Novel mechanism of alcohol self-administration and relapse

酒精自我管理和复发的新机制

• 批准号: 10615331
• 负责人: Clyde W Hodge
• 金额: $ 7.87万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10615331
• 关键词: AMPA Receptors; Abstinence; Administrative Supplement; Affect; Alcohol consumption; Alcohols; Amygdaloid structure; Behavior; Behavior Therapy; Behavioral; Behavioral Genetics; Behavioral Model; Brain; Brain region; Complement; Consummatory Behavior; Cues; Data; Development; Environment; Exposure to; G-substrate; Gene Expression; Genes; Genetic; Glutamates; Intake; Knowledge; Lead; Learning; Link; Maintenance; Mediating; Memory; Methods; Modeling; Molecular; Mus; Parents; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physiological; Process; Property; Prosencephalon; Protein Family; Proteins; Protocols documentation; Psychological reinforcement; Publications; Regulation; Relapse; Research Training; Rewards; Role; Scientist; Self Administration; Site; Slice; Stimulus; Synaptic plasticity; System; Techniques; Testing; Viral Vector; Work; addiction; alcohol effect; alcohol reinforcement; alcohol reward; alcohol seeking behavior; alcohol use disorder; behavioral pharmacology; behavioral plasticity; calmodulin-dependent protein kinase II; career; clinical practice; conditioned place preference; conditioning; craving; design; drug of abuse; drug reward; experimental study; genetic regulatory protein; incentive salience; inhibitor; innovation; insight; interdisciplinary approach; mind control; multidisciplinary; neuromechanism; novel; novel therapeutic intervention; overexpression; parent grant; pre-clinical; preclinical study; problem drinker; protein expression; public health relevance; receptor; relating to nervous system; therapeutic target; trafficking; transmission process

Project Summary / Abstract 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, the parent R01 project is conducting 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. In this Administrative Supplement to Promote Diversity, it is proposed that the candidate will enhance and extend this work by evaluating: 1) the mechanistic role of TARP γ-8 in alcohol reward using conditioned place preference (CPP); and 2) alcohol- induced changes in TARP γ-8 (Cacng8) gene expression in the amygdala and other reward- related brain regions in mice. These innovative experiments are within the scope but not redundant with studies proposed in the parent grant and will provide continued research training and additional publications to promote the candidate’s career trajectory toward being an independent academic scientist focused on evaluating the neural mechanisms of AUD. Successful completion of the studies proposed in this Administrative Supplement for Diversity will move 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.

项目总结/摘要 病理性酒精寻求行为部分受谷氨酸AMPA受体（AMPAR）调节 杏仁核的活动。跨膜AMPA受体调节蛋白（TARP） 影响AMPAR在突触和行为可塑性中的运输和功能。虽然 TARP蛋白家族在整个大脑中表达，TARP γ-8亚型仅限于 包括基底外侧杏仁核（BLA）在内的前脑区域;这是一个对 成瘾然而，TARP γ-8在酒精使用障碍（AUD）或其他成瘾中的作用是 未知为了填补这一知识空白，母R 01项目正在进行一系列创新的 行为、遗传、双向全身和位点特异性药理学、分子和 在小鼠中进行生理学研究以评估TARP γ-8在酒精中的机制作用 强化，自我管理升级，以及线索诱导的酒精寻求恢复 作为复发的模型。在这份促进多样性的行政补充文件中， 我建议候选人将通过评估来加强和扩展这项工作：1） TARP γ-8在使用条件性位置偏好（CPP）的酒精奖励中的作用; 2）酒精- 诱导杏仁核和其他奖赏核中TARP γ-8（Cacng 8）基因表达的变化。 相关的大脑区域。这些创新性的实验是在范围内，但不是 与父母补助金中提出的研究多余，并将提供持续的研究培训 以及其他出版物，以促进候选人的职业轨迹， 独立学术科学家专注于评估AUD的神经机制。 成功完成本多样性行政补充文件中提出的研究， 推动该领域在理解酒精劫持的分子机制 奖励过程，并有可能为新药物的开发提供信息 以高度选择性的大脑区域特异性方式靶向AMPAR功能的策略。