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）对中皮质边缘DA系统中枢神经系统（CMS）部位内饮酒行为的调节，这些部位被认为介导乙醇饮酒和药物奖励，并检查这些区域中由于乙醇暴露而发生的DA神经传递的神经元改变。最近的证据强烈暗示特定的神经解剖回路和子回路在药物奖励。构成这些回路的结构是中皮层边缘DA系统的组成部分。酒精和其他滥用药物的奖励效应最明显的相关区域包括后腹侧被盖区（VTA）、丘脑核（NAc）、腹侧苍白球（VP）和内侧前额叶皮层（MPF）。最近的证据还表明：（1）DA受体在乙醇自我给药的许多区域中起重要的介导作用：（2）将乙醇直接应用于VTA的奖赏效应似乎至少部分地通过DA受体介导;（3）乙醇的自我给药改变DA神经传递并产生“神经适应”在调节DA释放的受体中，通过NAc中DA的细胞外水平来测量。拟议的工作将继续和扩大研究乙醇自我管理如何改变DA神经传递内的VP，外壳和核心的NAC，MPF，和前，后腹侧被盖区。将研究乙醇在不同腹侧被盖区DA投射区域的强化作用，以参与介导饮酒。这些研究还试图确定参与D1，D2和/或5 HT 3受体内的腹侧被盖区（前部和后部），NAc（壳和核心）和VP对预定的访问乙醇饮酒，并提出实验检查参与其他腹侧被盖区DA投射区域调节饮酒。这些研究结果将提供有价值的信息，了解DA的中皮质边缘DA系统在饮酒中的作用。这些信息将是重要的基本了解中枢神经系统回路参与乙醇饮用行为，以及这些电路如何适应乙醇的持续存在。研究结果还应与今后发展治疗方法有关，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.