DRUG SELF-ADMINISTRATION /DOPAMINE TRANSPORTER /CONNEXIN

自我给药/多巴胺转运蛋白/CONNEXIN

• 批准号: 6695724
• 负责人: David Charles Stephen Roberts
• 金额: $ 20.6万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6695724
• 关键词: behavioral /social science research tag; cocaine; dopamine; dopamine transporter; drug abuse; drug addiction; drug tolerance; electrochemistry; electrophysiology; gap junctions; heroin; immunocytochemistry; laboratory rat; membrane channels; motivation; neurobiology; neuropharmacology; nucleus accumbens; psychopharmacology; reinforcer; sectioning; self medication; tissue /cell preparation; western blottings

Identifying the brain mechanisms that underlie drug addiction (a behaviorally defined disorder) requires neurobiological and behavioral tools of equal sophistication. This project will combine rigorous analytic techniques with a newly developed behavioral model that reveals an increased motivation to self-administer cocaine over time. The work will follow up on recent observations on two distinctly different neural systems. The first result is from a voltammetric analysis of nucleus accumbens slices from animals that have self-administered cocaine. The data demonstrate that autoreceptor function is down regulated during the 'incubation' or drug free phase, corresponding to a critical time period when the reinforcing efficacy of cocaine increases. Several voltammetric approaches (brain slices, in vivo anesthetized, freely moving animals) will be used to examine changes in the physiology of dopamine terminals at time points when rats are either tolerant or sensitized to the reinforcing effects of cocaine. Changes in the function of the dopamine system may contribute to the altered reinforcing efficacy of cocaine. A growing number of observations continue to confirm that gap junctions in brain change in response to drugs of abuse. Changes in gap junction proteins (connexins) will be examined after cocaine, heroin and speedbail self-administration across behaviorally relevant time points. Western blots and imunnohistochemical analysis will be used to assess regionally specific effects of connexin32 and connexin36 expression. This project will share tissue with subproject 0008 (Vrana) in which connexin RNAs and general proteomic screening will be performed.

确定构成药物成瘾（行为定义的疾病）的大脑机制需要同等成熟的神经生物学和行为工具。该项目将将严格的分析技术与新开发的行为模型相结合，该模型揭示了随着时间的推移自我管理可卡因的动机。这项工作将跟进最近对两个截然不同的神经系统的观察结果。 第一个结果是来自具有自我管理可卡因的动物的伏隔核的伏安分析。数据表明，在“孵育”或无药物阶段，自身受体功能受到调节，这是对应于关键时期可卡因增加疗效的关键时间。当大鼠对可卡因的增强作用耐受或敏感时，几种伏安方法（脑切片，体内麻醉，自由移动的动物）将用于检查多巴胺末端的生理学变化。多巴胺系统功能的变化可能导致可卡因的增强功效改变。越来越多的观察结果继续证实，脑部变化的差距因虐待药物而变化。在可卡因，海洛因和速度扣自给可卡因后，将检查间隙连接蛋白（连接蛋白）的变化（连接蛋白） 行为相关的时间点。 Western印迹和Imunno组织化学分析将用于评估connexin32和connexin36表达的区域特定影响。该项目将与副40008（VRANA）共享组织，其中将进行连接性RNA和一般蛋白质组学筛选。