Novel mechanism of alcohol self-administration and relapse

酒精自我管理和复发的新机制

• 批准号: 10403485
• 负责人: Clyde W Hodge
• 金额: $ 34.99万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-10 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403485
• 关键词: AMPA Receptors; Abstinence; Address; Affect; Alcohol consumption; Alcohols; Amygdaloid structure; Behavior; Behavior Therapy; Behavioral; Behavioral Genetics; Behavioral Model; Brain; Brain region; Cues; Data; Development; Exposure to; G-substrate; Genetic; Genetic Techniques; Glutamates; Intake; Knowledge; Lead; Link; Maintenance; Mediating; Methods; Modeling; Molecular; Molecular Genetics; Mus; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physiological; Process; Property; Prosencephalon; Protein Family; Proteins; Psychological reinforcement; Regulation; Relapse; Rewards; Role; Self Administration; Site; Slice; Stimulus; Synaptic plasticity; System; Techniques; Testing; Work; abuse liability; addiction; alcohol effect; alcohol reinforcement; alcohol seeking behavior; alcohol use disorder; behavioral pharmacology; behavioral plasticity; calmodulin-dependent protein kinase II; clinical practice; craving; design; drug of abuse; experimental study; genetic regulatory protein; inhibitor; innovation; insight; interdisciplinary approach; mind control; multidisciplinary; neuromechanism; novel; novel therapeutic intervention; pre-clinical; preclinical study; problem drinker; protein expression; public health relevance; receptor; relating to nervous system; therapeutic target; trafficking; transmission process

Project Summary Pathological alcohol-seeking behavior is regulated in part by glutamate AMPA receptor (AMPAR) activity in the amygdala. Transmembrane AMPA receptor regulatory proteins (TARPs) profoundly affect the trafficking and function of AMPARs in synaptic and behavioral plasticity. Although the TARP family of proteins is expressed throughout the brain, the TARP γ-8 subtype is restricted to forebrain regions including the basolateral amygdala (BLA); a brain region that is critical to addiction. However, the role of TARP γ-8 in alcohol use disorders (AUD) or other addictions is unknown. To fill this gap in knowledge, we propose an innovative set of behavioral, genetic, bidirectional systemic and site-specific pharmacological, molecular, and physiological studies in mice to evaluate the mechanistic role of TARP γ-8 in alcohol reinforcement, escalated self- administration, and cue-induced reinstatement of alcohol-seeking behavior as a model of relapse. Elucidating the neural mechanisms of these three critical behavioral domains has high translational value for understanding the development, progression, and maintenance of AUD. Successful completion of the studies in this application will provide fundamental mechanistic insights into TARP γ-8 regulation of pathological alcohol-seeking behavior. Moreover, this work moves the field forward in understanding the molecular mechanisms by which alcohol hijacks reward processes and has potential to inform development of new pharmacotherapeutic strategies that target AMPAR function in a highly selective brain region-specific manner.

项目摘要 病理性饮酒行为部分由谷氨酸AMPA接收器（AMPAR）调节 杏仁核的活动。跨膜AMPA受体调节蛋白（TARPS）深刻 影响AMPAR在突触和行为可塑性中的运输和功能。虽然 蛋白质的TARP家族在整个大脑中表达，TARPγ-8亚型仅限于 前脑区域，包括副杏仁核（BLA）；一个至关重要的大脑区域 瘾。但是，TARPγ-8在酒精使用障碍（AUD）或其他成瘾中的作用是 未知。为了填补知识中的这一空白，我们提出了一组创新的行为，遗传， 双向全身和特定地点的药物，分子和物理研究 小鼠评估TARPγ-8在酒精加固中的机理作用，升级了自我 给药，提示引起的恢复寻求酒精的行为是一种救济模型。 阐明这三个关键行为领域的神经机制高 理解AUD的开发，进步和维护的翻译价值。 在本应用中成功完成研究将提供基本的机械 洞察力γ-8调节病理性酒精的行为。而且，这项工作 在理解酒精劫持的分子机制方面向前移动领域 奖励流程，并有可能告知新药物治疗的开发 以高度选择性的大脑区域特异性方式靶向AMPAR的策略。