Ethanol regulation of signaling: from cells to behavior

描述（由申请人提供）：伏隔核（NAc）与饮酒的渴望、奖励和强化有关。NAc/纹状体在中枢神经系统（CNS）中表达最高水平的高亲和力腺苷A2A受体，其特征是A2A与多巴胺D2受体（D2）在同一神经元上共表达。我们有证据表明，阈以下浓度的D2激动剂NPA和乙醇，单独没有作用，当它们一起加入时协同作用，刺激PKA信号传导。协同作用需要β胺、二聚体和A2受体。在同一细胞上表达D2和A2的神经元，如NAc，同时在多巴胺能张力存在时对乙醇过敏，在乙醇存在时对D2信号过敏。协同作用可能在乙醇消费中起作用。NAc中β / γ抑制剂的表达减少了自愿乙醇消耗。我们的假设是，在NAc/纹状体神经元中，独特和特定的信号成分负责D2和乙醇/A2之间的协同作用，这些分子调节饮酒行为。该项目的总体目标是(a)确定NAc/纹状体神经元中调节乙醇诱导的PKA信号增加和乙醇消耗增强的特定分子信号成分，以及(b)开发酒精中毒的新疗法。

DESCRIPTION (provided by applicant): The Nucleus Accumbens (NAc) is implicated in craving, reward and reinforcement of alcohol drinking. The NAc/Striatum expresses the highest levels of high affinity adenosine A2A receptors in the central nervous system (CNS) and is characterized by co-expression of A2A with dopamine D2 receptors (D2) on the same neurons. We have evidence that subthreshold concentrations of the D2 agonist NPA and ethanol, that have no effect alone, act synergistically when added together to stimulate PKA signaling. Synergy requires bettayamma, dimers and A2 receptors. Neurons that express D2 and A2 on the same cells, as in the NAc, are simultaneously hypersensitive to ethanol in the presence of dopaminergic tone and hypersensitive to D2 signaling in the presence of ethanol. Synergy may play a role in ethanol consumption. Expression of a beta/gamma, inhibitor in NAc reduces voluntary ethanol consumption. Our hypothesis is that unique and specific signaling components are responsible for synergy between D2 and ethanol/A2 in NAc/striatal neurons and that these molecules regulate drinking behaviors. The overall goal of this project is (a) to identify the specific molecular signaling components in NAc/Striatal neurons which regulate ethanol-induced increases in PKA signaling and reinforcement of ethanol consumption, and, (b) to develop new therapeutics for alcoholism. Our specific aims are: I: Identify specific G-protein components responsible for synergy between ethanol and NPA for activation of PKA signaling; Il: Test whether a specific activator of G protein signaling, AGS3, selectively regulates synergy between D2 and ethanol; III: Test which specific beta/gamma dimers released upon D2 activation activate adenylyl cyclase II and/or IV in primary striatal neurons; and IV: Test the role of the ethanol/A2 and D2 signaling components in ethanol operant self-administration and in CNS responses to ethanol. The experiments in this proposal will identify and validate novel targets for the development of new therapeutic agents to treat alcoholism and alcohol abuse.