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

点击翻译按钮获取中文摘要

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.