Behavioral and molecular mechanisms of ethanol-induced depression

乙醇诱发抑郁症的行为和分子机制

• 批准号: 8100115
• 负责人: Clyde W Hodge
• 金额: $ 31.26万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100115
• 关键词: Abstinence; Address; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Antidepressive Agents; Attention; BDNF gene; Behavior; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; CREB1 gene; Chronic; Clinical; Clinical Research; Comorbidity; Cyclic AMP-Dependent Protein Kinases; Data; Depressed mood; Desipramine; Diagnosis; Disease; Dose; Employee Strikes; Ethanol; Gene Targeting; Genetic Transcription; Goals; Hippocampus (Brain); Infusion procedures; Investigation; Lead; Link; Measures; Mental Depression; Modeling; Molecular; Molecular Analysis; Molecular Target; Motor; Multivariate Analysis; Mus; Neurobiology; Parahippocampal Gyrus; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Psyche structure; Recovery; Relapse; Reporting; Research Personnel; Rewards; Site; Solutions; Specificity; Sucrose; Swimming; Symptoms; Testing; Therapeutic; Time; Variant; alcohol effect; alcohol exposure; base; brain tissue; chronic alcohol ingestion; dentate gyrus; depressive symptoms; drinking; dual diagnosis; experience; immunocytochemistry; immunoreactivity; insight; monoamine; neural circuit; neuroadaptation; neurobiological mechanism; neurogenesis; neuromechanism; preclinical study; problem drinker; programs; research study; response; theories; therapy development

DESCRIPTION (provided by applicant): Alcohol abuse and dependence have been linked clinically with negative affect and depression. Variations in the clinical presentation of alcoholism and depression have complicated diagnoses of "co-morbid depression," "dual diagnosis," "abstinence depression" and other negative affect symptoms, although it is generally agreed that alcohol dependent patients experience depression when they stop drinking. Further, the co-occurrence of negative affect or depression symptoms with alcoholism predicts more severe disease and a poor response to treatment. Prevailing theories of depression include the classic monoamine hypothesis as well as emerging molecular theories involving CREB gene transcription, neurotrophic pathways, and hippocampal neurogenesis. To date, however, no preclinical studies have addressed the neurobiological mechanisms of alcohol-induced depression. We have discovered that abstinence from chronic voluntary alcohol drinking is associated with increased immobility in the Porsolt swim test (PST), a validated model of depression-like behavior, in mice. This behavioral pathology is completely blocked by chronic administration of the antidepressant desipramine. Studies in Specific Aim 1 of this application will utilize this animal model to further characterize the relationship between chronic alcohol drinking and the emergence of depression-like behavior during abstinence. Specific Aim 2 will determine the efficacy and dose-response of several antidepressant medications to gain insight into potential therapeutic mechanisms. Specific Aim 3 of this project is to conduct an integrative analysis of molecular adaptations that are associated with 1) alcohol-induced depression and 2) antidepressant treatment. In support of this approach, we have discovered that alcohol-induced depression-like behavior is associated with significant decreases in p-CREB and BDNF expression and neurogenesis in the dentate gyrus of the hippocampus, each of which has been hypothesized to underlie depression. We have also found that desipramine reverses the alcohol- induced reduction in p-CREB and BDNF specifically in the dentate gyrus. Finally, Specific Aim 4 of this application is to manipulate CREB phosphorylation and BDNF levels in the hippocampus to determine if molecular adaptations in this important brain region functionally regulate alcohol-induced depression. This project has the potential to elucidate factors that lead to co-morbid depression in alcoholism, identify effective medications, and characterize underlying neurobiological adaptations that are associated (or dissociated) with alcohol-induced depression and its treatment. This information may be of major significance for the development of therapies that may benefit depression and alcoholism, as well as establishing the molecular basis of the interaction of these two mental diseases.

描述(由申请人提供)：酒精滥用和依赖在临床上与负面情绪和抑郁有关。尽管人们普遍认为，酒精依赖患者在停止饮酒时会经历抑郁，但酒精中毒和抑郁症的临床表现的不同，使“共病抑郁”、“双重诊断”、“禁欲抑郁”和其他负面影响症状的诊断变得复杂。此外，负面情绪或抑郁症状与酒精中毒并存预示着更严重的疾病和对治疗的不良反应。抑郁症的主流理论包括经典的单胺假说以及涉及CREB基因转录、神经营养通路和海马神经发生的新兴分子理论。然而，到目前为止，还没有临床前研究涉及酒精诱导的抑郁的神经生物学机制。我们已经发现，长期自愿饮酒与Porsolt游泳测试(PST)中的静止增加有关，PST是一种在小鼠身上验证的抑郁症样行为模型。这种行为病理完全被长期服用抗抑郁剂地塞帕明所阻断。本申请的具体目标1的研究将利用这一动物模型进一步表征长期饮酒与戒酒期间出现抑郁样行为之间的关系。具体目标2将确定几种抗抑郁药物的疗效和剂量反应，以深入了解潜在的治疗机制。该项目的具体目标3是对与1)酒精诱导的抑郁和2)抗抑郁治疗相关的分子适应进行综合分析。为了支持这一方法，我们发现酒精诱导的抑郁样行为与p-CREB和BDNF表达的显著减少以及海马齿状回的神经发生有关，其中每一种都被认为是抑郁症的基础。我们还发现，地塞帕明可以逆转酒精诱导的齿状回p-CREB和BDNF的减少。最后，这项应用的具体目标4是操纵海马区CREB磷酸化和BDNF水平，以确定这一重要脑区的分子适应是否在功能上调节酒精诱导的抑郁。该项目有可能阐明导致酒精中毒并发抑郁的因素，确定有效的药物，并表征与酒精诱导的抑郁及其治疗相关(或分离)的潜在神经生物学适应。这一信息可能对开发可能有益于抑郁症和酒精中毒的治疗方法以及建立这两种精神疾病相互作用的分子基础具有重要意义。