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。我们特别关注染色体区域的药物调控基因，这些基因使它们成为包含容易导致人类成瘾的人类个体变异的候选基因。在本实验室的人类基因组扫描研究中，我们加强了对人类吗啡调控基因NrCAM中与人类物质滥用脆弱性相关的单倍型的识别，并在今年报告了这项工作。在这一年里，我们报道了吗啡调节基因kepi的大脑分布和培育，kepi基因是一种强大的蛋白磷酸酶1活性抑制因子。Kepi基因敲除小鼠是存活的、有生育能力的，可以测试与药物和记忆相关的表型。我们回顾了这些研究在一篇被广泛引用的综述中发现的基因家族。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. 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.