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患上酒精中毒和创伤后应激障碍(PTSD)的易感性的风险因素，以便为这些障碍制定和实施适当的预防和治疗策略。内源性大麻素系统(ECS)调节焦虑相关的饮酒行为，已被确定为治疗焦虑症和酒精中毒的药物治疗的有前途的靶点。在这个R21项目中，一种独特的动物模型将被用来研究ECS在影响小鼠的恐惧相关行为中的作用，这些小鼠的酒精偏好遗传倾向不同。这种动物模型代表了人类患上酒精中毒和创伤后应激障碍的遗传风险增加。在具体目标1中，选择性地培育出高(HAP)和低(LAP)酒精偏好的雄性和雌性小鼠将被用来确定大脑区域特定水平的内源性大麻素、anandamine(AEA)和sn-2花生四烯基甘油(2-AG)是否与饮酒和恐惧相关行为的遗传倾向有关。在具体目标2中，将确定针对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对酒精偏好的遗传易感性。具体目标2的第二个目标是确定EC大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，关于ECS在调节酒精中毒和创伤后应激障碍共病的独特动物模型中与恐惧相关的行为方面的作用。该项目的结果可能有助于快速开发新的药理策略，以ECS为目标治疗酒精中毒和创伤后应激障碍的共病个体。这些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创伤后应激障碍的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)调节与焦虑相关的饮酒行为，已被确定为治疗焦虑症和酒精中毒的药物治疗的有前途的靶点。这个项目的目标是使用一种独特的动物模型，这种动物模型代表着增加的遗传风险，在人类中发展为酒精中毒和创伤后应激障碍的共病，以探索ECS在调节与焦虑相关的行为中的遗传差异方面的作用。该项目还将确定针对ECS的药物是否代表治疗酒精中毒和创伤后应激障碍共病的有效药物疗法。

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.