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.

项目概要 病理性寻酒行为部分受谷氨酸 AMPA 受体 (AMPAR) 调节 杏仁核中的跨膜 AMPA 受体调节蛋白 (TARP) 的活性。 影响 AMPAR 在突触和行为可塑性方面的运输和功能。 TARP 蛋白家族在整个大脑中表达，TARP γ-8 亚型仅限于 前脑区域，包括基底外侧杏仁核 (BLA)，该区域对于大脑的发育至关重要； 然而，TARP γ-8 在酒精使用障碍 (AUD) 或其他成瘾中的作用是不同的。 为了填补这一知识空白，我们提出了一套创新的行为、遗传、 双向系统性和位点特异性药理学、分子和生理学研究 小鼠评估 TARP γ-8 在酒精强化、自我升级中的机制作用 管理，以及线索诱导的酗酒行为恢复作为复发模型。 阐明这三个关键行为领域的神经机制具有很高的意义 对于理解 AUD 的发展、进展和维持具有转化价值。 成功完成本申请中的研究将提供基本机制 此外，这项工作还深入探讨了 TARP γ-8 对病理性饮酒行为的调节。 推动该领域进一步了解酒精劫持的分子机制 奖励过程并有可能为新药物治疗的开发提供信息 以高度选择性的大脑区域特异性方式针对 AMPAR 功能的策略。