EPIGENETIC IMPRINTING BY CHRONIC DRUGS OF ABUSE

这些研究建议调查可卡因的长期后果 和阿片剂给药对多巴胺能功能的分子指标的影响。 药物滥用研究的一个中心问题是确定慢性药物滥用 药物管理改变大脑，以解释长期的 身体依赖、心理成瘾和耐受性问题。 一种假设是，这些药物会产生一种表观遗传印记。也就是说， 长期服用药物改变了基因表达的模式， RNA和蛋白质的水平-这样它们就改变了 个脑袋中心申请书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， 在一个公认的药物滥用的神经解剖学基础上， 中脑边缘多巴胺通路利用重组DNA研究工具 在上一个供资周期制定的方案， 灵长类动物和啮齿类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。从这一点上进行先前的研究 实验室和中心内的其他人，SA #2将检查长期 给予托烷类似物的表观遗传学后果 与可卡因不同的药代动力学和转运体选择性。 计划进行进一步的实验，以确定分子相关性， 根据上下文观察到的生理和神经化学差异 药物管理。因此，SA#3将建立 表观遗传印记与反应依赖（自我， 与非反应依赖性可卡因给药相比， 啮齿动物。最后，SA #4将检验阿片类药物 给药可以改变多巴胺能功能的分子指数。这些 我们会继续进行研究，以了解需要多久- 长期给药会影响神经元的设定点， 考虑长期药物滥用负债。

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.