Gene-environment interaction: the brain CRF system in alcohol preferring msP rats

基因-环境相互作用：酒精偏好的 mP 大鼠的大脑 CRF 系统

• 批准号: 8101371
• 负责人: MARISA ROBERTO
• 金额: $ 35.51万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101371
• 关键词: Acute; Affective; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animals; Anxiety; Area; Autoradiography; Behavior; Behavioral; Blood alcohol level measurement; Brain; Breeding; CRF receptor type 1; Chronic; Consult; Corticotropin-Releasing Hormone; Data; Dependence; Development; Disease; Dose; Electrophysiology (science); Environment; Ethanol; Ethanol dependence; Etiology; Functional disorder; Genes; Genetic; Genetic Polymorphism; Health; Heavy Drinking; Heritability; Human Resources; Hypersensitivity; In Situ Hybridization; Individual; Inherited; Investigation; Lead; Limbic System; Link; Microdialysis; Modeling; Molecular; Molecular Biology; Molecular Genetics; Mutation; Nature; Negative Reinforcements; Neurobiology; Pattern; Phenotype; Play; Predisposition; Prevention strategy; Rattus; Receptor Gene; Recording of previous events; Regulation; Relapse; Research; Risk; Role; Self Medication; Signal Transduction; Stress; Symptoms; System; Techniques; Transcript; Up-Regulation; Work; alcohol exposure; alcohol preferring rats; alcohol seeking behavior; depressive symptoms; drinking; drinking behavior; gene environment interaction; innovation; insight; multidisciplinary; neuroadaptation; neurochemistry; preconditioning; prevent; problem drinker; programs; promoter; receptor density; receptor function; research study; response

DESCRIPTION (provided by applicant): Alcoholism is an etiologically and clinically heterogeneous disorder in which compulsive alcohol seeking and use represent core symptoms. Exposure to alcohol is a necessary precondition. Environment and heritability factors can also play a dramatic role in controlling individual vulnerability to developing alcohol abuse. However, the interaction between environmental stress and heritable factors in the development of alcoholism is still largely unexplored. Understanding the nature of this interaction in regulating individual risk of becoming an alcohol abuser represents a major challenge in this research area and may provide invaluable help for the development of preventive strategies or pharmacotherapeutic remedies. In this application we propose to use the genetically selected Marchigian Sardinian alcohol-preferring (msP) msP rats, which have genetic polymorphism of the Corticotropin-Releasing Factor 1 Receptor (CRF1R) promoter, CRF1R density in the limbic system, and are highly sensitive to stress and stress-induced alcohol seeking, to provide information on the basic mechanisms controlling alcohol abuse progression. This will be achieved by looking at the consequences of exposing subjects with different innate propensities to developing alcohol abuse, to stress and to intoxicating doses of ethanol. The long term objective is to identify new effective pharmacotherapeutic approaches to alcoholism. Experiments are planned to evaluate the effect of acute and chronic treatment with CRF1R antagonists on binge ethanol drinking, relapse and anxiety-like behaviors in nondependent and postdependent msP rats. Using electrophysiology together with in situ hybridization, autoradiography and brain microdialysis technique, we expect to obtain information at neurocircuitry and at functional levels on the significance of the CRF1R system in the innate predisposition or environmentally-induced (alcohol dependence) propensity to abuse ethanol. The key personnel involved in the present study possess all the necessary expertise needed to accomplish such a multidisciplinary program. In particular, Dr. R. Ciccocioppo will supervise behavioral experiments, breeding programs and animal selections. Dr. M. Roberto will be dedicated to electrophysiology experiments and to research program coordination. Dr. L. Parsons will work on neurochemistry experiments. Drs. M. Heilig and G. Schumann will consult and collaborate on molecular biology and genetic studies respectively. PUBLIC HEALTH RELEVANCE: Heritability factors play a dramatic role in controlling individual vulnerability to developing alcohol abuse. However, the interaction between environmental stress, prolonged alcohol exposure and these heritable factors in the etiology of alcohol dependence is not well understood. The present application studies the interaction of these factors in an innovative genetic animal model by determining whether rats selectively bred for excessive-drinking phenotype co-inherit a dysregulation of the brain stress system. The experiments will provide a systematic investigation at molecular, neurochemical and behavioural levels of the proposed rat model that will be critical to understanding the link between genetically determined vulnerability to excessive alcohol drinking, innate hypersensitivity to stress and ethanol-induced neuroadaptation of the brain stress system. Insight into the nature and influence of these interactions may be invaluable in the development of pharmacotherapeutics for alcoholism.

描述(申请人提供)：酒精中毒是一种病因和临床上不同的疾病，其中强迫性酒精寻求和使用是核心症状。接触酒精是一个必要的前提条件。环境和遗传因素也可以在控制个人发展成酗酒的脆弱性方面发挥重要作用。然而，在酒精中毒的发展过程中，环境压力和遗传因素之间的相互作用在很大程度上仍然没有被探索。了解这种相互作用在调节个体成为酒精滥用者的风险方面的性质是这一研究领域的一项重大挑战，并可能为制定预防战略或药物治疗疗法提供宝贵的帮助。在这项应用中，我们建议使用遗传选择的Marchigian Sardian酒精偏好(MSP)MSP大鼠，这些大鼠边缘系统具有促肾上腺皮质激素释放因子1受体(CRF1R)启动子的遗传多态和CRF1R密度，并且对应激和应激诱导的酒精寻求高度敏感，以提供控制酒精滥用进展的基本机制的信息。这将通过观察具有不同天生倾向的受试者发展成酗酒、压力和醉人剂量的乙醇的后果来实现。长期目标是寻找治疗酒精中毒的新的有效药物治疗方法。本实验旨在评价CRF1R拮抗剂的急慢性治疗对非依赖和后依赖MSP大鼠酗酒、复发和焦虑样行为的影响。利用电生理学，结合原位杂交、放射自显影和脑微透析技术，我们期望从神经回路和功能水平上获得CRF1R系统在先天性易感性或环境诱导(酒精依赖)滥用酒精倾向中的重要性的信息。参与本研究的关键人员拥有完成这样一个多学科方案所需的所有必要专业知识。尤其是，R·奇科乔波博士将监督行为实验、繁殖项目和动物选择。罗伯托博士将致力于电生理学实验和研究项目协调。帕森斯博士将从事神经化学实验。海利格博士和舒曼博士将分别在分子生物学和遗传学研究方面进行咨询和合作。与公共健康相关：遗传因素在控制个人对酒精滥用的易感性方面发挥着重要作用。然而，在酒精依赖的病因中，环境压力、长期酒精暴露和这些遗传因素之间的相互作用还没有被很好地理解。本申请通过确定选择性繁殖的过度饮酒表型的大鼠是否共同继承了大脑应激系统的失调，在一个创新的遗传动物模型中研究了这些因素的相互作用。这些实验将在分子、神经化学和行为水平上对所提出的大鼠模型进行系统的研究，这对于理解过度饮酒的遗传易感性、对压力的先天超敏反应和乙醇诱导的大脑应激系统的神经适应之间的联系至关重要。对这些相互作用的性质和影响的洞察可能对酒精中毒的药物治疗的发展是非常宝贵的。