Abused drugs produce long-lasting changes in behaviors via biochemical mechanisms that are largely unknown. Drug-altered changes in expression of specific genes in the brain can provide a major window on possible biochemical substrates for ddiction. During this year, we have enhanced characterization of candidate genes and the families of genes whose expression is regulated by amphetamine, cocaine and morphine. We have especially focused on drug-regulated genes in chromosomal regions that make them candidates to contain human individual variants that predispose to human addiction vulnerabilities. We have strengthened identification of human haplotypes in the morphine-regulated gene, NrCAM, that is associated with human substance abuse vulnerability in human genome scanning studies from this laboratory and reported this work during this year. During this year, we reported the brain distribution of and developed knockout mice for the morphine-regulated gene KEPI,a powerful inhibitor of protein phosphatase 1 activity. KEPI knockout mice are viable, fertile, and can be tested for drug related and memory related phenotypes. We reviewed the gene families that these studies have identified in a well-cited review. We have identified drug-regulation of another """"""""cell adhesion"""""""" molecule gene, PTPRbeta; PTPRbeta haplotypes are also associated with individual differences in human addiction vulnerability. These data provide powerful substrates for further convergence with studies of human drug abuse vulnerability genome scans and with studies of mechanisms of addiction neurobiology.
