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

描述(由申请人提供)：药物成瘾研究的关键目标是了解娱乐性药物使用和强制药物使用之间的差异，后者是成瘾的诊断。伏核(NAC)中的多巴胺(DA)传递是寻找与成瘾过程有关的神经适应的一个明显的起点。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效应中发挥作用，但DA系统的生理学变化是否导致成瘾的形成仍有待确定。这项申请中提议的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)与新开发的行为方法结合起来，帮助识别动物自我注射可卡因的动机的变化。以下问题将在获奖过程中得到解答：1.可卡因自我给药程序对伏隔核多巴胺动力学产生增强效应的后果是什么。2.可卡因自身给药后，大鼠腹侧被盖区、尾壳核和伏核的DA受体和DA转运体水平发生了什么变化。3.伏隔核快速DA信号(亚秒DA瞬变)与自身给药动机增强有何关系。这项研究计划有两方面的好处。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出色的指导培训。第二，将收集有关DA神经传递的前所未有的信息。具体地说，在可卡因自身给药过程中和给药后，伏隔核核和壳核的强直和时相DA释放、DA摄取和DA受体调节将被测量到。对大脑化学和药物动机行为之间关系的更好理解应该提供洞察力，从而制定更好的预防和治疗策略。

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.