacy.},
Doi = {10.1097/00004647-199805000-00010},
Key = {fds274391}
}
@article{fds274381,
Author = {Markwiese, BJ and Acheson, SK and Levin, ED and Wilson, WA and Swartzwelder, HS},
Title = {Differential effects of ethanol on memory in adolescent and
adult rats.},
Journal = {Alcohol Clin Exp Res},
Volume = {22},
Number = {2},
Pages = {416-421},
Year = {1998},
Month = {April},
ISSN = {0145-6008},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9581648},
Keywords = {Aging • Animals • Discrimination Learning •
Dose-Response Relationship, Drug • Escape Reaction
• Ethanol • Hippocampus • Injections,
Intraperitoneal • Male • Maze Learning •
Memory • Mental Recall • Neuronal Plasticity
• Orientation • Rats • Rats, Sprague-Dawley
• Synaptic Transmission • drug effects • drug
effects* • toxicity*},
Abstract = {Previous studies have shown that ethanol inhibits
memory-related synaptic activity and plasticity more
potently in hippocampal slices from immature rats, compared
with those taken from adults. We therefore hypothesized that
ethanol would more potently attenuate the acquisition of
spatial memory in adolescents, compared with adult rats.
Adult (65 days of age) and adolescent (30 days of age) male
rats were given five daily trials on a spatial memory task
in a Morris Water Maze. The animals from each age group were
subdivided into three subgroups. Each day, thirty minutes
before training, the animals in each subgroup were given an
intraperitoneal injection of 1.0 g/kg of ethanol, 2.0 g/kg
of ethanol, or the saline vehicle. Training continued daily
until the control animals had reached a performance
criterion. Ethanol treatment significantly impaired spatial
memory acquisition in the adolescent rats, but did not
impair acquisition in adult rats. A separate experiment with
identical treatment groups showed that ethanol did not
impair acquisition of a nonspatial memory task in the water
maze in animals from either age group. These experiments
show that the acquisition of spatial, but not nonspatial,
memory is more potently impaired by ethanol in adolescent
animals, compared with adults.},
Doi = {10.1097/00000374-199804000-00018},
Key = {fds274381}
}
@article{fds136380,
Title = {Kelly SA, CM Havrilla, TC Brady, KL Harris amd ED Levin.
Oxidative stress in toxicology: Established mammalian and
emerging piscine model systems. Environmental Health
Perspectives, 106:375-384, 1998.},
Year = {1998},
Key = {fds136380}
}
@article{fds136381,
Title = {Levin ED and TA Slotkin. Developmental neurotoxicity of
nicotine. In Handbook of Developmental Neurotoxicology, (W.
Slikker, Jr. and L.W. Chang eds.), Academic Press, San
Diego, pp. 587-615, 1998.},
Year = {1998},
Key = {fds136381}
}
@article{fds136382,
Title = {Levin ED, CK Conners, D Silva, SC Hinton , WH Meck, J March
and JE Rose. Transdermal nicotine effects on attention.
Psychopharmacology, 140:135-141, 1998.},
Year = {1998},
Key = {fds136382}
}
@article{fds136397,
Title = {Levin ED and BB Simon. Nicotinic acetylcholine involvement
in cognitive function in animals. Psychopharmacology,
138:217-230, 1998.},
Year = {1998},
Key = {fds136397}
}
@article{fds136398,
Title = {Levin ED, BB Simon and CK Conners. Transdermal nicotine
treatment of attention deficit/hyperactivity disorder. In:
Neuronal Nicotinic Receptors: Pharmacology and Therapeutic
Opportunities, S.P. Arneric and J.D. Brioni (eds.), John
Wiley, New York,349-357, 1998.},
Year = {1998},
Key = {fds136398}
}
@article{fds136399,
Title = {Levin ED, EC Hochrein, TC Brady, TD Oury, LM Jonsson, SL.
