CNS Sites Mediating Alcohol Drinking Behavior

描述(申请人提供)：这项研究的目的是调查多巴胺(DA)对酒精饮酒行为的调节，在中皮质边缘DA系统的中枢神经系统(CMS)位置被认为是调节酒精饮酒和药物奖励的场所，并检查这些区域因酒精暴露而发生的DA神经传递的神经元变化。最近的证据强烈表明，特定的神经解剖回路和亚回路与药物奖赏有关。构成这些回路的结构是中皮质边缘DA系统的组成部分。酒精和其他滥用药物的奖赏效应最明显的一些区域包括后腹侧被盖区(VTA)、伏隔核(NAC)、腹侧苍白球(VP)和内侧前额叶皮质(MPF)。最近的证据还表明：(1)DA受体在这些区域的乙醇自我给药中起着重要的中介作用；(2)乙醇直接作用于VTA的奖赏效应似乎至少部分是通过DA受体介导的；(3)乙醇自身给药改变了DA神经传递，并在受体中产生“神经适应”，通过测量NAC中DA的细胞外水平来调节DA的释放。这项拟议的工作将继续并扩大关于乙醇自我给药如何改变Vp、NAC的外壳和核心、MPF以及VTA前后部的DA神经传递的研究。乙醇在不同的VTA DA投射区域的增强效应将被研究，以参与调节酒精饮酒。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D_1、D_2和/或5-HT3受体是否参与了酒精饮酒，并试图通过实验来研究其他VTA DA投射区域对酒精饮酒的调节作用。这些研究结果将为了解中皮质边缘DA系统中DA在饮酒中的作用提供有价值的信息。这些信息对于基本理解涉及酒精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将是重要的。这些发现也应该与未来治疗方法的发展有关，特别是药物疗法，用于治疗酒精中毒和酒精滥用。

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.