Mouse Chronic Intermittent Ethanol (CIE) Core

描述(申请人提供)：虽然压力对乙醇消耗的影响已经在几个动物模型中进行了广泛的研究，但这些研究得出了模棱两可的结果，结果取决于各种因素，包括使用的应激源类型、压力呈现的时机、最初的酒精偏好等。INIAStress联合会为这篇文献做出了贡献，主要证明了各种应激源的急性/亚慢性给药导致各种小鼠模型的乙醇摄入受到抑制。相反，我们实验室的结果表明，反复的慢性间歇性乙醇(CIE)暴露可以可靠地导致C57BL/6J小鼠自愿饮酒的增加。此外，很明显，CIE的反复暴露本身就构成了一种强有力的压力源，在神经和生理系统中产生了深刻的干扰。这导致了一种普遍的观念，即慢性乙醇暴露和戒断经历会在应激和奖赏回路中的神经生理系统中产生持续的扰动，使生物体负担超过正常的体内平衡极限(即，异体平衡状态)。据推测，这些神经适应不仅影响应激反应，还在驱动/促进与依赖相关的过度饮酒方面发挥作用。这个小鼠CIE核心的一个主要目标是提供对酒精依赖(CIE暴露)和应激对各种遗传小鼠模型中自愿乙醇摄入的影响的全面的行为表型评估，并提供器官组织样本(例如，脑、血浆、肾上腺)，用于其他INIA应激项目。具体地说，在这个核心进行的研究将集中于表征CIE单独暴露以及与各种应激程序结合对依赖和非依赖动物自愿饮酒的影响。这些研究将在C57BL/6小鼠以及INIAStress Consortium建立的独特小鼠模型上进行，包括BXD RL品系和具有靶向基因缺失的条件性(可诱导)基因敲除小鼠。这将为指导INIAStress联合会的其他研究组成部分进行更深入的分析(内分泌、神经化学、电生理学、遗传/基因组)提供关键信息。通过这种方式，核心起到了集中作用，不仅向其他项目提供了关于CIE/STREST在不同小鼠基因类型中相互作用的最佳实验参数，而且它还创建了一个框架，将促进整合来自各种INIAStress项目的各种研究结果，这些项目与该联盟的整体研究主题和目标相关。 与公共健康相关：过度饮酒和酗酒是主要的公共健康问题。这个研究核心在INAress联盟中发挥着核心作用，它提供了关于压力-乙醇相互作用的有价值的信息和资源，这些信息和资源不仅将为该联盟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了解。这对于开发新的、更有效的酒精滥用和酒精中毒治疗方法至关重要。

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.