Marklund and J. Crapo Molecular manipulations of
extracellular superoxide dismutase: functional importance
for learning. Behavior Genetics, 28:381-390,
1998.},
Year = {1998},
Key = {fds136399}
}
@article{fds274356,
Author = {Levin, ED and Schmechel, DE and Burkholder, JB and Deamer-Melia, NJ and Moser, VC and Harry, GJ},
Title = {Persisting learning deficits in rats after exposure to
Pfiesteria piscicida.},
Journal = {Environ Health Perspect},
Volume = {105},
Number = {12},
Pages = {1320-1325},
Year = {1997},
Month = {December},
ISSN = {0091-6765},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9405328},
Keywords = {Animals • Dinoflagellida* • Female • Learning
Disorders • Maze Learning • Motor Activity •
Protozoan Infections, Animal • Rats • Rats,
Sprague-Dawley • blood • complications* •
etiology*},
Abstract = {Pfiesteria piscicida and other toxic Pfiesteria-like
dinoflagellates have been implicated as a cause of fish
kills in North Carolina estuaries and elsewhere. Accidental
laboratory exposure of humans to P. piscicida has been
reported to cause a complex syndrome including cognitive
impairment. The current project was conducted to
experimentally assess the possibility of cognitive effects
of P. piscicida exposure in rats. Samples of water from
aquaria in which P. piscicida zoospores were killing fish
were frozen, a procedure that has been found to induce
encystment. Thawed samples were injected into albino
Sprague-Dawley rats. A significant learning impairment was
documented in rats administered samples of P. piscicida that
were recently frozen. Prolonged storage of Pfiesteria
samples diminished the effect. No effect was seen in the
recall of a previously learned task, but when the rats were
called upon to learn a new task, the Pfiesteria-treated
animals showed a significant learning deficit. This effect
persisted up to at least 10 weeks after a single injection
of Pfiesteria. The Pfiesteria-induced learning deficit did
not seem to be associated with any obvious debilitation or
health impairment of the exposed rats. Deficits in
habituation of arousal and rearing behavior were detected
using a functional observational battery. No
Pfiesteria-induced effects on blood count and white cell
differential or in a standard pathological screening of
brain, liver, lung, kidney, and spleen tissue were seen at 2
months after exposure. These studies document a persistent
learning impairment in rats after exposure to the
dinoflagellate P.piscicida in otherwise physically
well-appearing rats. This effect may partially model the
symptoms of cognitive impairments that humans have shown
after Pfiesteria exposure.},
Doi = {10.1289/ehp.971051320},
Key = {fds274356}
}
@article{fds274405,
Author = {Levin, ED},
Title = {Chronic haloperidol administration does not block acute
nicotine-induced improvements in radial-arm maze performance
in the rat.},
Journal = {Pharmacol Biochem Behav},
Volume = {58},
Number = {4},
Pages = {899-902},
Year = {1997},
Month = {December},
ISSN = {0091-3057},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9408193},
Keywords = {Animals • Cholinergic Agents • Dopamine
Antagonists • Dose-Response Relationship, Drug •
Drug Implants • Female • Haloperidol • Maze
Learning • Memory, Short-Term • Nicotine •
Psychomotor Performance • Rats • Rats,
Sprague-Dawley • administration & dosage •
antagonists & inhibitors* • drug effects • drug
effects* • pharmacology • pharmacology*},
Abstract = {Nicotine has been found to improve cognitive performance in
a variety of tasks including the radial maze. Nicotine has
also been shown to promote the release of a variety of
neurotransmitters including dopamine (DA). DA has been found
to be important for nicotine's reinforcing effects. DA
involvement with nicotine's cognitive effects is unclear. In
the current study, the effects of acute nicotine injections
(0, 0.1, 0.2, or 0.4 mg/kg) were examined on radial-arm maze
performance in rats given chronic infusions the DA
antagonist haloperidol (0, 0.2, or 0.6 mg/kg/day). Chronic
haloperidol infusion was not found to attenuate the memory
improvement caused by acute nicotine injection. In fact, the
dose-related nicotine-induced memory improvement was clearer
in the haloperidol-treated groups than in controls. This is
similar to the effect of nicotine we saw in human subjects
given chronic doses of haloperidol. Our previous studies
demonstrated significant nicotinic-DA interactions with
regard to memory function. The current results suggest that
in the DA-nicotinic relationship DA stimulation is not
necessary for the memory improvement caused by
nicotine.},
Doi = {10.1016/s0091-3057(97)00052-x},
Key = {fds274405}
}
@article{fds274406,
Author = {Felix, R and Levin, ED},
