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）是一种慢性复发性疾病，构成退伍军人的主要健康问题。 众所周知，压力是导致酗酒和酗酒的一个重要因素，尤其是 与退伍军人相关，因为他们同时发生的 AUD 和压力相关疾病（例如后遗症）的患病率很高 尽管这个问题很重要，但创伤性应激障碍（PTSD）之间存在着复杂的相互作用。 压力和酒精（乙醇）饮用尚不完全清楚，动物模型的使用对于进展至关重要。 我们对潜在机制的理解并提供评估潜在新颖性的平台 针对患有 PTSD-AUD 合并症的退伍军人的治疗干预措施涉及我们已建立的近期工作。 乙醇依赖小鼠模型，涉及慢性间歇性乙醇（CIE）的重复循环 暴露导致发现背内侧前额皮质 (dmPFC) 的 BDNF 活性降低 在当前的资助期内，我们延长了与过度饮酒相关的显着神经适应。 这项工作表明，压力会促进和增强这种与乙醇依赖相关的升级 也就是说，强迫游泳压力（FSS）选择性地增强依赖性饮酒（CIE-）。 暴露）小鼠，同时不改变非依赖性小鼠的更适度的乙醇摄入量。 与长期接触乙醇相结合会放大前额叶 BDNF 表达的缺陷 此外，我们证明了 BDNF 的直接输注或病毒介导的 BDNF 的过度表达。 总的来说，这些数据支持了与 dmPFC 阻断依赖 (CIE) 相关的饮酒的总体原则。 dmPFC 中 BDNF 活性的降低在应激能力 (FSS) 增强方面发挥着重要作用 饮酒增加与依赖性相关。众所周知，运动可以提高大脑中的 BDNF 活性。 进行的试点研究表明，运动可以减轻与酒精依赖相关的酒精中毒 饮酒，以及减弱压力能力，进一步增强与过量饮酒相关的能力 有了这些支持性试点数据，拟议的研究计划将在这项工作的基础上进行扩展。 通过检查 BDNF 在运动中的作用，以减轻依赖性饮酒带来的压力 具体来说，该研究项目旨在利用我们已建立的压力-乙醇依赖性（Stress- CIE）饮酒模型，用于检查运动是否可以减轻压力增强的依赖相关的过度饮酒 饮酒是否通过 dmPFC 中的 BDNF-TrkB 受体信号传导进行研究。 （轮式运行）可阻止 CIE 暴露小鼠中压力 (FSS) 增强的饮酒量增加，并减弱 dmPFC 中 BDNF 表达减少，适应压力 CIE 饮酒模型中的过度饮酒 （目标 I）另一组研究将检查是否将 TrkB 受体拮抗剂 ANA-12 直接注射到体内。 dmPFC 阻止车轮行驶减弱应力 (FSS) 增强的 CIE 引起的升级的能力 饮酒以及通过 siRNA 输注敲低 dmPFC 中的 TrkB 受体是否会产生类似的效果（目的 II) 最后，研究将检验是否可以使用黄酮衍生物和 TrkB 受体进行全身治疗。 激动剂 7,8-DHF 替代运动以减轻压力增强的 CIE 相关饮酒，和/或是否 在没有运动的情况下使用 7,8-DHF 治疗模拟了压力-CIE 饮酒中运动的效果 此外，研究将检验这些类似运动的行为效应是否是由于激活所致。 TrkB 受体 (pTrkB) 和下游信号分子（pERK1/2 和 pAKT）的（磷酸化） 综上所述，该提案涉及一项非常重要且具有临床意义的研究。 该研究项目的结果将产生新的与退伍军人的健康护理密切相关的主题。 关于潜在新颖治疗方法潜在机制的发现，该方法解决了临床相关问题 健康问题 - 压力的加剧影响导致有害的过量饮酒 酗酒和 PTSD-AUD 合并症 - 对于我们的退伍军人来说是一个特别重要的问题。