EPIGENETIC IMPRINTING BY CHRONIC DRUGS OF ABUSE

慢性药物滥用造成的表观遗传印记

• 批准号: 6332490
• 负责人: KENT E VRANA
• 金额: $ 19.12万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6332490
• 关键词: Macaca fascicularis; animal tissue; cocaine; dopamine receptor; dopamine transporter; drug abuse; drug administration rate /duration; gene expression; genetic regulation; genomic imprinting; laboratory rat; pharmacogenetics; pharmacokinetics; polymerase chain reaction; recombinant DNA; reinforcer; tropanes; tyrosine 3 monooxygenase; western blottings

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.

这些研究建议研究可卡因的长期后果 和阿片类分子指数多巴胺能功能的施用。 药物滥用研究中的一个核心问题是确定如何慢性 药物管理局改变了大脑，以说明长期 身体依赖，心理成瘾和宽容的问题。 一种假设是这些药物会产生表观遗传印记。那是， 药物的长期给药改变了基因表达的模式 - RNA和蛋白质的水平使它们改变了 脑。中心申请的这一部分提出的实验 旨在通过集中精力以多学科的方式解决这个问题 在公认的药物滥用神经解剖学基质上 - 中唇多巴胺途径。利用重组DNA研究工具 在最后一个资金周期中开发，结合 灵长类动物和啮齿动物调查员的设施和专业知识 中心将实现以下特定目标。在SA＃1中，我们 将测试慢性可卡因调节多巴胺能基因的假设 在非人类灵长类动物中的表达。从中追求以前的研究 SA＃2的实验室和其他中心的其他人将检查长期 施用tropane类似物的表观遗传学后果明显 与可卡因不同的药代动力学和转运蛋白的选择性。 计划进一步实验以鉴定分子相关 根据环境观察到的生理和神经化学差异 药物管理局。因此，SA＃3将建立 依赖反应依赖性的表观遗传印迹之间的关系（自我 给药）与无反应的无可卡因给药 啮齿动物。最后，SA＃4将研究鸦片的假设 给药可以改变分子指数F多巴胺能功能。这些 研究将继续我们在理解长期的过程中取得的进步 药物管理术语会影响神经元设定点以及如何可能 负责长期药物滥用责任。