Title = {Nicotinic antagonist administration into the ventral
hippocampus and spatial working memory in
rats.},
Journal = {Neuroscience},
Volume = {81},
Number = {4},
Pages = {1009-1017},
Year = {1997},
Month = {December},
ISSN = {0306-4522},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9330363},
Keywords = {Aconitine • Animals • Cholinergic Antagonists
• Dihydro-beta-Erythroidine • Female •
Hippocampus • Maze Learning • Memory, Short-Term
• Neuromuscular Blocking Agents • Nicotinic
Antagonists • Rats • Rats, Sprague-Dawley •
Seizures • Space Perception • Tubocurarine •
administration & dosage • analogs & derivatives •
chemically induced • drug effects • drug effects*
• pharmacology • pharmacology*},
Abstract = {Nicotinic acetylcholine receptors are important for
maintaining optimal memory performance. In order to more
fully characterize the involvement of nicotinic systems in
memory, the contributions of nicotinic acetylcholine
receptor subtypes were investigated. This study targeted the
alpha 7 and alpha 4 beta 2 nicotinic receptors in the
ventral hippocampus, an area known to be important for
spatial working memory. Antagonists of alpha 7 and alpha 4
beta 2 receptors were locally infused into the ventral
hippocampus of rats and the effects on memory were examined
with the radial-arm maze. The subtype-specific competitive
antagonists infused into separate groups of rats were
methyllycaconitine citrate (an alpha 7 antagonist) and
dihydro-beta-erythroidine hydrobromide (an alpha 4 beta 2
antagonist). Their effects on radial-arm maze performance
were contrasted with the non-specific competitive
antagonist, D-tubocurarine chloride. Significant deficits in
radial-arm maze choice accuracy performance were found at
78.7 micrograms/side for methyllycaconitine and at 106.9
micrograms/side for dihydro-beta-erythroidine. Increased
response latency was also seen at these doses. Tubocurarine
induced seizures at doses previously reported to have no
effect. Wet dog shakes were seen in most rats at 0.1
microgram/side with tubocurarine, 26.3 micrograms/side with
methyllycaconitine and 106.9 micrograms/side with
dihydro-beta-erythroidine. This study suggests that both
alpha 7 and alpha 4 beta 2 nicotinic acetylcholine receptor
subtypes are involved in working memory formation and that
the hippocampus is a critical site for nicotinic cholinergic
involvement in memory function, though the high doses of
antagonists needed to produce the memory impairment may have
had less than completely specific effects.},
Doi = {10.1016/s0306-4522(97)00224-8},
Key = {fds274406}
}
@article{fds274410,
Author = {Piantadosi, CA and Zhang, J and Levin, ED and Folz, RJ and Schmechel,
DE},
Title = {Apoptosis and delayed neuronal damage after carbon monoxide
poisoning in the rat.},
Journal = {Exp Neurol},
Volume = {147},
Number = {1},
Pages = {103-114},
Year = {1997},
Month = {September},
ISSN = {0014-4886},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9294407},
Keywords = {Animals • Apoptosis • Behavior, Animal •
Brain • Carbon Monoxide Poisoning • DNA
Fragmentation • Glutamic Acid • Hydroxyl Radical
• Hydroxylation • Male • Microdialysis •
Microscopy, Electron • Neurons • Rats • Rats,
Sprague-Dawley • Time Factors • drug effects
• drug effects* • genetics • metabolism
• pathology • pathology* • physiology •
psychology • ultrastructure},
Abstract = {Delayed neurological damage after CO hypoxia was studied in
rats to determine whether programmed cell death (PCD), in
addition to necrosis, is involved in neuronal death. In rats
exposed to either air or CO (2500 ppm), microdialysis in
brain cortex and hippocampus was performed to determine the
extent of glutamate release and hydroxyl radical generation
during the exposures. Groups of control and CO-exposed rats
also were tested in a radial maze to assess the effects of
the CO exposures on learning and memory. At 3, 7, and 21
days after CO exposure brains were perfusion-fixed and
hematoxylin-eosin (H&E) was used to assess injury and to
select regions for further examination. DNA fragmentation
was sought by examining cryosections with the terminal
deoxynucleotidyl transferase-mediated dUTP-biotin nick-end
labeling (TUNEL) reaction. We found significant increases in
glutamate release and .OH generation during and immediately
after CO hypoxia. CO-exposed rats showed learning and memory
deficits after exposure associated with heterogeneous cell
loss in cortex, globus pallidus, and cerebellum. The frontal
cortex was affected most seriously; the damage was slight at
Day 3, increased at Day 7, and persistent at Day 21 after CO
exposure. TUNEL staining was positive at all three time
points, and TUNEL-labeled cells were distributed similarly
to eosinophilic cells. The number of cells stained by TUNEL
