The role of dopamine mechanisms in the development of addiction to cocaine

多巴胺机制在可卡因成瘾发展中的作用

• 批准号: 7132490
• 负责人: Evgeny Alexander BUDYGIN
• 金额: $ 9.81万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7132490
• 关键词: cocaine; dopamine; receptor; role

DESCRIPTION (provided by applicant): Critical goal of drug addiction research is to understand the differences between recreational and compulsive drug use, the latter being diagnostic of addiction. The dopamine (DA) transmission in the nucleus accumbens (NAc) is an obvious starting point in the search for neuroadaptations responsible for the addictive process. However, despite the evidence for the role of DA uptake in the acute reinforcing and psycho-stimulant effects of cocaine, it remains to be determined whether changes in the physiology of the DA system account for the development of addiction. The proposed studies in this application will bring together state-of-the-art neurochemical techniques (fast scan cyclic voltammetry and microdialysis) learned during the applicant's graduate and post-doctoral training with newly developed behavioral approaches that help identify changes in the motivation of animals to self-administer cocaine. The following questions will be answered over the course of the award: 1. What are the consequences of a cocaine self-administration procedure, which produces an increase in the reinforcing effect, on DA dynamics in the nucleus accumbens. 2. What changes occur in DA receptor and DA transporter levels in the ventral tegmental area, caudate putamen and nucleus accumbens following cocaine self-administration. 3. What is the relationship of fast DA signaling (sub-second DA transients) in the nucleus accumbens with increased motivation to self-administer cocaine. The benefits of this research plan are twofold. First, the Candidate will receive excellent mentored training both in state-of-the-art behavioral techniques and in areas of in vitro receptor pharmacology. Second, unprecedented information on DA neurotransmission will be gathered. Specifically, tonic and phasic DA release, DA uptake and DA receptor modulation will be measured in nucleus accumbens core and shell during and after cocaine self-administration. An improved understanding of the relationship between brain chemistry and drug motivated behavior should provide insights that will lead to the development of better prevention and treatment strategies.

药物成瘾研究的关键目标是了解娱乐性和强迫性药物使用之间的差异，后者是成瘾的诊断。多巴胺（DA）在丘脑核（NAc）的传递是一个明显的起点，在寻找神经适应负责成瘾过程。然而，尽管有证据表明DA摄取在可卡因的急性强化和精神刺激作用中的作用，但DA系统的生理学变化是否与成瘾的发展有关仍有待确定。本申请中的拟议研究将把申请人在研究生和博士后培训期间学到的最先进的神经化学技术（快速扫描循环伏安法和微透析法）与新开发的行为方法结合起来，这些方法有助于确定动物自我管理可卡因的动机变化。以下问题将在颁奖过程中回答：1。可卡因自我给药程序会对延髓核中的DA动力学产生增强效应，其后果是什么？2.可卡因自我给药后腹侧被盖区、尾壳核和延髓核的DA受体和DA转运体水平发生了什么变化？3.中脑核中快速DA信号（亚秒DA瞬变）与自我服用可卡因的动机增加之间的关系是什么？这项研究计划的好处是双重的。首先，候选人将在最先进的行为技术和体外受体药理学领域接受优秀的指导培训。第二，将收集有关DA神经传递的前所未有的信息。具体而言，紧张性和阶段性DA释放，DA摄取和DA受体调节将在可卡因自我给药期间和之后在延髓核芯和壳中测量。对脑化学和药物动机行为之间关系的更好理解应该提供见解，这将导致更好的预防和治疗策略的发展。