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

酒精中毒遗传动物模型中的焦虑：内源性大麻素的作用

基本信息

批准号：
8052898
负责人：
ERIC L BARKER
金额：
$ 21.99万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2013-03-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：目前迫切需要确定危险因素增加脆弱性，以开发酗酒和创伤后应激障碍（PTSD），以设计和实施这些疾病的适当预防和治疗策略。内源性大麻素系统（ECS）调节了与焦虑有关的和饮酒行为调节，并被确定为治疗焦虑症和酒精中毒的药物治疗的有希望的靶标。对于这个R21项目，一种独特的动物模型，代表了增加遗传风险在人类中发生合并性酒精中毒和PTSD的遗传风险，将用于研究EC在影响小鼠恐惧相关行为中的作用。在特定的目标1中，将使用针对高（HAP）和低（LAP）酒精偏爱的雄性和雌性小鼠确定大脑区域特定水平的内源性大麻素，anandamide（AEA）和SN-2 Arachidonyllglycerol（2-AGAG）），与饮酒和与恐惧相关的行为的遗传倾向有关。在特定的目标2中，将确定针对EC的药物是否会减少与恐惧相关的行为以及这些影响是否取决于遗传倾向对酒精偏爱。特定目标2的次要目标是确定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临床前数据，以了解EC在调节恐惧相关行为中的作用中，以用于病毒性酒精中毒和PTSD的独特动物模型。该项目的结果可能有助于促进针对EC的新型药理学策略的快速发展，以治疗患有酒精中毒和PTSD的个体。结果还可能有助于鉴定药物治疗或药物预防方法，这些方法对于那些对酒精中毒和PTSD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）调节与焦虑有关的饮酒行为，并被确定为治疗焦虑症和酒精中毒的药物治疗的有希望的靶标。该项目的目的是使用一种独特的动物模型，该模型代表了增加遗传风险，以发展人类合并症酒精中毒和PTSD，以探索ECS在调节焦虑相关行为中遗传差异中的作用。该项目还将确定针对ECS的药物是否可以代表有效的药物治疗，以治疗患有酒精中毒和PTSD的个体。