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

描述（由申请人提供）：目前迫切需要确定风险因素，增加发展共病酗酒和创伤后应激障碍（PTSD）的脆弱性，以便为这些疾病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，并已被确定为治疗焦虑症和酒精中毒的药物治疗的一个有前途的目标。对于这个R21项目，一个独特的动物模型，代表增加遗传风险，发展共病酒精中毒和创伤后应激障碍的人类将被用来研究ECS在影响小鼠的恐惧相关行为的作用，不同的遗传倾向对酒精的偏好。在特定目标1中，选择性饲养高（HAP）和低（HAP）酒精偏好的雄性和雌性小鼠将用于确定内源性大麻素，大麻素（AEA）和sn-2花生四烯酸甘油（2-AG）的大脑区域特异性水平是否与饮酒和恐惧相关行为的遗传倾向相关。在具体目标2中，将确定靶向ECS的药物是否减少与恐惧相关的行为，以及这些影响是否取决于酒精偏好的遗传倾向。具体目标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。该项目的结果将提供令人兴奋的新的临床前数据的作用，ECS在调节恐惧相关的行为在一个独特的动物模型，共病酒精中毒和创伤后应激障碍。该项目的结果可能有助于快速开发针对ECS的新药理学策略，以治疗患有酒精中毒和PTSD的患者。研究结果还可能有助于确定药物治疗或药物预防方法，这些方法对酒精中毒和PTSD遗传风险增加的人特别有效。 公共卫生相关性：内源性大麻素系统（ECS）调节焦虑相关和饮酒行为，并已被确定为治疗焦虑症和酒精中毒的药物治疗的一个有前途的目标。该项目的目标是使用一种独特的动物模型，该模型代表了人类发展酒精中毒和PTSD共病的遗传风险增加，以探索ECS在调节焦虑相关行为的遗传差异中的作用。该项目还将确定靶向ECS的药物是否可以代表治疗患有酒精中毒和创伤后应激障碍的个体的有效药物疗法。

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.