Pharmacogenetics of cocaine: a critical review.

The development of genetic models to help explain individual differences in sensitivity to and susceptibility to misuse certain CNS active substances, like ethanol and psychostimulants, spans a brief, thirty-plus years. The first animal models involved inbred strains and selected lines of mice and rats and predicted genetic-based differential sensitivity to ethanol and its misuse in humans found a few years later. With drugs like cocaine, tracking genetic differences in sensitivity and misuse liability in humans is difficult because of legal problems. Genetically-defined animals, however, have shown most if not all of cocaine-related behavioural, neurophysiological and toxicological effects to evince wide variation with most effects being influenced by several genes. Thus, we argue that animal and human studies of individual differences in drug sensitivity be studied from both quantitative and molecular genetic approaches. For the former, new techniques involving recombinant inbred strains of rodents, genetic correlational analysis and quantitative trait loci analysis are particularly useful, especially as genetic synteny between rodents and humans becomes better described. Also, because drug effects are highly labile to environmental conditions as well as genetic-based individual differences, multivariate, systems level studies should be developed to provide more complete descriptive and mechanistic views of a multifaceted problem.