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: 7930509
• 负责人: MARISA ROBERTO
• 金额: $ 36.95万
• 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/7930509
• 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; Heavy Drinking; Heritability; Human Resources; Hypersensitivity; In Situ Hybridization; Individual; Inherited; Investigation; Lead; Limbic System; Link; Microdialysis; Modeling; Molecular; Molecular Biology; 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; public health relevance; 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（由申请人提供）：酒精中毒是一种病因和临床异质性疾病，其中强迫性酒精寻求和使用是核心症状。酒精是一个必要的先决条件。环境和遗传因素也可以发挥巨大的作用，在控制个人的脆弱性，发展酒精滥用。然而，环境压力和遗传因素在酒精中毒发展中的相互作用在很大程度上仍未被探索。了解这种相互作用的性质，在调节个人风险，成为一个酒精滥用者是一个重大的挑战，在这一研究领域，并可能提供宝贵的帮助，预防策略或药物治疗的发展。在本申请中，我们建议使用遗传选择的Marchigian撒丁岛酒精偏好（msP）msP大鼠，其具有促肾上腺皮质激素释放因子1受体（CRF1R）启动子的遗传多态性，CRF1R在边缘系统中的密度，并且对压力和压力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。这将通过观察将具有不同先天倾向的受试者暴露于酒精滥用、压力和致醉剂量的乙醇的后果来实现。长期的目标是确定新的有效的药物治疗酗酒的方法。实验计划评估急性和慢性治疗与CRF1R拮抗剂对酗酒饮酒，复发和焦虑样行为的非依赖性和后依赖性msP大鼠的影响。使用电生理学与原位杂交，放射自显影和脑微透析技术，我们希望获得的信息，在神经回路和功能水平上的意义的CRF1R系统的先天易感性或环境诱导的（酒精依赖）倾向滥用乙醇。参与本研究的关键人员拥有完成这样一个多学科项目所需的所有必要的专业知识。特别是R博士。Ciccocioppo将监督行为实验，育种计划和动物选择。M博士罗伯托将致力于电生理学实验和研究项目协调。Dr. L.帕森斯将从事神经化学实验。M博士Heilig和G.舒曼将分别在分子生物学和遗传学研究方面进行咨询和合作。公共卫生相关性：遗传性因素在控制个体对酒精滥用的脆弱性方面发挥着巨大的作用。然而，环境压力，长期酒精暴露和这些遗传因素在酒精依赖的病因学之间的相互作用还没有得到很好的理解。本申请通过确定为过量饮酒表型选择性饲养的大鼠是否共同遗传了脑应激系统的失调来研究这些因素在创新的遗传动物模型中的相互作用。这些实验将在分子、神经化学和行为水平上对拟议的大鼠模型进行系统研究，这对于理解遗传决定的对过量饮酒的脆弱性、对压力的先天超敏反应和乙醇诱导的大脑压力系统神经适应之间的联系至关重要。深入了解这些相互作用的性质和影响可能是非常宝贵的药物治疗酒精中毒的发展。