was less than by H&E and amounted to 2 to 5% of all cell
nuclei in regions of injury. Ultrastructural features of
both neuronal necrosis and apoptosis also were observed
readily by electron microscopy. These findings indicate that
both necrosis and apoptosis (PCD) contribute to CO
poisoning-induced brain cell death.},
Doi = {10.1006/exnr.1997.6584},
Key = {fds274410}
}
@article{fds274446,
Author = {Newhouse, PA and Potter, A and Levin, ED},
Title = {Nicotinic system involvement in Alzheimer's and Parkinson's
diseases. Implications for therapeutics.},
Journal = {Drugs Aging},
Volume = {11},
Number = {3},
Pages = {206-228},
Year = {1997},
Month = {September},
ISSN = {1170-229X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9303280},
Keywords = {Alzheimer Disease • Animals • Cognition •
Cognition Disorders • Combined Modality Therapy •
Disease Models, Animal • Humans • Nicotine •
Nicotinic Agonists • Nicotinic Antagonists •
Parkinson Disease • Receptors, Nicotinic • drug
effects • drug therapy • etiology •
metabolism • metabolism* • pharmacology •
therapeutic use*},
Abstract = {Advances in our understanding of the structure, function and
distribution of nicotinic acetylcholine receptors in the CNS
have provided the impetus for new studies examining the
role(s) that these receptors and associated processes may
play in CNS functions. Further motivation has come from the
realisation that such receptors must be involved in the
maintenance of cigarette smoking, and from clues provided by
studies of degenerative neurological diseases such as
Alzheimer's disease and Parkinson's disease, in which the
loss of nicotinic receptors has been described. Ongoing
investigations of the molecular substructure of central
nicotinic receptors and their pharmacology have begun to
open up new possibilities for novel CNS therapeutics with
nicotinic agents. Exploiting these possibilities will
require understanding of the role(s) that these receptor
systems play in human cognitive, behavioural, motor and
sensory functioning. Clues from careful studies of human
cognition are beginning to emerge and will provide direction
for studies of potentially therapeutic novel nicotinic
agents. Despite the promising results of acute studies, few
long term studies with nicotine or nicotinic drugs have been
performed in dementing disorders. Thus there is uncertainty
as to whether long term nicotinic treatment will provide
sustained cognitive benefit. It is even more uncertain
whether such cognitive benefit will have a significant
clinical impact on patients and their families. To maximise
the potential benefit of long term treatment with nicotinic
agonists (or other cholinergic drugs), we suggest that drug
treatment should be combined with cognitive rehabilitation
strategies. This will enable patients and/or their families
to focus on the particular cognitive domains that may be
improved.},
Doi = {10.2165/00002512-199711030-00005},
Key = {fds274446}
}
@article{fds274432,
Author = {Levin, ED and Kaplan, S and Boardman, A},
Title = {Acute nicotine interactions with nicotinic and muscarinic
antagonists: working and reference memory effects in the
16-arm radial maze.},
Journal = {Behav Pharmacol},
Volume = {8},
Number = {2-3},
Pages = {236-242},
Year = {1997},
Month = {June},
ISSN = {0955-8810},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9833018},
Keywords = {Animals • Drug Interactions • Female • Maze
Learning • Mecamylamine • Memory, Short-Term
• Muscarinic Antagonists • Nicotine •
Nicotinic Agonists • Nicotinic Antagonists • Rats
• Rats, Sprague-Dawley • Scopolamine • drug
effects* • pharmacology • pharmacology*},
Abstract = {In the 8-arm radial maze and other tests, acute nicotine
administration has been found to improve memory performance
significantly, whereas acute administration of the nicotinic
antagonist mecamylamine has been found to impair memory
performance. However, questions remain concerning the
behavioral and pharmacological nature of acute nicotine
effects on memory. In the current studies, we examined acute
nicotine effects on working and reference memory in a 16-arm
radial maze. In the first study, nicotine caused a
significant improvement in working memory but not in
reference memory. The muscarinic antagonist scopolamine
caused significant deficits in working memory but not in
reference memory. Nicotine did not significantly attenuate
the scopolamine-induced deficit. In the second study, with
rats trained to near-perfect performance, a low dose of
mecamylamine (1.25 mg/kg) caused a significant working
memory impairment in the 16-arm maze. This deficit was
significantly attenuated by concurrent acute administration
of nicotine. These studies show that acute nicotine, like
