Anxiety and Alcohol Drinking in a Genetic Animal Model of Alcoholism

酒精中毒遗传动物模型中的焦虑和饮酒

• 批准号: 7369992
• 负责人: JULIA ANN CHESTER
• 金额: $ 25.41万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7369992
• 关键词: Adrenal Glands; Alcohol consumption; Alcoholism; Alcohols; Animal Model; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavioral; Biological Factors; Breeding; Chronic; Complex; Condition; Corticosterone; Data; Development; Disease; Etiology; Family history of; Fright; Genetic; Genetic Predisposition to Disease; Goals; Human; Hypothalamic structure; Incidence; Individual; Inherited; Learning; Maintenance; Measures; Modeling; Morbidity - disease rate; Mus; Pharmacological Treatment; Pituitary Gland; Population; Post-Traumatic Stress Disorders; Predisposition; Psyche structure; Risk; Risk Factors; Role; Signs and Symptoms; Stress; Testing; Work; alcohol effect; alcohol use disorder; chronic alcohol ingestion; conditioned fear; drinking behavior; human APEX1 protein; hypothalamic-pituitary-adrenal axis; novel; pre-clinical; preference; response

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.

描述（由申请人提供）：人群中创伤后应激障碍（PTSD）和酒精使用障碍之间的共病发生率非常高。一些证据表明，创伤后应激障碍和酒精使用障碍的同时发生可能是由于遗传和生物因素影响这两种疾病的风险。然而，这些危险因素在人类共病疾病发展中的作用尚未确定。 R01 项目的广泛、长期目标是利用酗酒的遗传动物模型来研究可能影响人类 PTSD 和共病酒精使用障碍风险的遗传和生物因素。这一目标将通过研究选择性培育高（HAP1和HAP2）或低（LAP1和LAP2）酒精偏好的小鼠品系对习得性恐惧/焦虑的易感性与先天饮酒行为倾向之间的关系来实现。将使用恐惧增强惊吓（FPS）作为 PTSD 动物模型来测量习得性恐惧/焦虑。具体目标 1 的目标是确定通过 FPS 测量的习得性恐惧/焦虑是否与饮酒的遗传倾向相关，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 的目标是测试习得性恐惧/焦虑的获得是否会增加随后的饮酒行为，并研究这种现象如何依赖于酒精偏好的遗传倾向。具体目标 3 的目标是通过测量皮质酮反应曲线来表征 HAP/LAP 系中下丘脑-垂体-肾上腺 (HPA) 轴功能对恐惧调节的反应，并检查外源性皮质酮给药对 FPS 获得的影响。该 R01 项目的结果将提供关于可能影响并发 PTSD 和酒精使用障碍风险的遗传和生物因素的令人兴奋且新颖的临床前数据。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共病 PTSD 和酒精使用障碍。在人群中，创伤后应激障碍 (PTSD) 是一种经常与酒精使用障碍一起发生的焦虑症，称为共病。该项目的目标是利用酗酒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，以减少共病创伤后应激障碍和酒精使用障碍的发生率。