Traumatic stress increases alcohol drinking via endocannabinoid disinhibition of basolateral amygdala

项目摘要 患有创伤后应激障碍（PTSD）的人更容易患上酒精使用障碍（AUD）， 一般人群，AUD是人类最常见的共同发生的精神健康障碍， 创伤后应激障碍这些疾病，单独或结合起来，影响着数百万美国人，导致数百万人死亡 全球范围内，并花费社会数十亿美元。这项建议将研究创伤性疾病的个体差异， 压力会影响男性和女性饮酒者的特定大脑回路，并会操纵这些回路， 测试他们在饮酒后压力升级中的作用。在这里，我们特别关注杏仁核去抑制 和内源性大麻素信号，但我们将收集血液和大脑样本， 预测性生物标志物，以及在替代大脑回路中的后续实验。 该项目福尔斯属于NIAAA支持生物学和行为学研究的使命范围 潜在的成瘾行为更重要的是，目前的建议解决了研究目标 通过在充分表征的PTSD动物模型中评估饮酒， 确定应激前饮酒与应激后酒精水平升高的关系， 饮酒，系统地测试性别对饮酒后应激升级的影响， 神经生物学过程，这些过程是饮酒后压力升级的基础，以及 确定PTSD患者酒精滥用潜在治疗的神经生物学靶点。具体来说， 一项应用提出了使用大鼠模型来研究神经生物学基础的压力诱导的升级 男性和女性动物的饮酒量。本申请提出了使用行为， 电生理学、生物化学和分子生物学技术，以确定创伤性脑回路的改变， 饮酒者亚群的压力，并直接测试这些回路在饮酒升级中的作用 压力之后。这项工作的总体目标是测试杏仁核和大脑的作用。 内源性大麻素信号在创伤应激诱导的饮酒升级中的作用 亚群

Project Summary Humans with post-traumatic stress disorder (PTSD) are more likely to develop alcohol use disorder (AUD) than the general population, and AUD is the most commonly co-occurring mental health disorder in humans with PTSD. These conditions, separately and combined, affect millions of American, cause millions of deaths worldwide, and cost society billions of dollars. This proposal will examine individual differences in traumatic stress effects on specific brain circuits in male and female alcohol drinkers, and will manipulate those circuits to test their role in post-stress escalation of alcohol drinking. Here, we focus specifically on amygdala disinhibition and endocannabinoid signaling, but we will collect blood and brain samples that allow for subsequent analysis of predictive biomarkers, as well as follow-up experiments in alternate brain circuits. This project falls within the scope of the NIAAA mission to support biological and behavioral research underlying addictive behaviors. More importantly, the current proposal addresses the research objectives outlined in RFA-AA-17-016 by assessing alcohol drinking in a well characterized animal model of PTSD, determining the association of pre-stress alcohol drikning with the development of post-stress escalation of alcohol drinking, systematically testing the effect of sex on post-stress escalation of alcohol drinking, identifying neurobiological processes that underlie the transition to post-stress escalation of alcohol drinking, and identifying neurobiological targets for potential treatment of alcohol abuse in PTSD patients. Specifically, this application proposes the use of rat models to examine the neurobiology underlying stress-induced escalation of alcohol drinking in male and female animals. This application proposes the use of behavioral, electrophysiology, biochemistry, and molecular biology techniques to identify brain circuits altered by traumatic stress in subsets of alcohol drinkers, and to directly test the role of those circuits in escalated alcohol drinking after stress. The overall goals of the proposed work are to test the role of 1) amygdala disnihibition and 2) brain endocannabinoid signaling in traumatic stress-induced escalation of alcohol drinking in a stress-susceptible subpopulation.