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: 7918896
• 负责人: JULIA ANN CHESTER
• 金额: $ 23.03万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918896
• 关键词: Adrenal Glands; Alcohol consumption; Alcoholism; Alcohols; Animal Model; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavioral; Biological Factors; Breeding; Chronic; Comorbidity; 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; 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）：人口中创伤后应激障碍（PTSD）（PTSD）和酒精使用障碍之间的合并症发生率非常高。一些证据表明，PTSD和酒精使用障碍的共同发生可能是由于影响两种疾病风险的遗传遗传和生物学因素引起的。但是，这些危险因素在合并疾病发展中的作用尚未在人类中定义。该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遗传和生物学因素，这些因素可能会影响人类中PTSD和合并症酒精使用障碍的风险。可以通过检查对恐惧/焦虑的敏感性与对饮酒行为的易感性之间的关系来实现这一目标，而小鼠管线中的饮酒行为有选择性地繁殖为高（HAP1和HAP2）或低（LAP1和LAP2）酒精偏爱。学习的恐惧/焦虑将使用恐惧感激发（FPS）作为PTSD的动物模型来衡量。特定目标1的目的是确定FPS测量的学习恐惧/焦虑是否与饮酒的遗传倾向有关，并检查酒精对HAP/LAP线中FPS的获取和表达的影响。特定目标2的目的是测试获得学习的恐惧/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爱的遗传倾向。特定目的3的目的是通过测量皮质酮反应曲线来表征下丘脑 - 垂体 - 肾上腺（HPA）轴的功能，以响应HAP/LAP线的恐惧调节，并检查外源性皮质酮对FPS采集的影响。该R01项目的结果将提供有关遗传和生物学因素的令人兴奋且新颖的临床前数据，这些数据可能影响开发合并症PTSD和酒精使用障碍的风险。这项工作可能有助于制定行为和药理治疗策略，以减少患有这些合并症风险增加的人的合并症PTSD和酒精使用障碍。在人群中，创伤后应激障碍（PTSD）是一种焦虑症，是一种焦虑症，经常会出现与酒精疾病有关的焦虑症，被称为统治统计的焦虑症。该项目的目的是使用酒精中毒的遗传动物模型来研究遗传和生物学因素，这些因素可能影响人类中PTSD和合并酒精使用障碍的风险。这项工作可能有助于制定行为和药理治疗策略，以减少合并症PTSD和酒精使用障碍的发生率。

项目成果

Effects of the novel endocannabinoid uptake inhibitor, LY2183240, on fear-potentiated startle and alcohol-seeking behaviors in mice selectively bred for high alcohol preference.

• DOI: 10.1007/s00213-010-1997-2
• 发表时间: 2010-12
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Powers, Matthew S.;Barrenha, Gustavo D.;Mlinac, Nate S.;Barker, Eric L.;Chester, Julia A.
• 通讯作者: Chester, Julia A.