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; 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）：酗酒和依赖性已与负面影响和抑郁症联系在一起。酒精中毒和抑郁症的临床表现的变化具有复杂的诊断“合并抑郁症”，“双重诊断”，“禁欲性抑郁症”和其他负面影响症状，尽管人们普遍认为，依赖酒精的患者在停止饮酒时会经历抑郁症。此外，负面影响或抑郁症状与酒精中毒的同时存在预测更严重的疾病和对治疗的反应不佳。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，尚无临床前研究涉及酒精引起的抑郁症的神经生物学机制。我们发现，在小鼠中，慢性自愿饮酒的禁欲与Porsolt游泳测试（PST）的固定性增加有关。长期给予抗抑郁药脱哌他胺，这种行为病理完全阻止了这种行为病理。该应用程序的特定目的1中的研究将利用该动物模型进一步表征慢性饮酒与戒酒期间抑郁症行为的出现之间的关系。具体目标2将确定几种抗抑郁药的功效和剂量反应，以深入了解潜在的治疗机制。该项目的特定目的3是对与1）酒精诱导的抑郁症和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，我们发现酒精诱导的抑郁症状行为与海马齿状回的P-CREB和BDNF表达显着降低以及神经发生有关，每种抑郁症的基础抑郁症。我们还发现，脱哌丁胺会逆转牙齿回旋中P-CREB和BDNF的酒精诱导的降低。最后，本应用的特定目的4是操纵海马中的CREB磷酸化和BDNF水平，以确定在这个重要大脑区域中的分子适应是否在功能上调节酒精诱导的抑郁症。该项目有可能阐明导致酒精中毒合并抑郁症，确定有效药物的因素，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。这些信息对于可能使抑郁症和酒精中毒的疗法的发展以及确定这两种精神疾病相互作用的分子基础可能具有重要意义。