CNS Sites Mediating Alcohol Drinking Behavior

描述（由申请人提供）：本研究的目的是研究多巴胺（DA）对中脑皮质边缘DA系统中枢神经系统（CMS）部位饮酒行为的调节，该部位被认为介导乙醇饮酒和药物奖励，并检查乙醇暴露导致这些区域DA神经传递的神经元改变。最近的证据强烈暗示了特定的神经解剖回路和亚回路在药物奖励。构成这些回路的结构是中脑皮质边缘DA系统的组成部分。一些与乙醇和其他滥用药物的奖励效应最明显相关的区域包括后腹侧被盖区（VTA）、伏隔核（NAc）、腹侧白球（VP）和内侧前额叶皮层（MPF）。最近的证据也表明：(1)DA受体在这些区域的乙醇自我给药中起重要的调节作用；(2)直接将乙醇应用于VTA的有益效果似乎至少部分是通过DA受体介导的；(3)乙醇的自我给药改变DA神经传递，并在调节DA释放的受体中产生“神经适应性”（通过NAc中DA的细胞外水平测量）。这项工作将继续并扩展乙醇自我给药如何改变VP、NAc外壳和核心、MPF和前、后VTA内DA神经传递的研究。乙醇在不同VTA - DA投射区的强化作用将被研究是否参与介导饮酒。这些研究还试图确定VTA（前部和后部）、NAc（外壳和核心）和VP内的D1、D2和/或5 HT3受体参与预定的通路酒精饮酒，并提出实验来检查其他VTA DA投射区域参与调节酒精饮酒。这些研究的结果将提供有价值的信息，以了解酒精饮酒中皮质边缘DA系统中DA的作用。这些信息对于基本了解涉及乙醇饮酒行为的中枢神经系统回路以及这些回路如何适应乙醇的持续存在是很重要的。研究结果还应与今后发展治疗方法，特别是治疗酗酒和酒精滥用的药物疗法有关。

DESCRIPTION (provided by applicant): The objectives of this research are to investigate dopamine (DA) regulation of alcohol drinking behavior within central nervous system (CMS) sites of the mesocorticolimbic DA system that are thought to mediate ethanol drinking and drug reward, and to examine the neuronal alterations on DA neurotransmission in these areas that occur as a result of ethanol exposure. Recent evidence strongly implicates specific neuroanatomical circuits and subcircuits in drug reward. The structures that make up these circuits are components of the mesocorticolimbic DA system. Some of the areas most clearly implicated in the rewarding effects of ethanol and other drugs of abuse include the posterior ventral tegmental area (VTA), the nucleus accumbens (NAc), the ventral pallidum (VP), and aspects of the medial prefrontal cortex (MPF). Recent evidence also shows that: (1) DA receptors play important mediating roles in ethanol self- administration within a number of these areas; (2) the rewarding effects of the direct application of ethanol into the VTA appear to be mediated, at least partly, through DA receptors; and (3) the self-administration of ethanol alters DA neurotransmission and produces "neuroadaptations" in receptors that regulate the DA release as measured by extracellular levels of DA in the NAc. The proposed work will continue and extend studies on how ethanol self-administration alters DA neurotransmission within the VP, the shell and core of the NAc, the MPF, and the anterior and posterior VTA. The reinforcing effects of ethanol in different VTA DA projection regions will be investigated for involvement in mediating alcohol drinking. The studies also seek to determine the involvement of D1, D2 and/or 5 HT3 receptors within the VTA (anterior and posterior), NAc (shell and core) and VP on scheduled access ethanol drinking, and experiments are proposed to examine the involvement of other VTA DA projection regions in regulating alcohol drinking. The results of these studies will provide valuable information toward understanding the role of DA within the mesocorticolimbic DA system in alcohol drinking. Such information would be important for basic understanding of CNS circuitries involved in ethanol drinking behavior and how these circuits may adapt to the continued presence of ethanol. The findings should also be relevant to future development of therapeutic approaches, particularly pharmacotherapies, for the treatment of alcoholism and alcohol abuse.