Functional Genomics of Cocaine Self-Administration

描述（由申请人提供）：可卡因滥用仍然是一个重大的社会问题。这项研究计划的一个中心主题，以及这项更新申请的主要假设是，慢性可卡因滥用会导致CNS基因表达发生显著变化，从而导致耐受性、致敏性、身体依赖性、渴望和戒断等临床问题。初步的发现增加了中枢神经系统中可卡因反应基因表达的数据库。在本申请中，提出了实验，扩展这些发现以鉴定在强制戒除可卡因自我给药后表达发生改变的那些基因。为了实现这一点，已经开发了一种新的行为模式，其中大鼠自我给予可卡因的狂欢模式，随后是一段时间的禁欲，产生了行为敏化，显示出人类成瘾过程的一些特征。这个强大的行为模型将被检查，以确定那些基因表现出持续的变化，在停止给药后的基因表达。第一系列实验将检查已知可卡因反应基因的表达，以确定它们是否与行为敏化相关。这些研究将集中在作为行为扰动的神经解剖学基底的丘脑核（核和壳）、内侧前额叶皮质、海马和杏仁核。此外，随后的研究将集中于建立基因表达的时间过程，以（a）建立改变的限度（它们将持续多久？），和（B）确定变化首次变得明显的时间（在禁欲期之前或期间？）。第二个系列的研究将使用新的Affyscore基因芯片技术（一次14，280个基因）来识别可能协调调节的基因家族，并识别可卡因作用的新靶点。拟议的实验将继续有助于我们理解基因组学在建立和维持可卡因成瘾中的作用。

DESCRIPTION (provided by applicant): Cocaine abuse remains a significant societal problem. A central theme of this research program, and the main hypothesis of this renewal application, is that chronic cocaine abuse produces significant changes in CNS gene expression that contribute to clinical issues such as tolerance, sensitization, physical dependence, craving, and withdrawal. Preliminary findings have added to the growing database on cocaine-responsive gene expression in the central nervous system. Experiments are proposed, within the present application, that extend these findings to identify those genes whose expression is altered following an enforced abstinence from cocaine self-administration. To accomplish this, a new behavioral paradigm has been developed in which a binge pattern of cocaine self-administration in rats, followed by a period of abstinence, produces a behavioral sensitization that displays some of the hallmarks of the addictive process in humans. This powerful behavioral model will be examined to identify those genes exhibiting persistent changes in gene expression following cessation of drug administration. The first series of experiments will examine the expression of known cocaine-responsive genes to see if they correlate with the behavioral sensitization. The studies will focus on the nucleus accumbens (core and shell), medial prefrontal cortex, hippocampus, and amygdala as neuroanatomical substrates of the behavioral perturbation. In addition, subsequent studies will concentrate on establishing the temporal course of gene expression to (a) establish the limits of the alterations (how long will they last?), and (b) determine the time at which the changes first become manifest (before or during the abstinence period?). The second series of studies will use new Affymetrix GeneChip technologies (14,280 genes at a time) to identify families of genes that may be coordinately regulated and to identify novel targets of cocaine's effects. The proposed experiments will continue to contribute to our understanding of the role of genomics in establishing and maintaining cocaine addiction.