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.

确定药物成瘾（一种行为定义的疾病）背后的大脑机制需要同样复杂的神经生物学和行为工具。该项目将联合收割机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增加。这项工作将跟进最近对两个明显不同的神经系统的观察。 第一个结果来自于对自我注射可卡因的动物的脑髓核切片的伏安分析。这些数据表明，自身受体功能在“孵育”或无药物阶段下调，对应于可卡因增强功效增加的关键时间段。几种伏安法（脑切片，在体内麻醉，自由移动的动物）将被用来检查在多巴胺终端的生理变化的时间点，当大鼠是耐受或敏感的可卡因的增强效果。多巴胺系统功能的改变可能导致可卡因的强化功效改变。越来越多的观察结果继续证实，大脑中的缝隙连接会对药物滥用作出反应。在可卡因、海洛因和Speedbail自我给药后，将检查间隙连接蛋白（连接蛋白）的变化。 行为相关的时间点。Western印迹和免疫组织化学分析将用于评估连接蛋白32和连接蛋白36表达的区域特异性作用。本项目将与子项目0008（Vrana）共享组织，其中将进行连接蛋白RNA和一般蛋白质组学筛选。