Genes Regulated By Abused Drugs

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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, especially those in chromosomal regions that make them candidates to contain human individual variants that migh predisopase 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. During this year, we reported the GBPI gene as a KEPI family member that is powerful inhibitor of protein phosphatase 1 activity when phosphorylated and is expressed in gut and in brain. 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.