Role of BDNF in Stress Effects on Ethanol Dependence-Induced Escalated Drinking

BDNF 在乙醇依赖引起的逐步饮酒的压力影响中的作用

• 批准号: 10013635
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013635
• 关键词: Address; Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Attenuated; Behavioral; Brain; Brain-Derived Neurotrophic Factor; Caring; Chronic; Chronic stress; Clinical; Complex; Data; Dependence; Ethanol; Ethanol dependence; Exercise; Exposure to; Flavones; Funding; Goals; Health; Healthcare; Heavy Drinking; High Prevalence; Individual; Infusion procedures; Injections; Intake; Intervention; Lead; Mediating; Modeling; Mus; Neurotrophic Tyrosine Kinase Receptor Type 2; Patients; Phosphorylation; Pilot Projects; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prevalence; Receptor Signaling; Recurrent disease; Relapse; Research; Research Project Grants; Research Proposals; Role; Running; Signal Transduction; Signaling Molecule; Small Interfering RNA; Societies; Stress; Swimming; Therapeutic Intervention; Veterans; Viral; Work; alcohol exposure; alcohol intervention; alcohol measurement; alcohol use disorder; care burden; clinically relevant; comorbidity; dependence relapse; drinking; effective therapy; insight; knock-down; mouse model; neuroadaptation; neuromechanism; neurotrophic factor; novel; novel therapeutic intervention; overexpression; prevent; programs; receptor; stress related disorder; treatment strategy

Alcohol use disorder (AUD) is a chronic relapsing disease that constitutes a major health problem for Veterans. Stress is known to be an important contributing factor to alcohol abuse and alcoholism, and this is especially relevant to Veterans given their high prevalence of co-occurring AUD and stress-related illnesses such as post- traumatic stress disorder (PTSD). Despite the significance of this problem, the complex interaction between stress and alcohol (ethanol) drinking is not fully understood. The use of animal models is critical for advancing our understanding of underlying mechanisms and providing platforms for evaluating potential new and novel treatment interventions for Veterans battling PTSD-AUD comorbidity. Recent work involving our established mouse model of ethanol dependence that involves repeated cycles of chronic intermittent ethanol (CIE) exposure led to the discovery that reduced BDNF activity in the dorsomedial prefrontal cortex (dmPFC) is a significant neuroadaptation associated with excessive drinking. During the current funding period, we extended this work to show that stress facilitates and enhances this dependence-related escalation of ethanol consumption. That is, forced swim stress (FSS) selectively enhances escalated drinking in dependent (CIE- exposed) mice while not altering more moderate ethanol intake in nondependent mice. Additionally, stress in combination with chronic ethanol exposure was shown to magnify deficits in BDNF expression in the prefrontal cortex. Further, we demonstrated that direct infusion of BDNF or viral-mediated overexpression of BDNF in the dmPFC blocked dependence (CIE)-related escalated drinking. Collectively, these data support the general tenet that reduced BDNF activity in the dmPFC plays a significant role in the ability of stress (FSS) to enhance escalated drinking associated with dependence. As exercise is known to elevate BDNF activity in brain, we conducted pilot studies that have demonstrated exercise attenuates dependence-related escalated ethanol drinking, as well as attenuating the ability of stress to further enhance excessive levels of drinking associated with dependence. With this supportive pilot data, the proposed research plan will build and expand on this work by examining the role of BDNF in the ability of exercise to attenuate stress-enhanced drinking in dependent mice. Specifically, this research project is aimed at utilizing our established stress-ethanol dependence (Stress- CIE) Drinking model to examine whether exercise attenuates stress-enhanced dependence-related excessive drinking via BDNF-TrkB receptor signaling in the dmPFC. Proposed studies will examine whether exercise (wheel-running) blocks stress (FSS)-enhanced escalated drinking in CIE-exposed mice, as well as attenuating reduced BDNF expression in dmPFC that accompanies excessive drinking in the Stress-CIE Drinking model (Aim I). Another set of studies will examine whether direct injection of the TrkB receptor antagonist ANA-12 into the dmPFC blocks the ability of wheel-running to attenuate stress (FSS)-enhanced CIE-induced escalated drinking and whether TrkB receptor knockdown in the dmPFC via siRNA infusion produces a similar effect (Aim II). Finally, studies will examine whether systemic treatment with the flavone derivative and TrkB receptor agonist 7,8-DHF substitutes for exercise in attenuating stress-enhanced CIE-related drinking, and/or whether treatment with 7,8-DHF in the absence of exercise mimics the effects of exercise in the Stress-CIE Drinking model. Additionally, studies will examine whether these exercise-like behavioral effects are due to activation (phosphorylation) of TrkB receptors (pTrkB) and downstream signaling molecules (pERK1/2 and pAKT) in the dmPFC (Aim III). Taken together, this proposal addresses a highly significant and clinically important research topic that is of great relevance to Veteran’s heath care. Results from this research project will generate new findings on mechanisms underlying a potential novel therapeutic approach that addresses a clinically relevant health problem - the exacerbating effects of stress that lead to harmful excessive drinking associated with alcoholism and PTSD-AUD comorbidity - an especially significant problem for our Veterans.

