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

Polygenic factors play important roles in animal models of substance abuse and susceptibility to dopaminergic neurodegeneration. Genetic factors are a lso likely to contribute to the etiology of human drug abuse disorders, and may alter human vulnerabilities to Parkinsonian neurodegeneration. The dop amine transporter (DAT; SLC6A3) is densely expressed by the dopaminergic mi dbrain 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 expr essed on neurons that are the primary targets of Parkinsonian neurodegenera tion. To study possible influences of variant DAT expression on these proce sses, we have constructed transgenic mice (THDAT) in which tyrosine hydroxy lase (TH) promoter sequences drive expression of a rat DAT cDNA variant, in crease 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 di splay enhanced reward conferred by cocaine, as measured by conditioned plac e preference. However, locomotor responses to cocaine administration are si milar to those of wildtype mice, except at high cocaine doses. THDAT mice d isplay more than 50% greater losses of dopaminergic neurons following a cou rse of MPTP treatment than do wildtype control mice. These results document a model for allelic variation at a gene locus that can exert significant e ffects in murine models of human substance abuse vulnerability and dopamine rgic neurodegeneration. (C) 1999 Elsevier Science B.V. All rights reserved.