chronic nicotine, preferentially improves working compared
with reference memory in the radial-arm maze. Mecamylamine
can impair working memory performance in the 16-arm maze at
low doses which are less likely to have effects at
N-methyl-D-aspartate receptors. Nicotine can selectively
reverse mecamylamine-induced deficits.},
Key = {fds274432}
}
@article{fds274434,
Author = {Levin, ED and Christopher, NC and Briggs, SJ},
Title = {Chronic nicotinic agonist and antagonist effects on T-maze
alternation.},
Journal = {Physiol Behav},
Volume = {61},
Number = {6},
Pages = {863-866},
Year = {1997},
Month = {June},
ISSN = {0031-9384},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9177558},
Keywords = {Animals • Female • Maze Learning •
Mecamylamine • Nicotine • Rats • Rats,
Sprague-Dawley • Time Factors • drug effects*
• pharmacology*},
Abstract = {A variety of studies have found that nicotine improves
working memory function. However, other studies have either
not found improvements or have found nicotine-induced
deficits. The demands of the particular memory test may be
critical for the expression of the nicotine effects. In
several studies, we have found that chronic nicotine
administration improves working memory performance in the
radial arm maze. Chronic mecamylamine coadministration
reversed this effect. The current study was conducted to
determine the effects of chronic nicotine and mecamylamine
on choice accuracy in a T-maze spatial alternation task. The
same dose and duration of nicotine administration that we
have previously found to significantly improve choice
accuracy in the radial-arm maze was not effective in
altering T-maze spatial alternation. The critical difference
in task demands may be the presence with T-maze alternation
of proactive interference. During a session, a choice
alternative repeatedly changes valence from correct to
incorrect and back again. In contrast, with the radial-arm
maze as run in our studies, in a session the valence of an
arm only changes once from correct to incorrect. Previous
work with nicotine effects on spatial alternation in an
operant task found evidence that nicotine increased the
negative effect of proactive interference on performance. In
the current study, chronic mecamylamine caused a significant
deficit in T-maze spatial alternation. This same dose did
not produce a deficit in the radial-arm maze and, in fact,
caused an improvement during the first week of
administration.},
Doi = {10.1016/s0031-9384(96)00609-9},
Key = {fds274434}
}
@article{fds136374,
Title = {Levin ED, DE Schmechel, JM Burkholder, HB Glasgow, Jr., N
Deamer-Melia, VC Moser and G.J. Harry. Persisting learning
deficits in rats after exposure to pfiesteria piscicida.
Environmental Health Perspectives, 105:1320-1325,
1997.},
Year = {1997},
Key = {fds136374}
}
@article{fds136379,
Title = {Levin ED, D Torry, NC Christopher, X Yu, G Einstein and R
Schwartz-Bloom. Is binding to nicotinic acetylcholine and
dopamine receptors related to working memory in rats?. Brain
Research Bulletin, 43:295-304, 1997.},
Year = {1997},
Key = {fds136379}
}
@article{fds136396,
Title = {Levin ED, NC Christopher and SJ Briggs. Chronic nicotinic
agonist and antagonist effects on T-maze alternation.
Physiology and Behavior, 61:863-866, 1997.},
Year = {1997},
Key = {fds136396}
}
@article{fds274385,
Author = {Levin, ED and Torry, D and Christopher, NC and Yu, X and Einstein, G and Schwartz-Bloom, RD},
Title = {Is binding to nicotinic acetylcholine and dopamine receptors
related to working memory in rats?},
Journal = {Brain Res Bull},
Volume = {43},
Number = {3},
Pages = {295-304},
Year = {1997},
ISSN = {0361-9230},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9227840},
Keywords = {Animals • Dose-Response Relationship, Drug • Maze
Learning • Mecamylamine • Memory • Nicotine
• Radioligand Assay • Rats • Rats,
Sprague-Dawley • Receptors, Dopamine • Receptors,
Nicotinic • drug effects • drug effects* •
pharmacology* • physiology*},
Abstract = {Nicotinic acetylcholine (ACh) and dopamine (DA) receptor
activation has been found to be important for working
memory. The regional distribution of these receptors in the
brain has been well characterized. However, the relationship
of the region-specific nicotinic ACh and DA binding density
to memory performance has not been well assessed. In the
current studies the relationship of receptor binding and
memory function was examined. Receptor binding and memory
performance were assessed in rats in three types of
conditions: 1) chronic nicotine and mecamylamine vs. vehicle
infusion; 2) lesions of the fimbria-fornix or medial
basalocortical projection vs. sham lesions; and 3)
2-year-old aged rats vs. 3-month-old young adult rats.
