FUNCTIONAL GENOMICS OF COCAINE SELF ADMINISTRATION

描述（申请人的摘要）：可卡因和快克成瘾仍然是一个问题。 严重医疗和社会问题。而多巴胺转运蛋白 被认为是急性增强效应的主要作用部位， 可卡因，可卡因使用的突触后后果和 促进成瘾过程的机制仍有待证实。的 确定可卡因成瘾背后的遗传成分是一个 这是确定治疗干预的潜在靶点的关键步骤。 这一应用的中心假设是，慢性药物滥用产生 亚稳定的表观遗传印记，可能导致临床问题， 耐受性、身体依赖性和戒断。本申请建议 使用多重DNA杂交阵列来检查功能界面， 基因组学和行为。- 在具体目标#1中，DNA杂交阵列将被 用于分析可卡因诱导的CNS表观遗传印记 大鼠自身给药。这将通过商业上使用 可用的阵列以及定制阵列，在这个机构印， 旨在检验关于可卡因滥用的特定假设。这些将 随后是具体目标2中的研究，该研究检查了一种新的狂欢禁欲 可卡因管理模式。该模型概括了几个关键特征 人类可卡因滥用（特别是，行为的逐渐丧失） 对照）。最后，资助期结束时的研究（具体目标3） 将建立停药后基因表达变化的时间进程 可卡因的自我管理。这些最后的实验将提供非常 对基因表达的稳定变化的重要见解， 长期停药，同时发现新的基因 在停药期间其表达发生改变。除了有 具体建议的实验，努力将与埃默里大学协调 在拨款期内，大学须设立一个中央资料库， 供NIDA研究团体一般访问的数组数据 （www.arraydata.org）以及组织/RNA库。研究结果 在本申请中描述的技术应当提供丰富的信息 关于可卡因成瘾过程的功能性基因组贡献。

DESCRIPTION (Applicant's Abstract): Cocaine and crack addiction remains a significant medical and social problem. While the dopamine transporter is thought to be the primary site of action for the acute reinforcing effects of cocaine, the post-synaptic consequences of cocaine use and the neurobiological mechanisms that subserve the addictive process remain to be confirmed. The identification of the genetic components underlying cocaine addiction is a critical step in identifying potential targets for therapeutic intervention. The central hypothesis of this application is that chronic drug abuse produces a metastable epigenetic imprint that may contribute to clinical issues such as tolerance, physical dependence, and withdrawal. This application proposes to use multiplex DNA hybridization arrays to examine the interface of functional genomics and behavior. - In Specific Aim # 1, DNA hybridization arrays will be used to profile the CNS epigenetic imprint induced by cocaine self-administration in rats. This will be accomplished using commercially available arrays as well as custom arrays, imprinted at this institution and designed to test specific hypotheses regarding cocaine abuse. These will then be followed by studies in Specific Aim #2 that examine a new binge abstinence model of cocaine administration. This model recapitulates several key features of human cocaine abuse (specifically, the progressive loss of behavioral control). Finally, studies at the end of the funding period (Specific Aim #3) will establish the time course for gene expression changes following cessation of cocaine self-administration. These last experiments will provide very important insights into the stable changes in gene expression that survive long-term cessation of the drug, while simultaneously identifying new genes whose expression is altered during the withdrawal period. In addition to the specific proposed experiments, efforts will be coordinated with Emory University, during the funding period, to establish a central repository for array data for general access by the NIDA research community (www.arraydata.org) as well as a tissue/RNA bank. The results of the studies described within the present application should provide a wealth of information concerning functional genomic contributions to the cocaine addiction process.