Ethanol Dependence and Stress Effects on Ethanol Drinking: CRF & Neurosteroids

描述（由申请人提供）：众多生物和环境因素之间的复杂相互作用决定了乙醇（EtOH）寻求和饮酒行为。虽然压力被认为是乙醇滥用和酒精中毒的一个重要因素，但压力和乙醇饮酒行为之间的相互作用还没有得到很好的理解。当人们考虑在EtOH依赖性的背景下应激对EtOH自我给药的作用/影响时，这一点尤其正确。长期过量使用EtOH可导致依赖性的发展，反复经历相关戒断事件可能构成一种强大的动力，导致EtOH使用/滥用的持续存在。此外，由于长期EtOH暴露导致的脑/神经内分泌应激和奖励系统的功能变化可能使受试者不仅更容易过度饮酒，而且更容易发生可能在戒断期（复发）后重新开始使用EtOH的事件（应激）。不幸的是，很少有人知道与压力和乙醇消耗之间的关系，以及这种相互作用的依赖性的背景下的机制相关的动态。在当前的资助期间，我们将EtOH依赖和饮酒模型联系起来，以证明慢性EtOH暴露和戒断经历的重复周期会增强随后的自愿EtOH消费。这项建议是在这项工作的基础上提出和扩大的，重点是阐明这一现象背后的机制。具体来说，拟议的研究将集中在神经肽CRF和神经活性类固醇allopregnanolone，因为它们与应激反应（涉及神经内分泌相关和独立的大脑应激途径）以及EtOH依赖性和EtOH自我管理行为密切相关。该提案的总体重点是利用已建立的EtOH依赖性小鼠模型来检查与慢性EtOH暴露/戒断（脑CRF和别普奈龙活性的变化）的重复循环相关的应激影响随后的EtOH自我给药行为以及应激诱导的复发行为的机制。因此，该项目不仅填补了与EtOH依赖和压力相关的文献空白，而且重要的是，它针对INIA压力联盟的主要总体主题，并补充了联盟中具有类似研究重点的其他项目。这项研究提案的结果将提供新的和新颖的信息，可能的机制基础/介导之间的相互作用EtOH依赖，压力和EtOH饮酒/复发行为，这是相关的INIA压力协会，以及一般的酒精领域。总的目标是提供一个更完整和全面的分析的生物学基础和环境条件下，压力有助于过量乙醇饮用和酗酒的发展。

DESCRIPTION (provided by applicant): A complex interplay among numerous biological and environmental factors govern both ethanol (EtOH) seeking and drinking behavior. While stress has been viewed as an important contributing factor to EtOH abuse and alcoholism, the interaction between stress and EtOH drinking behavior is not well understood. This is especially true when one considers the role/impact of stress on EtOH self-administration in the context of EtOH dependence. Chronic excessive consumption of EtOH can lead to the development of dependence, and repeated experience with associated withdrawal episodes may constitute a powerful motivational force that contributes to the perpetuation of EtOH use/abuse. Further, functional changes in brain/neuroendocrine stress and reward systems as a result of chronic EtOH exposure may render subjects not only more vulnerable to engage in excessive EtOH drinking, but also more susceptible to events (stress) that may trigger re-initiation of EtOH use after periods of abstinence (relapse). Unfortunately, little is known about the dynamics associated with the relationship between stress and EtOH consumption, as well as mechanisms underlying this interaction in the context of dependence. During the current funding period, we linked a model of EtOH dependence and drinking to demonstrate that repeated cycles of chronic EtOH exposure and withdrawal experience enhances subsequent voluntary EtOH consumption. This proposal builds and expands on this work, with an emphasis on elucidating mechanisms underlying the phenomenon. Specifically, proposed studies will focus on the neuropeptide CRF and the neuroactive steroid allopregnanolone because they are intimately related to stress responsiveness (involving both neuroendocrine-related and independent brain stress pathways), as well as EtOH dependence and EtOH self-administration behavior. The overall focus of this proposal is aimed at utilizing an established mouse model of EtOH dependence to examine mechanisms by which stress associated with repeated cycles of chronic EtOH exposure/withdrawal (changes in brain CRF and allopreqnanolone activity) influence subsequent EtOH self-administration behavior, as well as stress-induced relapse behavior. As such, this project not only fills a void in the literature related to EtOH dependence and stress, but importantly, it targets the major overarching theme of the INIA-Stress Consortium as well as complements other projects with a similar research focus in the Consortium. Results from this research proposal will provide new and novel information about possible mechanisms underlying/mediating the interaction between EtOH dependence, stress, and EtOH drinking/relapse behavior that is relevant to the INIA-Stress Consortium, as well as the alcohol field in general. The overall goal is to provide a more complete and comprehensive analysis of the biological underpinnings and environmental circumstances in which stress contributes to excessive EtOH drinking and the development of alcoholism.