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

乙醇依赖和压力对乙醇饮用的影响：CRF

• 批准号: 7564109
• 负责人: HOWARD C. BECKER
• 金额: $ 40.74万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564109
• 关键词: Abstinence; Acute; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Allopregnanolone; Animals; Behavior; Biological; Boutos; Brain; Chronic; Communities; Complement; Complex; Consumption; Corticosterone; Dependence; Development; Environmental Risk Factor; Ethanol; Ethanol dependence; Event; Funding; Goals; Hypothalamic structure; Lead; Link; Literature; Measures; Mediating; Modeling; Mus; Neuropeptides; Neurosecretory Systems; Pathway interactions; Peripheral; Pituitary Gland; Plasma; Play; Process; Recording of previous events; Relapse; Research; Research Personnel; Research Proposals; Rewards; Role; Self Administration; Stress; System; Withdrawal; Work; acute stress; addiction; alcohol exposure; alcohol relapse; alcohol research; alcohol seeking behavior; drinking; drinking behavior; environmental stressor; experience; mouse model; neurosteroids; novel; programs

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.

描述（由申请人提供）：众多生物和环境因素之间复杂的相互作用控制着乙醇（EtOH）的寻求和饮用行为。虽然压力被视为导致乙醇滥用和酗酒的重要因素，但压力与乙醇饮酒行为之间的相互作用尚不清楚。当人们考虑在乙醇依赖的情况下压力对乙醇自我给药的作用/影响时尤其如此。长期过量消耗乙醇会导致依赖性的发展，并且反复经历相关的戒断事件可能会构成强大的动力，导致乙醇使用/滥用的持续存在。此外，长期接触乙醇导致的大脑/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度饮酒，而且更容易受到可能触发戒酒期后重新开始使用乙醇（复发）的事件（压力）的影响。不幸的是，人们对压力与乙醇消耗之间关系的动态以及依赖性背景下这种相互作用的机制知之甚少。在当前资助期间，我们将乙醇依赖和饮酒模型联系起来，以证明长期乙醇暴露和戒断经历的重复循环会增强随后的自愿乙醇消费。该提案建立并扩展了这项工作，重点是阐明该现象背后的机制。具体来说，拟议的研究将重点关注神经肽 CRF 和神经活性类固醇四氢孕酮，因为它们与应激反应性（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。该提案的总体重点是利用已建立的 EtOH 依赖小鼠模型来检查与慢性 EtOH 暴露/戒断重复周期相关的压力（大脑 CRF 和别泼奈酮活性的变化）影响随后的 EtOH 自我给药行为以及压力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关于潜在/介导乙醇依赖、压力和乙醇饮酒/复发行为之间相互作用的可能机制的新颖信息，这些相互作用与 INIA-压力联盟以及整个酒精领域相关。总体目标是对压力导致过度饮酒和酗酒的生物学基础和环境条件进行更完整和全面的分析。