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

描述（由申请人提供）：酒精中毒是一种病因学和临床异质性疾病，其中强迫性酒精寻求和使用是核心症状。接触酒精是必要的先决条件。环境和遗传因素也可以在控制个体对酒精滥用的脆弱性方面发挥巨大作用。然而，环境压力和遗传因素在酗酒发展中的相互作用在很大程度上仍未被探索。了解这种相互作用在调节个人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，可能为制定预防战略或药物治疗补救措施提供宝贵的帮助。在这项应用中，我们建议使用遗传选择的Marchigian Sardinian酒精偏好（msP） msP大鼠，这些大鼠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，边缘系统中的CRF1R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、压力和酒精中毒剂量的后果来实现。长期目标是确定新的有效的药物治疗方法酒精中毒。实验计划评估急性和慢性治疗CRF1R拮抗剂对非依赖和依赖后msP大鼠狂欢酒精饮酒、复发和焦虑样行为的影响。利用电生理学、原位杂交、放射自显影和脑微透析技术，我们希望在神经回路和功能水平上获得CRF1R系统在先天易感或环境诱导（酒精依赖）滥用乙醇倾向中的意义。参与本研究的关键人员拥有完成这一多学科项目所需的所有必要专业知识。特别是，Dr. Ciccocioppo博士将监督行为实验、育种计划和动物选择。M. Roberto博士将致力于电生理学实验和研究项目协调。L. Parsons博士将进行神经化学实验。Drs。M. Heilig和G. Schumann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病因学中的相互作用尚不清楚。本应用程序研究了这些因素在一个创新的遗传动物模型中的相互作用，通过确定是否有选择地饲养过度饮酒表型的大鼠共同遗传了脑应激系统的失调。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的研究，这对于理解基因决定的对过量饮酒的易感性、对压力的先天超敏性和乙醇诱导的大脑压力系统的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对酒精中毒药物治疗的发展具有不可估量的价值。

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.