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: 7322882
• 负责人: Clyde W Hodge
• 金额: $ 32.85万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322882
• 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; Data; Dependence; 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; Purpose; 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; day; 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）：临床上酒精滥用和依赖与负面情绪和抑郁有关。酒精中毒和抑郁症临床表现的差异使“共病抑郁症”、“双重诊断”、“戒酒抑郁症”和其他负面影响症状的诊断变得复杂，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症。此外，负面情绪或抑郁症状与酗酒同时出现预示着更严重的疾病和对治疗的不良反应。流行的抑郁症理论包括经典的单胺假说以及涉及 CREB ​​基因转录、神经营养途径和海马神经发生的新兴分子理论。然而，迄今为止，还没有临床前研究解决酒精引起的抑郁症的神经生物学机制。我们发现，在 Porsolt 游泳测试（PST）中，长期自愿戒酒与不动的增加有关，PST 是一种经过验证的小鼠抑郁样行为模型。这种行为病理学可以通过长期服用抗抑郁药地昔帕明来完全阻断。本申请的具体目标 1 的研究将利用该动物模型来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功效和剂量反应，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) 酒精诱发的抑郁症和 2) 抗抑郁治疗相关的分子适应进行综合分析。为了支持这种方法，我们发现酒精诱发的抑郁样行为与 p-CREB ​​和 BDNF 表达以及海马齿状回神经发生的显着减少有关，这每一个都被假设为抑郁症的基础。我们还发现地昔帕明可以逆转酒精诱导的 p-CREB ​​和 BDNF 减少，特别是在齿状回中。最后，该应用的具体目标 4 是操纵海马体中的 CREB ​​磷酸化和 BDNF 水平，以确定这一重要大脑区域的分子适应是否能在功能上调节酒精引起的抑郁症。该项目有可能阐明导致酗酒者并发抑郁症的因素，确定有效的药物，并描述与酒精引起的抑郁症及其治疗相关（或无关）的潜在神经生物学适应。这些信息对于开发可能有益于抑郁症和酗酒的疗法以及建立这两种精神疾病相互作用的分子基础可能具有重要意义。