Role of BDNF in Ethanol Dependence and Escalation of Drinking

BDNF 在乙醇依赖和饮酒增加中的作用

• 批准号: 8397576
• 负责人: HOWARD C. BECKER
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397576
• 关键词: Address; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Area; Behavior; Behavioral; Biological Factors; Brain; Brain region; Brain-Derived Neurotrophic Factor; Chronic; Clinical; Complex; Data; Dependence; Development; Environmental Risk Factor; Ethanol; Ethanol dependence; Funding; Genetic; Goals; Health; Heavy Drinking; Individual; Intake; Lead; Literature; Mediating; Messenger RNA; Microinjections; Modeling; Motivation; Mus; Nucleus Accumbens; Pathway interactions; Patients; Play; Prefrontal Cortex; Process; Proteins; Recurrent disease; Regulation; Relapse; Research; Research Priority; Research Project Grants; Rewards; Role; Self Administration; Signal Transduction; Societies; Stress; Structure; System; Therapeutic Intervention; Time; Veterans; Withdrawal; Work; addiction; alcohol behavior; alcohol exposure; alcohol relapse; clinically relevant; drinking; drinking behavior; effective therapy; experience; insight; mouse model; neurobiological mechanism; neurotrophic factor; new therapeutic target; novel; pre-clinical; protein expression; public health relevance; response; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): PROJECT ABSTRACT Alcohol abuse and dependence constitute a significant health problem for our veterans and the general society alike. A complex interplay among genetic, environmental and experiential factors is known to govern motivation and regulation of alcohol (ethanol) drinking behavior throughout the addiction process. Chronic excessive ethanol consumption 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 ethanol use/abuse, as well as enhancing vulnerability to relapse. A wide array of neuroadaptive changes in several key motivational brain systems and pathways are known to play a role in behavioral manifestations of dependence and, in particular, contributing to excessive drinking associated with dependence. Identifying new and novel neuroadaptive mechanisms that are provoked in response to chronic ethanol exposure and withdrawal experience, and that underlie transition to excessive uncontrolled drinking is critical for advancing the field and, ultimately, facilitating development of new and more effective treatments for battling the problem of alcohol addiction. Recently, preclinical and clinical evidence has emerged implicating a role for the neurotrophic factor BDNF (Brain-Derived Neurotrophic Factor) in the homeostatic regulation of various ethanol-related behaviors, including ethanol self-administration behavior. However, relatively few studies have examined the role of BDNF in modulating ethanol drinking in the context of dependence. This proposal is aimed at addressing this void in the literature. During the current funding period, we characterized a mouse model of ethanol dependence that we developed, which involves repeated cycles of chronic ethanol exposure and withdrawal and results in robust escalation of voluntary ethanol drinking. Further, we recently collected some novel preliminary data using our dependence model that provides encouraging support for the notion that changes in brain BDNF expression relate to excessive drinking associated with dependence. Accordingly, a central tenet of this proposal is that adaptive changes in BDNF expression and function in specific brain regions as a consequence of chronic ethanol exposure and withdrawal experience plays a role in mediating and/or promoting excessive drinking associated with dependence. Our experimental strategy and approach for addressing this important research question involves use of our well- characterized mouse model of ethanol dependence and drinking. Proposed studies will examine the effects of repeated cycles of chronic ethanol exposure and withdrawal on time-dependent changes in Bdnf mRNA and BDNF protein expression in two brain structures intimately involved in ethanol dependence and drinking as well as BDNF-mediated behavioral effects: the prefrontal cortex (PFC) and the nucleus accumbens (NAc) (Aim I). A second set of studies will examine whether direct administration of BDNF into the PFC alters ethanol drinking in dependent compared to nondependent mice and whether this effect is selective for ethanol (Aim II). Studies also are proposed to investigate mechanisms underlying the ability of intra-PFC BDNF treatment to modulate ethanol drinking in our model of dependence and drinking (Aim III and Aim IV). These studies will focus on BDNF signaling mechanisms in the PFC and well as potential changes in BDNF activity in the NAc. Thus, this proposed research project will utilize our established mouse model of ethanol dependence and drinking to examine mechanisms by which neuroadaptive changes in BDNF expression and function contribute to escalation of drinking associated with ethanol dependence. As such, the proposal addresses a highly significant and clinically relevant research topic that will provide new information about potential therapeutic targets for treating ethanol dependence and harmful drinking associated with alcoholism.

描述（由申请人提供）： 项目摘要酒精滥用和依赖构成了一个重大的健康问题，我们的退伍军人和一般社会一样。遗传、环境和经验因素之间的复杂相互作用在整个成瘾过程中控制着酒精（乙醇）饮酒行为的动机和调节。长期过量乙醇消费可导致依赖性的发展，反复经历相关的戒断事件可能构成一种强大的动力，有助于乙醇使用/滥用的持续，以及增加复发的脆弱性。在几个关键的动机大脑系统和途径的神经适应性变化的广泛的已知发挥作用的依赖性的行为表现，特别是，导致过度饮酒与依赖。识别新的和新颖的神经适应性机制，这些机制是在慢性乙醇暴露和戒断经历中引起的，并且是过渡到过度不受控制的饮酒的基础，这对于推进该领域至关重要，并最终促进开发新的和更有效的治疗方法来对抗酒精成瘾问题。最近，临床前和临床证据表明，神经营养因子BDNF（脑源性神经营养因子）在各种乙醇相关行为（包括乙醇自我给药行为）的稳态调节中发挥作用。然而，相对较少的研究探讨了BDNF在调节酒精依赖背景下饮酒的作用。这项建议旨在解决文献中的这一空白。在当前的资助期间，我们描述了我们开发的乙醇依赖小鼠模型，该模型涉及慢性乙醇暴露和戒断的重复周期，并导致自愿乙醇饮用的强烈升级。此外，我们最近使用我们的依赖模型收集了一些新的初步数据，这些数据为大脑BDNF表达的变化与依赖性相关的过度饮酒有关的概念提供了令人鼓舞的支持。因此，该建议的中心原则是，由于慢性乙醇暴露和戒断经历，特定脑区BDNF表达和功能的适应性变化在介导和/或促进与依赖相关的过度饮酒中起作用。我们解决这一重要研究问题的实验策略和方法涉及使用我们充分表征的乙醇依赖和饮酒小鼠模型。拟议的研究将检查重复循环的慢性乙醇暴露和戒断对BDNF mRNA和BDNF蛋白表达的时间依赖性变化的影响，这两个脑结构密切参与乙醇依赖和饮酒以及BDNF介导的行为效应：前额叶皮层（PFC）和中脑核（NAc）（目的I）。第二组研究将检查是否直接管理的BDNF到PFC改变酒精饮用依赖性相比，非依赖性小鼠，这种效果是否是选择性的乙醇（目的II）。研究还提出了调查机制的能力，PFC内BDNF治疗，以调节酒精饮用在我们的依赖和饮酒模型（目的III和目的IV）。这些研究将集中在PFC中的BDNF信号传导机制以及NAc中BDNF活性的潜在变化。因此，这项研究计划将利用我们建立的酒精依赖和饮酒的小鼠模型来研究BDNF表达和功能的神经适应性变化有助于酒精依赖相关饮酒升级的机制。因此，该提案提出了一个非常重要和临床相关的研究课题，将提供有关治疗酒精依赖和与酒精中毒相关的有害饮酒的潜在治疗靶点的新信息。