Genes Regulated By Abused Drugs

滥用药物会通过生化机制对行为产生长期的改变，而这些机制在很大程度上是未知的。药物改变了大脑中特定基因表达的变化，可以为成瘾的可能生化基础提供一个主要窗口。在这一年中，我们加强了候选基因和表达受安非他明、可卡因和吗啡调节的基因家族的表征，特别是那些在染色体区域使它们候选包含可能易导致人类成瘾脆弱性的人类个体变异的基因。在本实验室的人类基因组扫描研究中，我们加强了与人类药物滥用脆弱性相关的吗啡调节基因NrCAM的人类单倍型鉴定。在这一年中，我们报道了GBPI基因作为KEPI家族成员，在磷酸化时是蛋白磷酸酶1活性的强大抑制剂，并在肠道和大脑中表达。我们已经确定了另一种“细胞粘附”分子基因PTPRbeta的药物调控；PTPRbeta单倍型也与人类成瘾易感性的个体差异有关。这些数据为进一步研究人类药物滥用脆弱性基因组扫描和成瘾神经生物学机制提供了强有力的基础。

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 i 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 have 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.