Novel mechanism of alcohol self-administration and relapse

项目摘要/摘要 病理性寻酒行为部分受谷氨酸AMPA受体(AMPAR)调节 杏仁核的活动。深刻的跨膜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。尽管 TARP家族蛋白在整个大脑中表达，TARPγ-8亚型仅限于 前脑区域，包括基底外侧杏仁核(BLA)；这是一个对 上瘾。然而，TARPγ-8在酒精使用障碍或其他成瘾中的作用是 未知。为了填补这一知识空白，父R01项目正在进行一系列创新的 行为、遗传、双向系统和特定部位的药理、分子和 TARPγ-8在小鼠体内酒精作用机制的生理学研究 强化、自我管理升级和线索诱导的酒精寻觅恢复 将行为作为旧病复发的模式。在这份促进多样性的行政副刊中， 建议候选人通过以下方式加强和扩展这项工作：1)机械性 TARPγ-8在条件性位置偏爱酒精奖赏中的作用 诱导杏仁核TARPγ-8(Cacng8)基因表达的变化及其他奖赏- 小鼠的相关脑区。这些创新的实验是在范围之内的，但不是 与家长资助中建议的研究重复，并将提供持续的研究培训 和其他出版物，以促进候选人的职业轨迹成为 独立的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编中提议的研究将 推动该领域在理解酒精劫持的分子机制方面取得进展 奖励过程，并有可能为新药物疗法的开发提供信息 以高度选择性的大脑区域特定方式瞄准AMPAR功能的策略。

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.