Drug abuse vulnerability, like many behavioral disorders, is likely influenced by genetic and environmental factors

Data from family, twin and adoption studies indicate significant genetic contributions to several drug abuse phenotypes [28]. In animal models of substance abuse, genetic influences on drug abuse behaviors can be ascertained by strain comparison, selective breeding, quantitative trait locus, overexpression-transgenic and knockout-transgenic mouse studies [16,29].

Identifying which gene variants contribute to these individual differences in vulnerability to drug abuse provides a major current challenge to drug abuse research. Approaches to studying this problem in humans and in animal models have focused attention on several classes of candidate genes. These include genes that encode for drug receptors and genes expressed in the dopamine brain systems that may play such prominent roles in the reward exerted by abused drugs of a number of different chemical classes. Genes whose expression is altered by administration of abused substances are also candidates for human studies, as are mouse drug abuse vulnerability loci identified by quantitative trait locus approaches.

Studies in transgenic mice in which expression of specific genes is specifically modified can aid in nominating candidate genes for studies in humans. Altered expression of specific dopaminergic genes can substantially influence behavioral responses in principal models of drug abuse vulnerability [9–11]. Studies of the sites for cocaine and amphetamine reward and reinforcement in the brain have focused on actions at the plasma membrane DAT and serotonin transporters (SERT) and on the synaptic vesicles, whose transmitter content is regulated by the synaptic vesicular monoamine transporter, and on dopamine receptors, including D1 and D2 family members [30] (see Chap. 12). Mice overexpressing DAT in catecholaminergic neurons show significantly greater cocaine preference than control mice, although DAT knockout mice retain their reward response to cocaine. Conversely, mice with reduced expression of the synaptic vesicular monoamine transporter gene show no effect on cocaine reward but do manifest reduced amphetamine reward [11]. Mice with dopamine D1 receptor knockouts show slower acquisition of cocaine self-administration but ultimate expression of cocaine reward similar to that of control mice [30].

Human studies of functional allelic differences in the genes expressed in dopamine circuits provide an example of a provisional association of a functional gene variant with substance abuse vulnerability. In initial studies, the proportions of a high activity of the human dopamine-metabolizing gene catechol-O-methyltransferase were nearly twice as frequent in polysubstance abusers as in controls free from such use [31]. Replication of this result and identification of genes contributing to complex behavioral disorders will likely permit us to further understand disease nosology, to improve prevention strategies and to better target behavioral and pharmacological treatments (see Box 53-1).