Ethanol regulation of signaling: from cells to behavior

乙醇对信号传导的调节：从细胞到行为

• 批准号: 7125953
• 负责人: Ivan Diamond
• 金额: $ 48.39万
• 依托单位: CV THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125953
• 关键词: G protein; adenylate cyclase; alcoholic beverage consumption; behavioral /social science research tag; biological signal transduction; craving; dopamine agonists; dopamine receptor; enzyme activity; ethanol; laboratory mouse; laboratory rat; neurochemistry; neuropharmacology; nucleus accumbens; protein kinase A; purinergic receptor; receptor binding; receptor expression; receptor sensitivity; reinforcer; self medication; tissue /cell culture

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.

描述（由申请人提供）：伏隔核（NAc）与饮酒的渴望、奖赏和强化有关。 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，其特征是在同一神经元上 A2A 与多巴胺 D2 受体 (D2) 共表达。我们有证据表明，阈下浓度的 D2 激动剂 NPA 和乙醇单独使用没有效果，但当添加在一起时会产生协同作用，刺激 PKA 信号传导。协同作用需要 betayamma、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同时对乙醇过敏，并且在乙醇存在下对 D2 信号传导过敏。协同作用可能在乙醇消耗中发挥作用。 NAc 中 β/γ 抑制剂的表达减少了自愿的乙醇消耗。我们的假设是，独特且特定的信号传导成分负责 NAc/纹状体神经元中 D2 和乙醇/A2 之间的协同作用，并且这些分子调节饮酒行为。该项目的总体目标是 (a) 识别 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：鉴定负责乙醇和 NPA 之间协同作用以激活 PKA 信号传导的特定 G 蛋白成分； II：测试G蛋白信号传导的特异性激活剂AGS3是否选择性调节D2和乙醇之间的协同作用； III：测试D2激活后释放的特定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； IV：测试乙醇/A2和D2信号成分在乙醇操作性自我施用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并验证开发治疗酗酒和酒精滥用的新治疗药物的新靶标。