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。这个研究项目的一个中心主题，也是这个更新应用的主要假设，是慢性可卡因滥用会产生CNS基因表达的显著变化，从而导致临床问题，如耐受性、敏化、身体依赖、渴望和戒断。初步的研究结果增加了对中枢神经系统中可卡因反应性基因表达的数据库。在目前的应用中，提出了实验，将这些发现扩展到识别那些在强制戒除可卡因自我管理后表达改变的基因。为了实现这一目标，一种新的行为模式已经被开发出来，在这种模式下，大鼠自我服用可卡因的暴食模式，随后是一段时间的戒断，产生了一种行为敏感性，表现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变化的基因表达后停止给药。第一个系列的实验将检查已知的可卡因反应基因的表达，看看它们是否与行为敏感相关。研究将集中在伏隔核（核和壳）、内侧前额皮质、海马体和杏仁核作为行为扰动的神经解剖学基础。此外，后续的研究将集中于确定基因表达的时间过程，以(a)确定改变的限制（它们将持续多长时间？）和(b)确定变化首次显现的时间（在禁欲期之前或期间？）。第二系列研究将使用新的Affymetrix基因芯片技术（一次14280个基因）来确定可能被协调调节的基因家族，并确定可卡因作用的新目标。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.