Novel mechanism of alcohol self-administration and relapse

项目摘要 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，我们提出了一套创新的行为，遗传， 双向全身性和部位特异性药理学、分子和生理学研究， 小鼠，以评估TARP γ-8在酒精强化、增强的自我调节、 给药，和线索诱导的酒精寻求行为的恢复作为复发的模型。 阐明这三个关键行为域的神经机制具有很高的 对理解AUD的发展、进展和维持具有翻译价值。 成功完成本申请中的研究将提供基本的机制 TARP γ-8对病理性酒精寻求行为的调节。此外，这项工作 推动了对酒精劫持分子机制的理解 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。

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.