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Titolo:
Cocaine reward and MPTP toxicity: alteration by regional variant dopamine transporter overexpression
Autore:
Donovan, DM; Miner, LL; Perry, MP; Revay, RS; Sharpe, LG; Przedborski, S; Kostic, V; Philpot, RM; Kirstein, CL; Rothman, RB; Schindler, CW; Uhl, GR;
Indirizzi:
NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA NIDA BaltimoreMD USA 21224 ral Res Program, NIH, Baltimore, MD 21224 USA NIDA, Clin Psychopharmacol Branches, Intramural Res Program, NIH, Baltimore, MD 21224 USA NIDA Baltimore MD USA 21224 ral Res Program, NIH, Baltimore, MD 21224 USA Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21224 USA Johns Hopkins Univ Baltimore MD USA 21224 Neurol, Baltimore, MD 21224 USA Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21224 USA Johns Hopkins Univ Baltimore MD USA 21224 urosci, Baltimore, MD 21224 USA Columbia Univ, Dept Neurol, New York, NY 10032 USA Columbia Univ New YorkNY USA 10032 , Dept Neurol, New York, NY 10032 USA Columbia Univ, Dept Pathol, New York, NY 10032 USA Columbia Univ New YorkNY USA 10032 , Dept Pathol, New York, NY 10032 USA Univ S Florida, Coll Arts & Sci, Dept Psychol, Tampa, FL 33620 USA Univ S Florida Tampa FL USA 33620 Sci, Dept Psychol, Tampa, FL 33620 USA
Titolo Testata:
MOLECULAR BRAIN RESEARCH
fascicolo: 1-2, volume: 73, anno: 1999,
pagine: 37 - 49
SICI:
0169-328X(19991110)73:1-2<37:CRAMTA>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
PARKINSONISM-INDUCING NEUROTOXIN; TYROSINE-HYDROXYLASE; TRANSGENIC MICE; UPTAKE SITES; RAT-BRAIN; DISEASE; RECEPTOR; BINDING; SEROTONIN; EXPRESSION;
Keywords:
cocaine; dopamine transporter; transgenic mice; conditioned place preference; drug reward; MPTP;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
63
Recensione:
Indirizzi per estratti:
Indirizzo: Donovan, DM Ctr Gerontol Res, Transgen & Knockout Facil, 5600 Nathan ShockDr, Baltimore, MD 21224 USA Ctr Gerontol Res 5600 Nathan Shock Dr Baltimore MD USA 21224 A
Citazione:
D.M. Donovan et al., "Cocaine reward and MPTP toxicity: alteration by regional variant dopamine transporter overexpression", MOL BRAIN R, 73(1-2), 1999, pp. 37-49

Abstract

Polygenic factors play important roles in animal models of substance abuseand susceptibility to dopaminergic neurodegeneration. Genetic factors are also likely to contribute to the etiology of human drug abuse disorders, and may alter human vulnerabilities to Parkinsonian neurodegeneration. The dopamine transporter (DAT; SLC6A3) is densely expressed by the dopaminergic midbrain neurons that play central roles in drug reward and is believed to be a primary site of action for cocaine reward. This transporter is necessary for the action of selective dopaminergic neurotoxins, and is uniquely expressed on neurons that are the primary targets of Parkinsonian neurodegeneration. To study possible influences of variant DAT expression on these processes, we have constructed transgenic mice (THDAT) in which tyrosine hydroxylase (TH) promoter sequences drive expression of a rat DAT cDNA variant, increase striatal DAT expression by 20-30%, and provide modest alterations in striatal levels of dopamine and its metabolites. THDAT mice habituate more rapidly to a novel environment than wildtype Littermates. These animals display enhanced reward conferred by cocaine, as measured by conditioned place preference. However, locomotor responses to cocaine administration are similar to those of wildtype mice, except at high cocaine doses. THDAT mice display more than 50% greater losses of dopaminergic neurons following a course of MPTP treatment than do wildtype control mice. These results document a model for allelic variation at a gene locus that can exert significant effects in murine models of human substance abuse vulnerability and dopaminergic neurodegeneration. (C) 1999 Elsevier Science B.V. All rights reserved.

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Documento generato il 09/07/20 alle ore 13:31:45