PHARMACOGENETICS OF COCAINE - A CRITICAL-REVIEW

The development of genetic models to help explain individual differenc es in sensitivity to and susceptibility to misuse certain CNS active s ubstances, like ethanol and psychostimulants, spans a brief, thirty-pl us years. The first animal models involved inbred strains and selected lines of mice and rats and predicted genetic-based differential sensi tivity to ethanol and its misuse in humans found a few years later. Wi th drugs like cocaine, tracking genetic differences in sensitivity and misuse liability in humans is difficult because of legal problems. Ge netically-defined animals, however, have shown most if not all of coca ine-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 dif ferences in drug sensitivity be studied from both quantitative and mol ecular genetic approaches, for the former, new techniques involving re combinant inbred strains of rodents, genetic correlational analysis an d quantitative trait loci analysis are particularly useful, especially as genetic synteny between rodents and humans becomes better describe d. Also, because drug effects are highly labile to environmental condi tions as well as genetic-based individual differences, multivariate, s ystems level studies should be developed to provide more complete desc riptive and mechanistic views of a multifaceted problem.