Molecular and Genetic Adaptations Associated with Compulsive Cocaine Intake

与强迫性可卡因摄入相关的分子和遗传适应

基本信息

批准号：
7566001
负责人：
Wei-Dong Yao
金额：
$ 38.26万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-10 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7566001
关键词：
Behavioral Paradigm Brain Brain Diseases Candidate Disease Gene Chronic Cocaine Cocaine Abuse Cocaine Dependence Complex Dopamine Drug Exposure Drug usage Environmental Risk Factor Experimental Designs Gene Chips Gene Expression Gene Expression Profile Genes Genome Glutamates Immunoblotting In Situ Hybridization Individual Injection of therapeutic agent Intake Macaca mulatta Mediating Medical Modeling Molecular Molecular Genetics Molecular Profiling Monkeys Mus Neurobiology Outcomes Research Pattern Pharmaceutical Preparations Physiological Primates Procedures Regulation Research Rewards Role Saline Self Administration Self-Administered Staging Structure Sucrose System Techniques Testing Time addiction base cocaine exposure cocaine use density dopamine system effective therapy genome-wide neuroadaptation neurochemistry non-drug nonhuman primate novel novel strategies recreational drug use reinforcer reward circuitry social socioeconomics theories

项目摘要

DESCRIPTION (provided by applicant): A central feature of addiction is compulsive drug taking, characterized by loss of control over drug use despite adverse physiological and social consequences. A prevailing theory in the neurobiology of cocaine addiction is that repeated drug exposure imposes persistent neurochemical and molecular changes, e.g. altered gene expression, in the mesocorticolimbic brain circuitry underlying reward. These cocaine-induced neuroadaptations may contribute to the complex manifestations of addiction but are poorly defined, especially in primates. The purpose of this application is to comprehensively investigate gene expression dysregulation within the reward circuit that may mediate compulsive cocaine taking, using nonhuman primate models of moderate or excessive cocaine self-administration. Monkeys self-administering cocaine will be yoked to monkeys passively receiving cocaine or saline injections for different exposure periods that reflect initial stages of addiction, or "recreational", drug use and more chronic cocaine use associated with addiction. A similar study will be conducted in which monkeys self-administer a non-drug reinforcer (sucrose pellets). We postulate that a dysregulation of the dopamine (DA) and glutamate (Glu) systems is associated with chronic cocaine taking. We further postulate that ensemble adaptations in multiple brain structures within the reward circuit as a consequence of DA/Glu dysregulation may accompany chronic cocaine taking. We specifically will investigate adaptations in mesocorticolimbic DA and Glu systems induced by initial and chronic cocaine self-administration by characterizing changes in key components of DA and Glu systems using in situ hybridization, quantitative PCR, and immunoblotting (Aim I). Aim II will define gene expression patterns at the genome level associated with initial and chronic cocaine self-administration, using a newly developed Rhesus Macaque Gene Chip. Successful completion of the proposed research will provide an integrated assessment of the DA and Glu systems, identify individual novel dysregulated gene candidates, and provide a near genome view of transcriptome changes associated with the reinforcing effects of cocaine in multiple brain structures within the reward circuit. The outcome of the research should deepen our understanding of the molecular and cellular basis of compulsive drug taking.

描述（由申请人提供）：成瘾的一个核心特征是强迫性药物服用，其特征是尽管生理和社会后果不利，但对药物使用的控制丧失。可卡因成瘾神经生物学中的一种流行理论是，反复的药物暴露施加了持续的神经化学和分子变化，例如基因表达的改变，在奖励的中质体脑电路中。这些可卡因诱导的神经适应可能有助于成瘾的复杂表现，但定义很差，尤其是在灵长类动物中。本应用的目的是使用中度或过度可卡因自我给药的非人类灵长类动物模型，全面研究奖励电路中可能介导强迫可卡因的基因表达失调。猴子自我管理可卡因将在不同的暴露期间被动接受可卡因或盐水注射的猴子，反映了成瘾的初始阶段，或“休闲”，药物使用和更多与成瘾相关的慢性可卡因使用。将进行类似的研究，其中猴子自助剂是非药水增强剂（蔗糖颗粒）。我们假设多巴胺（DA）和谷氨酸（GLU）系统的失调与慢性可卡因服用有关。我们进一步假设，由于DA/GLU失调可能伴随着慢性可卡因，因此奖励电路中多个大脑结构的整体适应。我们将通过原位杂交，定量PCR和免疫印迹来表征DA和GLU系统的关键组件的变化，并通过表征DA和GLU系统的关键组件的变化来调查由初始和慢性可卡因自我给药引起的中皮质胶DA和GLU系统的适应。 AIM II将使用新开发的恒河猴基因芯片在与初始和慢性可卡因自我给药相关的基因组水平上定义基因表达模式。拟议研究的成功完成将提供对DA和GLU系统的综合评估，确定单个新型的基因候选基因的失调，并提供了与可卡因在奖励电路中多个大脑结构中增强效应相关的转录组变化的近乎基因组观点。研究的结果应加深我们对服用强迫性药物的分子和细胞基础的理解。