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支配着乙醇(Etoh)的寻求和饮酒行为。虽然压力被认为是酒精滥用和酒精中毒的一个重要因素，但压力和酒精饮酒行为之间的相互作用还没有被很好地理解。在乙醇依赖的背景下，当人们考虑到压力对乙醇自我管理的作用/影响时，情况尤其如此。长期过量摄入乙醇会导致依赖的发展，反复经历与之相关的戒断发作可能构成一种强大的动机力量，有助于乙醇的长期使用/滥用。此外，由于长期接触乙醇，大脑/神经内分泌压力和奖励系统的功能变化可能不仅使受试者更容易过量饮用乙醇，而且更容易受到事件(应激)的影响，这些事件可能会在戒酒后再次开始使用乙醇(复发)。不幸的是，关于压力和乙醇消耗之间的动态关系，以及依赖背景下这种相互作用的机制，人们知之甚少。在目前的资助期间，我们将乙醇依赖和饮酒的模型联系起来，以证明反复循环的慢性乙醇暴露和戒断经历会增强随后的自愿乙醇消费。这项提案建立并扩展了这项工作，重点是阐明这一现象背后的机制。具体地说，拟议的研究将集中在神经肽CRF和神经活性类固醇别孕酮上，因为它们与应激反应密切相关(涉及神经内分泌相关和独立的大脑应激途径)，以及乙醇依赖和乙醇自我给药行为。这项建议的总体重点是利用已建立的乙醇依赖小鼠模型来研究与重复循环慢性乙醇暴露/戒断相关的应激(脑CRF和别孕酮活性的变化)如何影响随后的乙醇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乙醇依赖和压力相关的文献中的空白，而且重要的是，它针对INIA-压力联盟的主要总体主题，并补充了该联盟中具有类似研究重点的其他项目。这项研究计划的结果将为乙醇依赖、压力和酒精饮酒/复发行为之间相互作用的潜在/调节机制提供新的和新的信息，这与INIA-Stress联合体以及一般的酒精领域有关。总体目标是对压力导致过量饮酒和酗酒的生物基础和环境环境进行更全面和全面的分析。

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.