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: 7681096
• 负责人: JULIA ANN CHESTER
• 金额: $ 23.31万
• 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/7681096
• 关键词: Adrenal Glands; Alcohol consumption; Alcoholism; Alcohols; Animal Model; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavioral; Biological Factors; Breeding; Chronic; Complex; 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; Testing; Work; alcohol availability; alcohol effect; alcohol use disorder; chronic alcohol ingestion; conditioned fear; drinking behavior; human APEX1 protein; hypothalamic-pituitary-adrenal axis; novel; pre-clinical; preference; response; treatment strategy

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）：在人群中，创伤后应激障碍（PTSD）和酒精使用障碍之间的共病率非常高。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源于影响这两种疾病风险的遗传和生物因素。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R 01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。这一目标将通过检查对学习的恐惧/焦虑的易感性和对饮酒行为的先天倾向之间的关系来实现，这些小鼠系被选择性地培育为高（HAP 1和HAP 2）或低（LAP 1和LAP 2）酒精偏好。习得性恐惧/焦虑将使用恐惧增强惊吓（FPS）作为PTSD的动物模型进行测量。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/HAP细胞系中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/焦虑是否会增加随后的饮酒行为，并研究这种现象如何取决于对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）轴对恐惧条件反射的反应功能，并检查外源性皮质酮给药对FPS获得的影响。该R 01项目的结果将提供有关遗传和生物学因素的令人兴奋和新颖的临床前数据，这些因素可能影响患上PTSD和酒精使用障碍共病的风险。这项工作可能有助于行为和药物治疗策略的发展，以减少共病PTSD和酒精使用障碍的人谁有这些共病diseases.In人类population的风险增加，创伤后应激障碍（PTSD）是一种焦虑症，经常发生与酒精使用障碍，称为共病。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PTSD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行为和药物治疗策略的发展，以减少并发PTSD和酒精使用障碍的发生率。