Functional Genomics of Cocaine Self-Administration

可卡因自我给药的功能基因组学

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：可卡因滥用仍然是一个重大的社会问题。该研究计划的一个核心主题，以及这种更新应用的主要假设是，慢性可卡因滥用会在中枢神经系统基因表达中产生重大变化，这有助于临床问题，例如耐受性，敏感性，身体依赖，渴望和戒断。初步发现增加了中枢神经系统中可卡因反应性基因表达的数据库。在本应用程序中提出了实验，以扩展这些发现，以识别那些在对可卡因自我管理强制戒酒后表达改变的基因。为此，已经开发出一种新的行为范式，在这种行为范式中，可卡因在大鼠中的狂饮模式，随后是禁欲时期，产生了一种行为敏感性，显示出在人类中成瘾过程的某些标志。将检查这种强大的行为模型，以识别那些在停止药物后表现出持续变化的基因。第一个实验将检查已知可卡因响应基因的表达，以查看它们是否与行为敏化相关。这些研究将重点放在伏隔核（核心和壳），内侧前额叶皮层，海马和杏仁核作为行为扰动的神经解剖底物。此外，随后的研究将集中于建立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？），以及（b）确定更改首先变化的时间（弃权期之前或期间？）。第二系列研究将使用新的Affymetrix Genechip Technologies（一次14,280个基因）来识别可能受到协调调节的基因家族，并确定可卡因效应的新颖靶标。提出的实验将继续为我们理解基因组学在建立和维持可卡因成瘾中的作用。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.