Role of Neuropeptides in Stress-Induced Escalation of Alcohol Drinking

描述（由申请人提供）：酒精使用障碍（AUD）每年在全球造成250多万人死亡，全球损失5800多万生命年，仅在美国就造成2200亿美元的经济损失。创伤后应激障碍（PTSD）影响着770万美国人，每年耗费美国数十亿美元。在美国不断卷入海外军事冲突的时期，这些问题的范围将会扩大。目前缺乏直接调查创伤性应激导致酒精使用增加的神经生物学研究。本研究旨在确定PTSD患者酒精滥用的神经生物学基础，最终目标是制定有效的治疗策略，以减少PTSD患者的饮酒。该项目属于NIAAA的任务范围，即支持对酗酒的原因和治疗进行生物医学和行为研究。更具体地说，本申请建议使用大鼠模型，通过综合行为学、药理学、分子生物学和光遗传学技术的多学科方法，研究创伤应激后过度饮酒的生物学基础。这个问题对于NIAAA的使命来说尤其重要，因为创伤性应激障碍患者酗酒的比例很高，而且AUD和PTSD都提高了人类的死亡率，缩短了人类的寿命。这项应用的长期目标是了解AUD和PTSD合并症的神经生物学基础，并确定有希望减少PTSD患者酒精滥用的药物治疗。提出的目的是研究杏仁核神经肽和特定杏仁核输出通路在介导创伤应激诱导的饮酒和负面情绪中的作用。这一提议的首要假设是，杏仁核中的神经肽介导创伤性应激引起的饮酒升级。

DESCRIPTION (provided by applicant): Alcohol Use Disorder (AUD) is responsible each year for more than 2.5 million deaths worldwide, more than 58 million life years lost worldwide, and $220 billion financial cost in the United States alone. Post-Traumatic Stress Disorder (PTSD) affects 7.7 million Americans, and PTSD costs the U.S. billions of dollars annually. These problems will increase in scope during a time of perpetual U.S. involvement in overseas military conflicts. There is a lack of research directly investigating the neurobiology of traumatic stress-induced escalation of alcohol use. This proposal seeks to identify the neurobiological basis for alcohol abuse in individuals with PTSD, with the ultimate goal of contributing to the tailoring of effective therapeutic strategies to reduce alcohol drinking in humans with PTSD. This project falls within the scope of the NIAAA mission to support biomedical and behavioral research on the causes and treatment of alcoholism. More specifically, this application proposes the use of rat models to investigate the biological basis for excessive alcohol drinking following exposure to traumatic stress by using a multi-disciplinary approach that integrates behavior, pharmacology, molecular biology, and optogenetics techniques. This question is particularly important for the mission of the NIAAA because of the high rate of alcohol abuse in individuals with traumatic stress disorders, and the fact that AUD and PTSD each promote mortality and shorten life spans in humans. The long-term goals of this application are to understand the neurobiological basis of co-morbid AUD and PTSD, and to identify pharmacotherapies with promise for reducing alcohol abuse in individuals with PTSD. The proposed aims will investigate the role of amygdala neuropeptides and specific amygdala output pathways in mediating traumatic stress-induced alcohol drinking and negative affect. The overarching hypothesis of this proposal is that neuropeptides in the amygdala mediate traumatic stress-induced escalation of alcohol drinking.