Anxiety in a genetic animal model of alcoholism: role of endocannabinoids

描述（由申请人提供）：目前迫切需要确定增加酗酒和创伤后应激障碍（PTSD）共病易感性的风险因素，以便设计和实施适当的预防和治疗策略。内源性大麻素系统（ECS）调节焦虑相关和饮酒行为，已被确定为药物治疗焦虑障碍和酒精中毒的有希望的目标。在这个R21项目中，一个独特的动物模型代表了人类酒精中毒和创伤后应激障碍共病的遗传风险增加，将用于研究ECS在影响酒精偏好基因倾向不同的小鼠的恐惧相关行为中的作用。在Specific Aim 1中，选择高（HAP）和低（LAP）酒精偏好的雄性和雌性小鼠将被用来确定内源性大麻素，anandamide （AEA）和sn-2花生四烯酰基甘油（2-AG）的大脑区域特定水平是否与饮酒和恐惧相关行为的遗传倾向有关。在Specific Aim 2中，将确定靶向ECS的药物是否会减少恐惧相关行为，以及这些影响是否取决于酒精偏好的遗传易感性。Specific Aim 2的第二个目标是确定EC脑水平是否与观察到的药物对恐惧相关行为表达的影响相关。这个项目的结果将提供令人兴奋的新的临床前数据，在一个独特的酒精中毒和创伤后应激障碍共病的动物模型中，ECS在调节恐惧相关行为中的作用。这个项目的结果可能会促进新的药理学策略的快速发展，以ECS为目标，治疗酗酒和创伤后应激障碍合并症。研究结果还可能有助于确定药物治疗或药物预防方法，这些方法对酗酒和创伤后应激障碍遗传风险增加的人群特别有效。

DESCRIPTION (provided by applicant): There is currently an urgent need to identify risk factors that increase vulnerability to develop co-morbid alcoholism and post-traumatic stress disorder (PTSD) in order to devise and implement appropriate prevention and treatment strategies for these disorders. The endocannabinoid system (ECS) modulates anxiety-related and alcohol drinking behaviors and has been identified as a promising target for pharmacotherapies to treat anxiety disorders and alcoholism. For this R21 project, a unique animal model that represents increased genetic risk to develop co-morbid alcoholism and PTSD in humans will be used to study the role of the ECS in influencing fear-related behavior in mice that differ in genetic propensity toward alcohol preference. In Specific Aim 1, male and female mice selectively bred for high (HAP) and low (LAP) alcohol preference will be used to determine whether brain region specific levels of the endocannabinoids, anandamide (AEA) and sn-2 arachidonylglycerol (2-AG), are associated with genetic propensity toward alcohol drinking and fear-related behavior. In Specific Aim 2, it will be determined whether drugs that target the ECS reduce fear-related behavior and whether these effects depend on genetic predisposition toward alcohol preference. The secondary goal of Specific Aim 2 is to determine whether EC brain levels are correlated with observed drug effects on the expression of fear-related behavior. The results of this project will provide exciting new preclinical data on the role of the ECS in modulating fear-related behavior in a unique animal model for co- morbid alcoholism and PTSD. Results from this project may facilitate rapid development of novel pharmacological strategies that target the ECS to treat individuals with co-morbid alcoholism and PTSD. The results may also help identify pharmacotherapy or pharmacoprevention approaches that are particularly effective in people who are at increased genetic risk for both alcoholism and PTSD. PUBLIC HEALTH RELEVANCE: The endocannabinoid system (ECS) modulates anxiety-related and alcohol drinking behaviors and has been identified as a promising target for pharmacotherapies to treat anxiety disorders and alcoholism. The goal of this project is to use a use a unique animal model that represents increased genetic risk to develop co-morbid alcoholism and PTSD in humans to explore the role of the ECS in regulating genetic differences in anxiety- related behavior. The project will also determine whether drugs that target the ECS may represent effective pharmacotherapies to treat individuals with co-morbid alcoholism and PTSD.