Mouse Chronic Intermittent Ethanol (CIE) Core

描述（由申请人提供）：虽然已经在几种动物模型中广泛研究了应激对乙醇消耗的影响，但这些研究产生了模棱两可的结果，结果取决于无数因素，包括所用应激源的类型、应激表现的时间、初始乙醇偏好等。INIastress联盟对此文献做出了贡献，主要证明各种应激源的急性/亚慢性给药导致各种小鼠模型中乙醇摄入量的抑制。相比之下，我们实验室的结果表明，重复周期的慢性间歇性乙醇（CIE）暴露可靠地产生C57 BL/6 J小鼠自愿饮酒的升级。此外，很明显，CIE暴露的重复周期本身构成了一个强大的应激源，在神经和生理系统中产生深刻的干扰。这导致了一个总体概念，即慢性乙醇暴露和戒断经历在压力和奖励回路内的神经生理系统中产生持续的扰动，使生物体超过正常的稳态极限（即，一种非稳态状态）。这些神经适应性被认为不仅影响压力反应，而且在驱动/促进与依赖相关的过度饮酒方面发挥作用。该小鼠CIE核心的主要目的是提供各种遗传小鼠模型中乙醇依赖（CIE暴露）和应激对自愿乙醇摄入的影响的综合行为表型评价，以及提供器官组织样品（例如，脑、血浆、肾上腺）用于其他INIA应激项目。具体而言，在本核心中进行的研究将侧重于描述CIE暴露单独以及与各种应激程序相结合对依赖性和非依赖性动物自愿饮酒的影响。这些研究将用C57 BL/6小鼠以及由INIastress Consortium产生的独特小鼠模型进行，包括BXD R1品系和具有靶向基因缺失的条件性（诱导型）敲除小鼠。这将为指导INIA应激联合会其他研究组成部分的更深入分析（内分泌、神经化学、电生理、遗传/基因组）提供重要信息。通过这种方式，核心服务于一个集中的功能，不仅告知其他项目有关CIE/压力相互作用在各种小鼠基因型的最佳实验参数，但它也创建了一个框架，将促进整合不同的研究结果从各种INIAstress项目相关的整体研究主题和目标的联盟。 公共卫生相关性：过度饮酒和酗酒是主要的公共卫生问题。该研究核心通过提供有关压力-乙醇相互作用的有价值的信息和资源，在INAstress联盟中发挥核心作用，这些信息和资源不仅将为联盟中的其他研究项目提供信息和指导，而且还将为一般领域提供新颖和独特的信息，这些信息将促进我们对促进过度饮酒的因素和机制的理解。这对于开发新的和更有效的治疗酒精滥用和酒精中毒的方法至关重要。

DESCRIPTION (provided by applicant): While the effect of stress on ethanol consumption has been extensively studied in several animal models, these studies have yielded equivocal findings, with results depending on a myriad of factors including the type of stressor used, timing of stress presentation, initial ethanol preference, among many others. The INIAstress Consortium has contributed to this literature, mostly demonstrating that acute/sub-chronic administration of various stressors results in suppression of ethanol intake in various mouse models. In contrast, results from our laboratory have demonstrated that repeated cycles of chronic intermittent ethanol (CIE) exposure reliably produces escalation of voluntary ethanol drinking in C57BL/6J mice. Further, it has become evident that repeated cycles of CIE exposure constitutes a potent stressor itself, producing profound disturbances in neural and physiological systems. This has led to the overarching notion that chronic ethanol exposure and withdrawal experience produces persistent perturbations in neurophysiological systems within stress and reward circuits that tax the organism beyond normal homeostatic limits (i.e., a state of allostasis). These neuroadaptations are postulated to not only impact stress responsiveness, but also play a role in driving/promoting excessive levels of drinking associated with dependence. A major objective of this Mouse CIE Core is to provide comprehensive behavioral phenotypic evaluation of the effect of ethanol dependence (CIE exposure) and stress on voluntary ethanol intake in various genetic mouse models, as well as provide organ tissue samples (e.g., brain, plasma, adrenals) for use in other INIAstress projects. Specifically, studies conducted in this Core will focus on characterizing the effects of CIE exposure alone and in combination with various stress procedures on voluntary drinking in dependent and nondependent animals. These studies will be conducted with C57BL/6 mice, as well as unique mouse models that have been generated by the INIAstress Consortium, including BXD Rl strains and conditional (inducible) knockout mice with targeted gene deletions. This will provide critical information for guiding more in-depth analyses (endocrine, neurochemical, electrophysiological, genetic/genomic) in other research components of the INIAstress Consortium. In this way, the Core serves a centralized function in not only informing other projects about optimal experimental parameters regarding CIE/stress interactions in various mouse genotypes, but it also creates a framework that will facilitate integration of diverse research findings from various INIAstress projects relevant to the overall research theme and goals of the Consortium. PUBLIC HEALTH RELEVANCE: Excessive alcohol consumption and alcoholism are major public health concerns. This Research Core serves a central function in the INAstress Consortium by providing valuable information and resources regarding stress-ethanol interactions that will not only inform and guide other research projects in the Consortium, but also provide the general field with novel and unique information that will advance our understanding about factors and mechanisms that promote excessive drinking. This is critical for development of new and more effective treatments for alcohol abuse and alcoholism.