EPIGENETIC IMPRINTING BY CHRONIC DRUGS OF ABUSE

这些研究建议调查可卡因的长期后果。 阿片类药物给药对多巴胺能功能分子指标的影响。 物质滥用研究中的一个中心问题是确定慢性 给药改变了大脑，以解决长期的 身体上的依赖、心理上的成瘾和耐受性的问题。 一种假设是，这些药物会产生表观遗传印记。那是, 长期服药改变了基因的表达模式-- RNA和蛋白质的水平-这样它们就会改变细胞的状态 大脑。中心申请的这一部分中提出的实验 旨在以多学科的方式解决这一问题 关于物质滥用的公认神经解剖学基础-- 中脑边缘多巴胺通路。利用重组DNA研究工具 在上一个供资周期期间制定的，与 灵长类和啮齿动物调查人员的设施和专业知识 为了建立该中心，将实现以下具体目标。在SA#1中，我们 将检验慢性可卡因调节多巴胺能基因的假设 在非人灵长类动物中的表达。从这一点追寻以前的研究 实验室和中心内的其他人，SA#2将检查长期 服用托烷类似物显著的表观遗传学后果 不同于可卡因的药物动力学和转运体选择性。 计划进行进一步的实验，以确定分子与 根据上下文观察到的生理和神经化学差异 药品管理部门的。因此，SA#3将建立 表观遗传印记与反应依赖(自体) 管理)与反应独立的可卡因管理 啮齿动物。最后，SA#4将检验阿片类药物的假设 给药可改变多巴胺能功能的分子指标。这些 研究将继续我们在理解多长时间- 术语给药影响神经元设定点及其可能的影响 对长期滥用药物的责任负责。

These studies propose to investigate the long-term consequences of cocaine and opiate administration on molecular indices of dopaminergic function. A central problem in substance abuse research is identifying how chronic drug administration changes the brain so as to account for the long-term problems of physical dependence, psychological addiction, and tolerance. One hypothesis is that the drugs create an epigenetic imprint. That is, the chronic administration of drug alters the pattern of gene expression- the levels of RNA and protein- such that they change the state of the brain. The experiments proposed in this portion of the center application are designed to address this issue in a multi-disciplinary way by focusing on a recognized neuroanatomical substrate of substance abuse- the mesolimbic dopamine pathway. Utilizing recombinant DNA research tools developed during the last funding cycle, in combination with the facilities and expertise of both primate and rodent investigators within the Center, the following specific aims will be undertaken. In SA #1, we will test the hypothesis that chronic cocaine regulates dopaminergic gene expression in the non-human primate. Pursuing previous studies from this laboratory and others within the Center, SA #2 will examine the long-term epigenetic consequences of administration of tropane analogs with markedly different pharmacokinetics and transporter selectivity than cocaine. Further experiments are planned to identify molecular correlates for physiological and neurochemical disparities observed based on the context of drug administration. Accordingly, SA #3 will establish the relationships between epigenetic imprinting by response-dependent (self- administration) versus response-independent cocaine administration in the rodent. Finally, SA #4 will examine the hypothesis that opiate administration can alter molecular indices f dopaminergic function. These studies will continue the progress we have made in understanding how long- term drug administration affects neuronal set-points and how this might account for long-term drug abuse liabilities.