Ethanol regulation of signaling: from cells to behavior

描述(申请人提供)：伏隔核(NAC)与饮酒的渴望、奖励和强化有关。在中枢神经系统(CNS)中，NAc/纹状体表达最高水平的高亲和力腺苷A2a受体，其特征是A2a和多巴胺D2受体(D2)在同一神经元上共同表达。我们有证据表明，D2激动剂NPA和乙醇的亚阈值浓度单独没有作用，当它们加在一起刺激PKA信号时，它们协同作用。协同作用需要Bettayamma、二聚体和A2受体。在同一细胞上表达D2和A2的神经元，就像在NAC中一样，在多巴胺能张力存在的情况下对乙醇同时超敏，在乙醇存在的情况下对D2信号超敏。协同效应可能会在乙醇消费中发挥作用。在NAC中表达β/伽马抑制物可减少自愿的乙醇消耗。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，并且这些分子调节饮酒行为。本项目的总体目标是(A)确定NAC/纹状体神经元中调节乙醇诱导的PKA信号增加和酒精消耗增加的特定分子信号成分，以及(B)开发治疗酒精中毒的新疗法。 我们的具体目标是：I：确定负责乙醇和NPA之间协同激活PKA信号的特定G蛋白成分；IL：测试G蛋白信号的特定激活剂AGS3是否选择性地调节D2和乙醇之间的协同作用；III：测试D2激活时释放的哪些特定的β/伽马二聚体激活原代纹状体神经元中的腺酰环化酶II和/或IV；以及IV：测试乙醇/A2和D2信号成分在乙醇操纵者自身给药和中枢神经系统对乙醇的反应中的作用。这项提案中的实验将确定和验证开发治疗酒精中毒和酒精滥用的新治疗剂的新靶点。

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.