Genes Regulated By Abused Drugs

滥用药物通过生化机制产生持久的行为变化，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，可以为药物成瘾的可能生化底物提供一个重要的窗口。在这一年中，我们加强了对候选基因和基因家族的表征，这些基因的表达受到安非他明、可卡因和吗啡的调节，特别是那些位于染色体区域的基因，这些基因使它们成为含有人类个体变异的候选基因，这些变异可能导致人类成瘾的脆弱性。我们加强了对吗啡调节基因NrCAM中人类单倍型的鉴定，该基因与本实验室人类基因组扫描研究中人类药物滥用脆弱性相关。在这一年中，我们报道了GBPI基因作为KEPI家族成员，其在磷酸化时是蛋白磷酸酶1活性的强效抑制剂，并在肠道和大脑中表达。我们已经确定了另一个“细胞粘附”分子基因PTPR β的药物调节; PTPR β单倍型也与人类成瘾易感性的个体差异有关。这些数据提供了强有力的基板进一步融合与人类药物滥用脆弱性基因组扫描的研究和成瘾神经生物学机制的研究。

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.