Analysis of the nucleus accumbens in ethanol's discriminative stimulus effects

 描述（由申请人提供）：酒精中毒是一种慢性进行性疾病，通常以酗酒模式为特征，导致有害的健康后果和对社会的巨大经济负担。已知酒精会产生主观效应（即醉酒感），这与酗酒的持续有关，这表明这些主观效应有助于酒精的滥用潜力。药物辨别是一种可靠的体内药理学测定，可用于表征酒精主观效应的受体基础，如通过行为输出测量的。以前使用这种技术的工作已经确定，酒精（或乙醇）是一种刺激复合物，由啮齿动物和灵长类动物多个受体系统的并发活动组成。具体而言，酒精作为GABAA受体的正调节剂和NMDA受体的拮抗剂，导致神经元活动的总体抑制。虽然大量的研究致力于酒精在大脑中的受体基础，但对酒精主观影响的基础电路知之甚少。重要的是，迄今为止还没有发表的研究直接研究了猴子介导乙醇主观效应的脑回路。绘制灵长类动物大脑中调节乙醇主观影响的回路，将有助于弥合我们对酒精的认识。 了解从啮齿动物到灵长类动物介导酒精中毒的大脑机制，并改善潜在药物治疗的靶向策略。啮齿动物和人类的证据表明，延髓核（NAc）参与主观酒精中毒，这些作用由GABA能和NMDA能机制组成。因此，作为映射与乙醇中毒的刺激效应相关的电路的第一步，目前的建议利用化学发生策略来直接操纵NAc核心内的神经活动。此外，本研究建议使用药物歧视的药理学基础的NAC核心参与乙醇的主观影响，提供了一个新的调查电路和药理学之间的交叉点。总的来说，这些研究的目标是更好地了解灵长类动物大脑中酒精中毒的基础，这将改善酒精使用的靶向治疗策略 紊乱

 DESCRIPTION (provided by applicant): Alcoholism is a chronic, progressive disorder often characterized by patterns of binge drinking that lead to detrimental health consequences and a great economic burden on society. Alcohol is known to produce subjective effects (i.e. feelings of intoxication) that have been associated with the perpetuation of binge drinking, suggesting that these subjective effects contribute to alcohol's abuse potential. Drug discrimination is a reliable in vivo pharmacological assay that can be used to characterize the receptor basis of alcohol's subjective effects, as measured through a behavioral output. Previous work using this technique has established that alcohol (or ethanol) is a stimulus complex made up of concurrent activity at multiple receptor systems in rodents and primates. Specifically, alcohol acts as a positive modulator at the GABAA receptor and an antagonist at the NMDA receptor, leading to an overall dampening of neuronal activity. While a great deal of research has been dedicated to alcohol's receptor basis in the brain, very little is known about the circuitry that underlies ethanol's subjective effects. Importantly, there are no published studies to date that have directly examined brain circuitry that mediates ethanol subjective effects in monkeys. Mapping circuitry that mediates the subjective effects of ethanol in the primate brain will help bridge our understanding of brain mechanisms mediating alcohol intoxication from rodents to primates and improve targeting strategies for potential pharmacotherapies. There is converging evidence from both rodents and humans suggesting that the nucleus accumbens (NAc) is involved in subjective alcohol intoxication, and that these effects are composed of both GABAergic and NMDA glutamatergic mechanisms. Thus, as a first step in mapping the circuitry related to the stimulus effects of ethanol intoxication, the current proposal utilizes a chemogenetic strategy to directly manipulate neural activity within the NAc core. Further, this study proposes to use drug discrimination to characterize the pharmacological basis of NAc core involvement in ethanol's subjective effects, providing a novel investigation of the intersection between circuitry and pharmacology. Overall, the goal of these studies is to better understand the basis of alcohol intoxication in the primate brain, which will improve targeted treatment strategies for alcohol use disorders.