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.

这些研究旨在调查可卡因的长期后果 和阿片类药物给药对多巴胺能功能分子指标的影响。 药物滥用研究的一个中心问题是确定药物滥用的慢性程度 药物管理会改变大脑，以考虑长期的问题 身体依赖、心理成瘾、耐受性问题。 一种假设是这些药物会产生表观遗传印记。那是， 长期服用药物会改变基因表达模式 RNA 和蛋白质的水平——从而改变细胞的状态 脑。中心申请的这一部分提出的实验 旨在以多学科的方式解决这个问题 基于公认的药物滥用的神经解剖学基础 - 中脑边缘多巴胺通路。利用重组 DNA 研究工具 结合上一个融资周期制定的 灵长类动物和啮齿动物研究人员的设施和专业知识 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 在非人类灵长类动物中的表达。以此为基础继续前人的研究 实验室和中心内的其他人员，SA #2 将检查长期 托烷类似物给药的表观遗传后果 与可卡因不同的药代动力学和转运蛋白选择性。 计划进一步进行实验以确定分子相关性 根据上下文观察到的生理和神经化学差异 的药物管理。因此，SA #3 将建立 表观遗传印记之间的关系依赖于反应（自我 给药）与反应无关的可卡因给药 啮齿动物。 Finally, SA #4 will examine the hypothesis that opiate 给药可以改变多巴胺能功能的分子指数。这些 研究将继续我们在了解多久- 术语药物管理会影响神经元设定点以及这可能如何 考虑长期药物滥用负债。