Nicotinic ACh receptors were labeled by [3H]N-methyl-carbamylcholine
([3H]MCC), D1 receptors by [3H]SCH 23390, and D2 receptors
by [125I]iodosulpiride. Working memory was assessed using
the radial-arm maze and T-maze delayed spatial alternation
tasks. Chronic nicotine infusion substantially increased
nicotinic receptor binding in a variety of brain areas and
significantly improved working memory performance in the
radial-arm maze. However, nicotinic receptor binding did not
correlate well with memory performance. The nicotinic
antagonist mecamylamine did not block nicotine-induced
increased nicotinic binding, but it did block
nicotine-induced memory improvement. Aged rats relative to
young adults showed both a decrease in nicotinic binding and
impaired memory performance. However, chronic effects of
nicotine on nicotinic receptor binding and memory
performance did not correlate in the aged rats. Nicotine
also increased nicotinic receptor binding in the aged rats
in brain areas except for the VTA, but did not improve
memory performance. Lesions of the medial basalocortical
projection or the fimbria-fornix did not cause significant
changes in nicotinic binding in their target fields, but
they did cause significant deficits in memory performance.
Finally, there were no significant correlations of nicotinic
binding in any brain region and memory performance. DA
receptor binding was not altered by chronic nicotine or
mecamylamine infusion, fimbria-fornix lesions, medial
basalocortical lesions, or in aged rats. However, DA
receptor binding did correlate with memory performance.
There was a positive correlation of T-maze accuracy and D1
receptor binding in the frontal cortex and a negative
correlation of T-maze accuracy and D1 receptor binding in
the VTA and dentate gyrus. In contrast, a positive
correlation was seen between radial-arm maze accuracy and D1
receptor binding in the VTA. Radial-arm maze accuracy was
positively correlated with D2 receptor binding in the
striatum and dentate gyrus. There are significant
relationships between the extent of DA receptor binding and
working memory, but relationship between nicotinic ACh
receptor binding density and memory is weak.},
Doi = {10.1016/s0361-9230(97)00009-9},
Key = {fds274385}
}
@article{fds274345,
Author = {Levin, ED and Wilkerson, A and Jones, JP and Christopher, NC and Briggs,
SJ},
Title = {Prenatal nicotine effects on memory in rats: pharmacological
and behavioral challenges.},
Journal = {Brain Res Dev Brain Res},
Volume = {97},
Number = {2},
Pages = {207-215},
Year = {1996},
Month = {December},
ISSN = {0165-3806},
url = {http://www.ncbi.nlm.nih.gov/pubmed/8997505},
Keywords = {Animals • Drug Evaluation, Preclinical • Female
• Infusion Pumps • Male • Maze Learning
• Memory Disorders • Nicotine • Nicotinic
Agonists • Osmotic Pressure • Pregnancy •
Prenatal Exposure Delayed Effects* • Rats • Rats,
Sprague-Dawley • Receptors, Adrenergic • Sex
Distribution • chemically induced* • drug effects
• drug effects* • pharmacology* • physiology*
• physiopathology},
Abstract = {Cigarette smoking during pregnancy has been shown in a
variety of studies to be associated with cognitive deficits
in the children. Nicotine administration to rats during
gestation has been found to cause subtle cognitive effects
in the offspring. Some individual differences in cognitive
impairment may be related to prenatal nicotine effects on
noradrenergic (NE) systems. In the current study, 10
Sprague-Dawley rat dams were infused with approximately 2
mg/kg/day of nicotine ditartrate via osmotic minipumps and
10 control dams were exposed to vehicle-containing minipumps
from gestational day (GD) 4-20. Starting on postnatal day
(PND) 50, the offspring were tested for T-maze rewarded
spatial alternation with intertrial intervals of 0, 10, 20,
or 40 s. There was a sex- and delay-dependent effect of
prenatal nicotine exposure on T-maze alternation.
