FUNCTIONAL GENOMICS OF COCAINE SELF ADMINISTRATION

可卡因自我服用的功能基因组学

• 批准号: 6379114
• 负责人: KENT E VRANA
• 金额: $ 32.52万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6379114
• 关键词: cocaine; dopamine receptor; drug abuse; drug tolerance; drug withdrawal; functional /structural genomics; gap junctions; gene expression; genomic imprinting; laboratory rat; limbic system; membrane channels; microarray technology; pharmacogenetics; self medication

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.

描述（申请人的摘要）：可卡因和裂缝成瘾仍然是 重大的医疗和社会问题。多巴胺转运蛋白是 被认为是急性增强作用的主要作用部位 可卡因，可卡因使用的突触后后果和神经生物学 维持成瘾过程的机制仍有待确认。这 鉴定可卡因成瘾基础的遗传成分是一个 确定治疗干预潜在目标的关键步骤。 该应用的核心假设是长期滥用药物会产生 可能导致临床问题的亚稳态表观遗传印记 耐受性，身体依赖和戒断。此申请提出 使用多重DNA杂交阵列检查功能的界面 基因组学和行为。 - 在特定的目标＃1中，DNA杂交阵列将是 用于介绍可卡因诱导的中枢神经系统表观遗传烙印 在大鼠中进行自我管理。这将在商业上实现 可用阵列和自定义阵列，印在该机构， 旨在检验有关可卡因滥用的特定假设。这些会 其次是在特定目标＃2中进行的研究，该目标检查了新的狂欢节制 可卡因给药的模型。该模型概括了几个关键功能 人类可卡因滥用（特别是行为的逐渐丧失 控制）。最后，在资金期结束时进行研究（特定目的＃3） 将建立戒烟后基因表达变化的时间过程 可卡因自我管理。这些最后的实验将提供非常 对生存的基因表达稳定变化的重要见解 长期停止药物，同时识别新基因 其表达在撤回期间发生了变化。除了 具体提出的实验，努力将与Emory协调 在资金期间，大学建立了一个中央存储库 NIDA研究社区的一般访问阵列数据 （www.arraydata.org）以及组织/RNA库。研究结果 本应用程序中的描述应提供大量信息 关于对可卡因成瘾过程的功能基因组贡献。