Dopaminergic Genes and Substance Abuse

Abstract

Publisher Summary This chapter reviews several recent cases in which transgenic mouse and human data provide increasingly compelling evidence that variants in genes important for dopaminergic neurotransmission are strong candidates to contribute to interindividual differences in drug abuse vulnerabilities. Studies of cocaine's primary site for reward and reinforcement in the brain have focused on the dopamine transporter (DAT). In studying this transporter, the effects of several mutations on transporter function have been characterized. To model the effects that a DAT gene variant might have on drug abuse phenotypes, the researchers have constructed transgenic animals that express this DAT variant in catecholaminergic neurons. In these animals, although baseline locomotor activities are altered, cocaine induces virtually no excess locomotion. Vesicular monoamine stores accumulated by normal vesicular monoamine transporter (VMAT2) function may play significant roles in the locomotor stimulation and/or the behavioral reward produced by amphetamines. Catechol-O-Methyltransferase (COMT) is expressed in dopaminergic brain regions, where its activity provides a major pathway by which extraneuronally released dopamine is inactivated. Significant differences in the distributions of both COMT genotypes and allele frequencies between controls and substance abusers have been identified. The data suggest that high COMT activities might contribute to the genetic underpinnings of drug abuse vulnerability. Thus the chapter supports potentially prominent roles for dopaminergic gene variants in contributing to individual differences in vulnerability to drug abuse. However, other genes are quite likely also to be involved.