Genes Regulated By Abused Drugs

滥用药物通过在很大程度上不为人所知的生化机制，在行为上产生长期的变化。药物改变大脑中特定基因的表达变化，可以为吸毒的可能生化底物提供一个主要窗口。在这一年里，我们加强了候选基因和其表达受苯丙胺、可卡因和吗啡调控的基因家族的特征，特别是那些使它们成为候选基因的I染色体区域，这些区域包含可能导致人类成瘾易感性的人类个体变异。在本实验室的人类基因组扫描研究中，我们加强了对吗啡调节基因NrCAM中人类单倍型的鉴定，该基因与人类物质滥用的脆弱性有关。在这一年里，我们已经报道了GBPI基因是一个KEPI家族成员，当被磷酸化时，它是蛋白磷酸酶1活性的强大抑制者，并且在肠道和脑中表达。我们已经确定了另一种“细胞黏附”分子基因PTPRbeta的药物调节作用；PTPRbeta单倍型也与人类成瘾易感性的个体差异有关。这些数据为进一步与人类药物滥用脆弱性的研究、基因组扫描和成瘾神经生物学机制的研究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.