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）： 项目抽象的酒精滥用和依赖性构成了我们的退伍军人和一般社会的重大健康问题。众所周知，遗传，环境和经验因素之间的复杂相互作用可以控制整个成瘾过程中酒精（乙醇）饮酒行为的动机和调节。慢性过度乙醇消耗可以导致依赖性的发展，而相关的撤回发作的反复经验可能构成强大的动机力量，这有助于对乙醇使用/滥用的永久化以及增强复发的脆弱性。已知几种关键的动机大脑系统和途径中的各种神经适应性变化在依赖行为表现中起作用，尤其是导致与依赖性相关的过度饮酒。确定新的和新颖的神经适应性机制，这些机制是针对慢性乙醇暴露和戒断经验而引起的，并且过渡到过度不受控制的饮酒是至关重要的，这对于推进该领域，并最终促进新的，更有效的治疗方法来抗衡酒精成瘾问题。最近，临床前和临床证据已经出现了对神经营养因子BDNF（脑衍生的神经营养因子）在各种乙醇相关行为（包括乙醇自我加热行为）中的作用。但是，相对较少的研究研究了BDNF在依赖背景下调节乙醇饮用中的作用。该建议旨在解决文献中的这个空白。在当前的资金期间，我们表征了我们开发的乙醇依赖性小鼠模型，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劲升级。此外，我们最近使用我们的依赖模型收集了一些新型的初步数据，该模型为脑BDNF表达变化的概念提供了鼓励的支持，即与依赖性相关的过量饮酒有关。因此，该提案的核心宗旨是，由于慢性乙醇暴露和撤回经验，特定大脑区域的BDNF表达和功能的自适应变化在介导和/或促进与依赖性相关的过量饮酒中起作用。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特征良好的乙醇依赖性和饮酒的小鼠模型。拟议的研究将研究慢性乙醇暴露和戒断的反复循环对BDNF mRNA和BDNF蛋白表达的时间依赖性变化的影响，这两个大脑结构与乙醇依赖性和饮酒密切相关，以及BDNF介导的行为效应：前额叶皮质（PFC）和核us un ucleus Accumbens（NAC）（nac）（nac）（nac）（AIM）。第二组研究将检查与非依赖性小鼠相比，将BDNF直接给予PFC中的乙醇饮酒是否会改变乙醇饮酒，以及这种作用是否对乙醇有选择性（AIM II）。还提出了研究来研究PFC内BDNF治疗能力在我们的依赖和饮酒模型中调节乙醇饮用的能力的基础机制（AIM III和AIM IV）。这些研究将集中于PFC中的BDNF信号传导机制，以及NAC中BDNF活性的潜在变化。因此，该提出的研究项目将利用我们既定的乙醇依赖性小鼠模型和饮酒模型来检查BDNF表达中神经适应性变化的机制，并有助于与乙醇依赖性相关的饮酒升级。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性和与酒精中毒相关的潜在治疗靶标的新信息。