FUNCTIONAL GENOMICS OF COCAINE SELF ADMINISTRATION

描述(申请人摘要)：可卡因和可卡因成瘾仍然是一种 重大的医疗和社会问题。而多巴胺转运体 被认为是急性增强效应的主要作用场所 可卡因、可卡因使用的突触后后果和神经生物学 有助于成瘾过程的机制仍有待证实。这个 确定可卡因成瘾的遗传成分是一项 在确定治疗干预的潜在目标方面迈出了关键一步。 这一应用的中心假设是慢性药物滥用会产生 一种亚稳定的表观遗传学印记，可能导致临床问题，如 容忍、身体依赖和退缩。此应用程序建议 用多重DNA杂交阵列检测功能细胞的界面 基因组学和行为学。-在具体目标#1中，DNA杂交阵列将 用来描述可卡因诱导的中枢神经系统表观遗传印记 大鼠的自我给药。这将通过商业手段来实现。 可用阵列以及自定义阵列，印制在该机构和 旨在测试有关可卡因滥用的具体假设。那么这些人就会 紧随其后的是针对特定目标#2的研究，这些研究考察了一种新的狂欢禁欲 可卡因的给药模式。该模型概括了几个关键特性 人类可卡因滥用(具体地说，行为能力的逐渐丧失 控制)。最后，在资助期结束时进行研究(具体目标3) 将确定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 对存活下来的基因表达的稳定变化的重要见解 长期停药，同时识别新基因 在戒断期间，其表达会发生变化。除 具体提出的实验，努力将与埃默里协调 大学，在资助期间，建立一个中央储存库，以供 NIDA研究界一般访问的数组数据 (www.arraydata.org)以及组织/RNA库。这些研究的结果 在本申请中描述的内容应该提供丰富的信息 关于功能基因组对可卡因成瘾过程的贡献。

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.