Anxiety and Alcohol Drinking in a Genetic Animal Model of Alcoholism

描述（由申请人提供）：在人群中，创伤后应激障碍（PTSD）和酒精使用障碍之间的合并症发病率非常高。一些证据表明，创伤后应激障碍和酒精使用障碍的共同发生可能是由影响两种疾病风险的遗传、遗传和生物学因素引起的。然而，这些危险因素在人类共病发展中的作用尚未确定。这个R01项目的广泛、长期目标是使用酒精中毒的遗传动物模型来研究可能影响人类创伤后应激障碍和共病酒精使用障碍风险的遗传和生物学因素。这一目标将通过对高（HAP1和HAP2）或低（LAP1和LAP2）酒精偏好的小鼠品系进行选择性繁殖，研究习得性恐惧/焦虑的易感性与先天饮酒行为倾向之间的关系来实现。习得性恐惧/焦虑将使用恐惧增强惊吓（FPS）作为创伤后应激障碍的动物模型进行测量。具体目标1的目的是确定习得性恐惧/焦虑（通过FPS测量）是否与饮酒的遗传倾向有关，并检查酒精对HAP/LAP系中FPS的获得和表达的影响。具体目标2的目的是测试习得性恐惧/焦虑是否会增加随后的饮酒行为，并检查这种现象如何取决于酒精偏好的遗传倾向。具体目标3的目的是通过测量皮质酮反应谱来表征HAP/LAP系中下丘脑-垂体-肾上腺（HPA）轴对恐惧调节的反应，并检查外源性皮质酮给药对FPS获得的影响。这个R01项目的结果将为可能影响PTSD和酒精使用障碍共病风险的遗传和生物学因素提供令人兴奋和新颖的临床前数据。这项工作可能有助于制定行为和药物治疗策略，以减少患有这些共病疾病风险增加的人群的PTSD和酒精使用障碍的共病。在人群中，创伤后应激障碍（PTSD）是一种焦虑障碍，经常与酒精使用障碍一起发生，称为合并症。该项目的目标是使用酒精中毒的遗传动物模型来研究可能影响人类创伤后应激障碍和共病酒精使用障碍风险的遗传和生物学因素。这项工作可能有助于制定行为和药物治疗策略，以减少PTSD和酒精使用障碍共病的发生率。

DESCRIPTION (provided by applicant): There is a remarkably high incidence of co-morbidity between post-traumatic stress disorder (PTSD) and alcohol use disorders in the human population. Some evidence suggests that the co-occurrence of PTSD and alcohol use disorders may arise from inherited genetic and biological factors that influence the risk for both diseases. However, the roles of these risk factors in the development of co-morbid disease have not been defined in humans. The broad, long-term objective of this R01 project is to use a genetic animal model of alcoholism to study genetic and biological factors that may influence risk for PTSD and co-morbid alcohol use disorders in humans. This goal will be achieved by examining the relationship between susceptibility toward learned fear/anxiety and innate propensity toward alcohol drinking behavior in mouse lines that have been selectively bred for high (HAP1 and HAP2) or low (LAP1 and LAP2) alcohol preference. Learned fear/anxiety will be measured using fear-potentiated startle (FPS) as an animal model of PTSD. The goal of Specific Aim 1 is to determine if learned fear/anxiety, as measured by FPS, is associated with a genetic propensity toward alcohol drinking and to examine the effects of alcohol on the acquisition and expression of FPS in HAP/LAP lines. The goal of Specific Aim 2 is to test whether acquisition of learned fear/anxiety increases subsequent alcohol drinking behavior and to examine how this phenomenon may depend on a genetic predisposition toward alcohol preference. The goal of Specific Aim 3 is to characterize hypothalamic-pituitary-adrenal (HPA) axis function in response to fear-conditioning in HAP/LAP lines by measuring corticosterone response profiles and to examine the effect of exogenous corticosterone administration on the acquisition of FPS. The results of this R01 project will provide exciting and novel preclinical data on the genetic and biological factors that may influence risk for developing co-morbid PTSD and alcohol use disorders. This work may aid in the development of behavioral and pharmacological treatment strategies to reduce co-morbid PTSD and alcohol use disorders in people who have an increased risk for these co-morbid diseases.In the human population, post-traumatic stress disorder (PTSD) is an anxiety disorder that occurs frequently with alcohol use disorders, termed co-morbidity. The goal of this project is to use a genetic animal model of alcoholism to study genetic and biological factors that may influence risk for PTSD and co-morbid alcohol use disorders in humans. This work may aid in the development of behavioral and pharmacological treatment strategies to reduce the incidence of co-morbid PTSD and alcohol use disorders.