GABAB receptor-dependent signaling in alcohol consumption and reward

酒精消耗和奖励中的 GABAB 受体依赖性信号传导

• 批准号: 10231447
• 负责人: Margot Clara DeBaker
• 金额: $ 3.15万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-24 至 2022-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231447
• 关键词: Ablation; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcohols; Baclofen; Behavioral; Brain; Brain region; CRISPR/Cas technology; Clinical; Cocaine; Consumption; Data; Diagnosis; Disulfiram; Dopamine; Electrophysiology (science); Evaluation; FDA approved; Food; GTP-Binding Proteins; Genes; Genetic Enhancement; Goals; Health; Hippocampus (Brain); Human; Human Genome; Individual; Intake; Investigation; Knowledge; Learning; Measures; Mediating; Messenger RNA; Molecular; Morphine; Mus; Naltrexone; Neurons; Output; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Play; Population; Prevalence; Proteins; RGS Proteins; Regulation; Relapse; Research; Research Project Grants; Rewards; Rodent; Role; Signal Pathway; Signal Transduction; Slice; Societies; Source; Symptoms; System; Testing; Therapeutic; United States; Ventral Tegmental Area; Withdrawal; Withdrawal Symptom; Work; acamprosate; addiction; alcohol abuse therapy; alcohol behavior; alcohol reward; alcohol use disorder; associated symptom; behavioral response; craving; deter alcohol use; dopaminergic neuron; drug of abuse; genome wide association study; improved; member; negative emotional state; novel strategies; novel therapeutic intervention; patient population; pre-clinical; receptor; success; therapeutically effective; tool; treatment strategy

PROJECT SUMMARY Over 16 million people in the United States are diagnosed with Alcohol use disorder (AUD) each year. AUD is characterized by compulsive alcohol use, loss of control over intake, and negative emotional states during periods of withdrawal. The long-term success of current treatment strategies for AUD is low, emphasizing the need for new approaches to treat a broader patient population. The premise of my research is that by better understanding the cellular and molecular mechanisms in the brain that regulate alcohol consumption and reward, new or improved therapeutic strategies for treatment of AUD can be envisioned and developed. My project will investigate the influence of an inhibitory G protein-dependent signaling pathway on alcohol consumption and reward. Baclofen, a GABAB receptor (GABABR) agonist, decreases AUD-associated symptoms in preclinical and clinical settings. In rodents, baclofen suppresses consumption and reward when administered either systemically or directly to the ventral tegmental area (VTA), a key reward-related brain region. The output of VTA dopamine (DA) neurons, the largest sub-population of neurons in the VTA, is moderated by inhibitory G protein-dependent signaling pathways, including signaling mediated by GABABR. Additionally, different proteins, including Regulator of G protein Signaling (RGS) proteins, act to modulate GABABR-dependent inhibition. The AIMS of my project are to probe the impact of GABABR-dependent signaling in VTA DA neurons on alcohol-related behavior (AIM 1), and to Identify the role of R7 RGS proteins in GABABR-dependent signaling in VTA DA neurons (AIM 2). My working hypothesis is that GABABR-dependent signaling in VTA DA neurons suppresses alcohol consumption and reward, and that this signaling pathway is subject to negative regulation by a specific subtype of RGS protein, RGS6. I propose to test this hypothesis using CRISPR/Cas9-mediated gene ablation targeting VTA DA neurons, in addition to ex vivo slice electrophysiology and behavioral analysis. Successful completion of this proposal will improve our understanding of the role that GABABR-dependent signaling in VTA DA neurons plays in alcohol consumption and reward, and reveal whether pharmacologic or genetic enhancement of this inhibitory signaling pathway holds promise as a novel approach to treat aspects of AUD. Knowledge gained in this effort will help inform the improvement of treatment and prevention of AUD.

项目摘要 美国每年有超过1600万人被诊断患有酒精使用障碍（AUD）。AUD是 其特征是强迫性饮酒，对摄入量失去控制，以及在 撤退的时期。目前AUD治疗策略的长期成功率较低，强调 需要新的方法来治疗更广泛的患者群体。我研究的前提是， 了解大脑中调节酒精消耗和奖励的细胞和分子机制， 可以设想和开发用于治疗AUD的新的或改进的治疗策略。我的项目将 研究抑制性G蛋白依赖性信号通路对饮酒的影响， 奖励巴氯芬是一种GABAB受体（GABABR）激动剂，在临床前和临床试验中减少AUD相关症状。 临床环境。在啮齿类动物中，巴氯芬抑制消费和奖励时，管理系统或 或者直接到腹侧被盖区（VTA），一个与奖励相关的关键大脑区域。腹侧被盖区多巴胺的输出 (DA)神经元是腹侧被盖区最大的神经元亚群，由抑制性G蛋白依赖性调节。 信号传导途径，包括GABABR介导的信号传导。此外，不同的蛋白质，包括 G蛋白信号转导调节因子（RGS）蛋白，用于调节GABABR依赖性抑制。的目的 我的项目是探索腹侧被盖区DA神经元中GABABR依赖性信号对酒精相关性神经元的影响。 行为（AIM 1），并确定R7 RGS蛋白在VTA DA神经元中GABABR依赖性信号传导中的作用 (AIM 2）的情况。我的工作假设是腹侧被盖区DA神经元中的GABABR依赖性信号抑制了酒精 消费和奖励，并且这种信号传导途径受到特定亚型的负调控 RGS蛋白，RGS 6。我建议使用CRISPR/Cas9介导的基因消融靶向来验证这一假设。 腹侧被盖区DA神经元，除了离体切片电生理学和行为分析。成功完成 这一建议将提高我们对GABABR依赖性信号在腹侧被盖区DA神经元中的作用的理解， 在酒精消耗和奖励中起作用，并揭示这种作用是否是药理学或遗传增强的。 抑制性信号通路有望成为治疗AUD的新方法。获得的知识 这一努力将有助于改善AUD的治疗和预防。