酒精使用障碍（AUD）是一种慢性传递疾病，构成了退伍军人的主要健康问题。 已知压力是导致酗酒和酒精中毒的重要因素，这尤其是 与退伍军人相关的鉴于他们的高流行率，同时发生的AUD和与压力相关的疾病（例如 创伤应力障碍（PTSD）。尽管这个问题具有重要意义，但 压力和酒精（乙醇）尚未完全了解。动物模型的使用对于前进至关重要 我们对基本机制的理解，并提供了评估潜在新颖新颖的平台 退伍军人战役PTSD审计合并症的治疗干预措施。最近的工作涉及我们已建立的 乙醇依赖的小鼠模型，涉及慢性间歇性乙醇（CIE）的重复循环 暴露导致发现降低了背额前额叶皮层（DMPFC）中的BDNF活性为 与多余的饮酒有关的重要神经适应。在当前的资金期间，我们扩展了 这项工作表明压力有助于并增强与乙醇相关的依赖性升级 消耗。也就是说，强迫游泳压力（FSS）有选择地增强了依赖的饮酒升级（cie- 暴露的）小鼠虽然没有改变非依赖性小鼠的现代乙醇摄入量。另外，压力在 证明与慢性乙醇暴露的结合显示了前额叶中BDNF表达的定义 皮质。此外，我们证明了BDNF或病毒介导的BDNF的直接输注 DMPFC阻止了依赖（CIE）相关的升级饮酒。总的来说，这些数据支持一般宗旨 DMPFC中的BDNF活性降低在压力（FSS）增强的能力中起着重要作用 与依赖相关的饮酒升级。由于已知运动可以提升大脑的BDNF活性，因此我们 进行了试验的试验研究，这些研究表明运动衰减依赖性相关的升级乙醇 饮酒，以及减轻压力进一步增强的能力超过相关的饮酒水平 有了这些支持的飞行员数据，拟议的研究计划将在这项工作上建立和扩展 通过检查BDNF在锻炼能力中衰减压力增强的饮酒能力的作用 特别是小鼠，该研究项目旨在利用我们既定的压力 - 乙醇依赖性（压力 - CIE）饮酒模型，以检查运动是否会减轻与压力相关的过量 通过DMPFC中的BDNF-TRKB受体信号传导饮用。拟议的研究将检查是否运动 （车轮运行）阻止压力（FSS）在暴露于CIE的小鼠中加强升级的饮酒，并减轻 DMPFC中的BDNF表达降低，涉及压力饮酒模型中饮酒过量 （AIM I）。另一组研究将检查是否将TRKB受体拮抗剂ANA-12直接注射到 DMPFC阻止了轮子运行的能力减轻压力（FSS）增强CIE诱导的升级 饮酒以及通过siRNA输注中DMPFC中的TRKB受体敲低是否会产生相似的效果（AIM ii）。最后，研究将检查使用黄酮衍生物和TRKB接收器的全身治疗 激动剂7,8-DHF替代锻炼以减轻与CIE相关的压力增强的饮酒和/或是否是否 在没有运动的情况下，用7,8-DHF进行治疗 模型。此外，研究将检查这些类似运动的行为效应是否是由于激活引起的 TRKB受体（PTRKB）和下游信号分子（PERK1/2和PAKT）的（磷酸化）（磷酸化） DMPFC（AIM III）。综上所述，该提案地址是一项非常重要且在临床上重要的研究 与退伍军人的健康护理非常相关的主题。该研究项目的结果将产生新的 关于潜在的新型治疗方法的基础机制的发现，该方法涉及临床相关的 健康问题 - 压力的加剧影响，导致与 酒精中毒和PTSD -aud合并症 - 对我们的退伍军人特别重要的问题。