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

描述（由申请人提供）：许多生物和环境因素之间的复杂相互作用决定了乙醇（EtOH）的寻求和饮酒行为。虽然压力被认为是造成EtOH滥用和酗酒的重要因素，但压力与EtOH饮酒行为之间的相互作用尚未得到很好的理解。当一个人考虑到压力在EtOH依赖背景下对EtOH自我管理的作用/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，反复出现相关的戒断发作可能构成一种强大的动力，有助于EtOH的长期使用/滥用。此外，由于长期暴露于EtOH，大脑/神经内分泌压力和奖励系统的功能变化可能使受试者不仅更容易过量饮酒，而且更容易受到可能在戒断一段时间后（复发）重新开始使用EtOH的事件（压力）的影响。不幸的是，人们对压力和EtOH消耗之间的动态关系知之甚少，以及在依赖的背景下这种相互作用的机制。在目前的资助期内，我们将EtOH依赖和饮酒模型联系起来，以证明慢性EtOH暴露和戒断经历的反复循环会增强随后的自愿EtOH消费。本建议建立并扩展了这项工作，重点是阐明该现象背后的机制。具体而言，拟开展的研究将集中于神经肽CRF和神经活性类固醇异孕酮，因为它们与应激反应（涉及神经内分泌相关和独立的脑应激途径）以及EtOH依赖和EtOH自我给药行为密切相关。本提案的总体重点是利用已建立的EtOH依赖小鼠模型来研究慢性EtOH暴露/戒断（脑CRF和别preqnanolone活性的变化）重复周期相关的应激影响随后的EtOH自我给药行为的机制，以及应激诱导的复发行为。因此，该项目不仅填补了与EtOH依赖性和压力相关的文献空白，而且重要的是，它针对nia -压力联盟的主要主题，并补充了联盟中具有类似研究重点的其他项目。本研究计划的结果将提供新的和新颖的信息，可能的机制，介导EtOH依赖、压力和EtOH饮酒/复发行为之间的相互作用，这与nia - stress Consortium以及一般的酒精领域有关。总体目标是提供一个更完整和全面的生物学基础和环境环境的分析，其中压力导致过量的EtOH饮酒和酗酒的发展。

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.