Ethanol regulation of signaling: from cells to behavior

描述（由申请人提供）：伏核（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A2 A受体，并且特征在于A2 A与多巴胺D2受体（D2）在相同神经元上的共表达。我们有证据表明，阈下浓度的D2激动剂NPA和乙醇，单独没有效果，协同作用时，加在一起刺激PKA信号。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，如在NAc中，在多巴胺能张力存在下对乙醇同时过敏，并且在乙醇存在下对D2信号传导过敏。协同效应可能在乙醇消费中发挥作用。β/γ抑制剂在NAc中的表达减少了自愿的乙醇消耗。我们的假设是，独特的和特定的信号成分是负责D2和乙醇/A2之间的协同作用，在NAc/纹状体神经元，这些分子调节饮酒行为。该项目的总体目标是（a）鉴定NAc/纹状体神经元中调节乙醇诱导的PKA信号传导增加和乙醇消耗增强的特定分子信号传导组分，和（B）开发新的酒精中毒治疗剂。 我们的具体目标是：我：Il：测试G蛋白信号传导的特异性激活剂AGS 3是否选择性地调节D2和乙醇之间的协同作用; III：测试在D2激活时释放的哪些特异性β/γ二聚体激活初级纹状体神经元中的腺苷酸环化酶II和/或IV;以及IV：测试乙醇/A2和D2信号传导组分在乙醇操作性自我给药和中枢神经系统对乙醇的反应中的作用。该提案中的实验将确定和验证用于开发治疗酒精中毒和酒精滥用的新治疗药物的新靶点。

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.