Functional Genomics of Cocaine Self-Administration

可卡因自我给药的功能基因组学

• 批准号: 7104824
• 负责人: KENT E VRANA
• 金额: $ 25.74万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104824
• 关键词: amygdala; behavioral /social science research tag; behavioral habituation /sensitization; cocaine; drug abuse; functional /structural genomics; gene expression; hippocampus; laboratory rat; microarray technology; neuropharmacology; nucleus accumbens; pharmacogenetics; prefrontal lobe /cortex; self medication; substance abuse related behavior

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.

描述(申请人提供)：可卡因滥用仍然是一个严重的社会问题。这项研究计划的一个中心主题，也是这次更新应用的主要假设是，慢性可卡因滥用会导致中枢神经系统基因表达的显著变化，从而导致临床问题，如耐受性、敏感化、身体依赖、渴望和戒断。关于中枢神经系统中可卡因反应基因表达的数据库不断增长，初步发现增加了这一发现。在本申请中，有人提议进行实验，扩展这些发现，以确定在强制戒除可卡因自我给药后表达发生变化的基因。为了实现这一点，已经开发了一种新的行为范式，在这种范式中，大鼠自我服用可卡因的狂欢模式，然后是一段时间的禁欲，产生了一种行为敏感化，显示出人类成瘾过程的一些特征。这一强大的行为模型将被用来识别那些在停止给药后基因表达持续变化的基因。第一系列实验将检查已知的可卡因反应基因的表达，以确定它们是否与行为敏化相关。研究将集中在伏隔核(核心和外壳)、内侧前额叶皮质、海马体和杏仁核作为行为扰动的神经解剖学基础。此外，后续研究将集中于确定基因表达的时间进程，以(A)确定变化的限度(它们将持续多长时间？)，以及(B)确定变化第一次变得明显的时间(在戒断期之前或期间？)。第二系列研究将使用新的Affymetrix基因芯片技术(一次14280个基因)来确定可能受到协调调控的基因家族，并确定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方面的作用。

项目成果

Gene expression changes following extinction testing in a heroin behavioral incubation model.

• DOI: 10.1186/1471-2202-10-95
• 发表时间: 2009-08-07
• 期刊: BMC neuroscience
• 影响因子: 2.4
• 作者: Kuntz-Melcavage KL;Brucklacher RM;Grigson PS;Freeman WM;Vrana KE
• 通讯作者: Vrana KE

Persistent proteomic alterations in the medial prefrontal cortex with abstinence from cocaine self-administration.

• DOI: 10.1002/prca.200800055
• 发表时间: 2009-03-17
• 期刊: PROTEOMICS CLINICAL APPLICATIONS
• 影响因子: 2
• 作者: Lull, Melinda E.;Erwin, Mandi S.;Morgan, Drake;Roberts, David C. S.;Vrana, Kent E.;Freeman, Willard M.
• 通讯作者: Freeman, Willard M.

Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration.

• DOI: 10.1186/1471-2202-11-29
• 发表时间: 2010-02-26
• 期刊: BMC neuroscience
• 影响因子: 2.4
• 作者: Freeman WM;Lull ME;Patel KM;Brucklacher RM;Morgan D;Roberts DC;Vrana KE
• 通讯作者: Vrana KE