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 酒精滥用和依赖对我们的退伍军人和整个社会来说都是一个重大的健康问题。众所周知，遗传、环境和经验因素之间复杂的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。慢性过量乙醇消耗可能导致依赖性的发展，并且反复经历相关的戒断事件可能构成强大的动力，导致乙醇使用/滥用的长期存在，并增加复发的可能性。众所周知，几个关键的大脑动机系统和通路中的一系列神经适应性变化在依赖性的行为表现中发挥着作用，特别是导致与依赖性相关的过度饮酒。识别因长期接触乙醇和戒断经历而引发的新的和新颖的神经适应性机制，以及向过度不受控制的饮酒过渡的基础，对于推进该领域至关重要，并最终促进开发新的、更有效的治疗方法来解决酒精问题。酒精成瘾。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 在调节酒精依赖的情况下的作用。该提案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循环，并导致自愿乙醇饮用量的急剧增加。此外，我们最近使用我们的依赖模型收集了一些新颖的初步数据，这些数据为大脑 BDNF 表达的变化与依赖相关的过度饮酒有关的观点提供了令人鼓舞的支持。因此，该提议的核心原则是，由于长期乙醇暴露和戒断经历，特定大脑区域 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发挥作用。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明确描述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与乙醇依赖和饮酒密切相关的两个大脑结构中 Bdnf mRNA 和 BDNF 蛋白表达的时间依赖性变化的影响以及 BDNF 介导的行为效应：前额皮质(PFC) 和伏隔核 (NAc)（目标 I）。第二组研究将检验直接将 BDNF 注入 PFC 是否会改变依赖小鼠与非依赖小鼠的乙醇饮用情况，以及这种效应是否对乙醇具有选择性（目标 II）。还提出了研究来调查 PFC 内 BDNF 治疗在我们的依赖和饮酒模型（目标 III 和目标 IV）中调节乙醇饮酒的能力的机制。这些研究将重点关注 PFC 中的 BDNF 信号传导机制以及 NAc 中 BDNF 活性的潜在变化。因此，这个拟议的研究项目将利用我们建立的乙醇依赖和饮酒小鼠模型来检查 BDNF 表达和功能的神经适应性变化导致与乙醇依赖相关的饮酒升级的机制。因此，该提案涉及一个非常重要且与临床相关的研究主题，该主题将提供有关治疗乙醇依赖和与酗酒相关的有害饮酒的潜在治疗目标的新信息。