Nicotine-exposed males showed a significant deficit at the 0
s delay. In radial-arm maze (RAM) acquisition training there
were no significant nicotine effects. However, significant
nicotine-related effects were seen with subsequent
behavioral and pharmacological challenges in the RAM.
Changing the RAM testing location to an identical maze in a
different room elicited a significant choice accuracy
deficit in the prenatal nicotine-exposed rats compared with
controls. Acute nicotine challenge did not cause any
differential effects in the prenatal nicotine and control
groups. During the isoproterenol (beta-NE agonist) challenge
phase there appeared a significant facilitation of choice
accuracy and speeding of response in the prenatal nicotine
exposure group which was not seen in the control group. The
alpha-NE agonist phenylpropanolamine caused a significant
deficit in control females but not in the females prenatally
exposed to nicotine. No differential effects of the alpha-NE
antagonist phenoxybenzamine were seen in the prenatal
nicotine and control groups. Throughout RAM testing there
was a significant sex effect with males having better choice
accuracy than females. These results demonstrate that the
persisting cognitive effects of prenatal exposure to 2
mg/kg/day cause subtle effects in cognitive performance
which can be elicited with behavioral and pharmacological
challenge. These results also support previous studies
suggesting the involvement of NE systems in persisting
effects of prenatal nicotine exposure.},
Doi = {10.1016/s0165-3806(96)00144-7},
Key = {fds274345}
}
@article{fds274211,
Author = {Levin, ED and Rose, JE and Lippelio, P and Robinson,
J},
Title = {Nicotine and neurobehavioral function},
Journal = {Drug Development Research},
Volume = {38},
Number = {3-4},
Pages = {135},
Publisher = {WILEY},
Year = {1996},
Month = {December},
ISSN = {0272-4391},
url = {http://dx.doi.org/10.1002/(SICI)1098-2299(199607/08)38:3/4<135::AID-DDR1>3.0.C},
Doi = {10.1002/(SICI)1098-2299(199607/08)38:3/4<135::AID-DDR1>3.0.C},
Key = {fds274211}
}
@article{fds274335,
Author = {Levin, ED and Toll, K and Chang, G and Christopher, NC and Briggs, SJ and Fiedler, W},
Title = {Epibatidine, a potent nicotinic agonist: Effects on learning
and memory in the radial-arm maze},
Journal = {Medicinal Chemistry Research},
Volume = {6},
Number = {7-8},
Pages = {543-554},
Year = {1996},
Month = {December},
Abstract = {Epibatidine is a potent nicotinic agonist originally
isolated from frog skin. Nicotine has been found in a
variety of studies to improve working memory function in
several different tests including the radial-arm maze (RAM).
The current studies were conducted to determine if
epibatidine would affect learning and memory in the
radial-arm maze. Three studies were conducted. In the first
study, rats were pretrained on the radial-arm maze and then
given acute doses of epibatidine (0, 0.25, 0.5 and 1.0
μg/kg) in a repeated measures counter-balanced design.
Compared to memory performance either before or after the
drug study, performance during the drug study was
significantly improved. This was true even with the
intercurrent saline injections. This may have resulted from
persisting effects of epibatidine administration. Because of
this possibility of carryover effects the other studies both
used between subjects designs. In the second study the rats
were given 0, 0.5 or 1.0 μg/kg of epibatidine in a between
subjects design throughout 24 sessions of RAM training. The
rats given 0.5 μg/kg had a trend toward improved choice
accuracy performance relative to control during the middle
phase of learning. The higher dose had no apparent effect.
To determine if the transience of the improvement caused by
0.5 μg/kg of epibatidine was due to the chronicity of the
treatment or the phase of training a third study was
conducted in which rats were pretrained for 12 sessions and
then were given 0.5 μg/kg of epibatidine in a between
subjects design for an additional 24 sessions of training.
In this study when epibatidine was only given during the
later phases of training no improvement was seen. In fact, a
significant epibatidine deficit was seen during the final
phase of training. These studies show that the potent
nicotinic agonist epibatidine can significantly impair
choice accuracy performance in the radial-arm maze. The
expression of its effect depends critically on when during
training it is given.},
Key = {fds274335}
}
@article{fds274336,
Author = {Levin, ED and Christopher, NC and Briggs, SJ and Todd Auman,
J},
Title = {Chronic nicotine-induced improvement of spatial working
memory and D
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