Ethanol, Stress and Dopamine

描述（由申请人提供）：此竞争性修订是对通知编号（NOT-OD-09-058）的回应，标题为：“NIH宣布恢复法案资金可用于竞争性修订申请”。介导乙醇致醉和增强作用的细胞机制尚未完全了解。然而，大量的证据支持这一假设，增加中脑边缘DA系统的活动是许多药物滥用，包括乙醇的增强效果的重要组成部分之一。下视丘泌素是近年来发现的一类神经肽，参与唤醒和各种动机性行为的调节。新出现的证据表明，下丘脑泌素系统对奖赏功能产生促进作用，这些作用涉及腹侧被盖区多巴胺神经元的激活。例如，下丘脑泌素信号传导的阻断减少了乙醇的自我施用并降低了乙醇对多巴胺信号传导的影响。鉴于下丘脑泌素系统调节与药物滥用相关的奖励的潜力，拟议的研究将采用多学科方法来调查下丘脑泌素是否调节乙醇诱导的多巴胺信号传导的变化。研究将审查：1）使用体外快速扫描伏安法技术，下丘脑泌素系统影响基底和乙醇诱导的多巴胺信号传导水平的程度;以及2）使用自由移动微透析，下丘脑泌素系统调节基底和乙醇诱导的多巴胺信号传导水平的程度。这项工作的完成将提供试点信息的程度下丘脑分泌素参与奖励处理，在何种程度上，这些行动涉及中脑边缘DA系统，并将提供深入了解成瘾过程的神经机制。此外，这些信息可能有助于形成基础，以产生新的药物治疗酗酒。 公共卫生相关性：HCRT系统可能是调节滥用药物（包括乙醇）强化特性的重要参与者。了解这个系统如何调节乙醇强化过程的神经相关性，特别是当它涉及到中脑边缘DA系统时，可以为合理的药物设计提供基础。

DESCRIPTION (provided by applicant): This competitive revision is in response to Notice Number (NOT-OD-09-058), Titled: "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications". The cellular mechanisms that mediate the intoxicating and reinforcing effects of ethanol are not completely understood. However, considerable evidence supports the hypothesis that increased mesolimbic DA system activity is one of the important components of the reinforcing effects of many drugs of abuse, including ethanol. The hypocretins are recently identified neuropeptides that participate in the regulation of arousal and a variety of motivated behaviors. Emerging evidence indicates that the hypocretin system exerts a facilitatory influence on reward function and that these actions involve activation of dopamine neurons of the ventral tegmental area. For example blockade of hypocretin signaling reduces self-administration of ethanol and reduces the effects of ethanol on dopamine signaling. Given the potential that the hypocretin system regulates reward associated with drug abuse, the proposed studies will employ a multidisciplinary approach to investigate whether hypocretin regulates ethanol-induced changes in dopamine signaling. Studies will examine: 1) The extent to which the hypocretin system influences baseline and ethanol-induced levels of phasic dopamine signaling in the nucleus accumbens using in vitro fast scan voltammetry techniques; and 2) To what degree the hypocretin systems regulates baseline and ethanol-induced levels of tonic dopamine signaling in the nucleus accumbens using freely moving microdialysis. Completion of this work will provide pilot information on the extent to which hypocretin participates in reward processing, the extent to which these actions involve the mesolimbic DA system, and will offer insight into the neural mechanisms underlying the addiction process. Additionally this information and may help shape the foundations to generate novel pharmacotherapies for alcoholism. PUBLIC HEALTH RELEVANCE: The HCRT system may be an essential participant in the regulation of reinforcement properties of drugs of abuse, including ethanol. Understanding how this system modulates the neural correlates underlying ethanol-reinforcement processes, particularly as it relates to the mesolimbic DA system, could provide the basis for a rational drug design to treat addiction.