Cocaine reward and MPTP toxicity: alteration by regional variant dopamine transporter overexpression

• Published in: Brain research. Molecular brain research. 1999-11, Vol.73 (1), p.37-49
• Main Authors: Donovan, David M, Miner, Lucinda L, Perry, Michael P, Revay, Randal S, Sharpe, Lawrence G, Przedborski, Serge, Kostic, Vladimir, Philpot, Rex M, Kirstein, Cheryl L, Rothman, Richard B, Schindler, Charles W, Uhl, George R
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - administration & dosage; 3,4-Dihydroxyphenylacetic Acid - metabolism; Animals; Behavior, Animal - physiology; Biological and medical sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Chromatography, High Pressure Liquid; Cocaine; Cocaine - pharmacology; Conditioned place preference; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins; Dopamine transporter; Drug addictions; Drug reward; Female; Gene Expression Regulation; Genetic Variation; Homovanillic Acid - metabolism; Hydroxyindoleacetic Acid - metabolism; Male; Medical sciences; Membrane Glycoproteins; Membrane Transport Proteins; Mice; Mice, Inbred Strains; Mice, Transgenic; Motor Activity - drug effects; Motor Activity - genetics; MPTP; MPTP Poisoning - genetics; MPTP Poisoning - metabolism; Nerve Tissue Proteins; Promoter Regions, Genetic - genetics; Rats; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Reward; Serotonin - metabolism; Substantia Nigra - cytology; Substantia Nigra - drug effects; Substantia Nigra - enzymology; Toxicology; Transgenes - genetics; Transgenic mice; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0169-328X; 1872-6941
• DOI: 10.1016/S0169-328X(99)00235-1

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.