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| Research article summary (published 8 Nov 1999): |
Cocaine reward and MPTP toxicity: alteration by regional variant dopamine transporter overexpression.
Full Abstract
Polygenic factors play important roles in animal models of substance abuse and 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.
Author information
Author/s: Donovan, D M (DM); Miner, L L (LL); Perry, M P (MP); Revay, R S (RS); Sharpe, L G (LG); Przedborski, S (S); Kostic, V (V); Philpot, R M (RM); Kirstein, C L (CL); Rothman, R B (RB); Schindler, C W (CW); Uhl, G R (GR);
Affiliation: Molecular Neurobiology, Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD 20857, USA. donovand(-atsign-)grc.nia.nih.gov
Grants: R01 NS 38586 (Agency:NINDS NIH HHS) ; R29 NS37345 (Agency:NINDS NIH HHS)
Journal and publication information
Publication Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.
Journal: Brain research. Molecular brain research (Brain Res Mol Brain Res), published in NETHERLANDS. (Language: eng)
Reference: 1999-Nov; vol 73 (issue 1-2) : pp 37-49
Dates: Created 2000/02/14; Completed 2000/02/14; Revised 2008/11/21;
PMID: 10581396, status: MEDLINE (last retrieved date: 2/18/2009)
Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.
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Associated Chemicals: Carrier Proteins (0) ; Dopamine Plasma Membrane Transport Proteins (0) ; Membrane Glycoproteins (0) ; Membrane Transport Proteins (0) ; Nerve Tissue Proteins (0) ; Recombinant Fusion Proteins (0) ; Slc6a3 protein, mouse (0) ; Slc6a3 protein, rat (0) ; 3,4-Dihydroxyphenylacetic Acid (102-32-9) ; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (28289-54-5) ; Homovanillic Acid (306-08-1) ; Cocaine (50-36-2) ; Serotonin (50-67-9) ; Dopamine (51-61-6) ; Hydroxyindoleacetic Acid (54-16-0) ; Tyrosine 3-Monooxygenase (EC 1.14.16.2)Related articles
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