Role of the Endocannabinoid System in the Neurobiology of Depressive Behavior

内源性大麻素系统在抑郁行为神经生物学中的作用

基本信息

批准号：
7738873
负责人：
VINOD K YARAGUDRI
金额：
$ 7.9万
依托单位：
NATHAN S. KLINE INSTITUTE FOR PSYCH RES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7738873
关键词：
Accounting Acute Address Animal Model Antidepressive Agents Attenuated Autopsy Behavior Behavioral Biochemical Biological Brain Brain region Cannabinoids Cells Chronic Clinical Cognition Complex Control Groups Depressive disorder Development Disease Emotional Endocannabinoids Enzymes Exhibits Functional disorder G-Protein-Coupled Receptors GTP-Binding Proteins Genetic Genetic Predisposition to Disease Goals Impairment Inbred WKY Rats Ligands Major Depressive Disorder Mediating Medical Modeling Molecular Moods Morbidity - disease rate Motivation Neurobiology Neurotransmitters Patients Pharmaceutical Preparations Philadelphia Physiological Play Predisposition Process Property Rattus Relapse Reporting Rodent Role Science Signal Pathway Signal Transduction Suicide System Testing Therapeutic Agents United States Universities World Health Organization base depressed depression depressive symptoms design disability fatty acid amide hydrolase inhibitor/antagonist monoamine mortality neural circuit neurochemistry new therapeutic target professor protein activation public health relevance receptor receptor density receptor-mediated signaling suicide victim therapeutic target trait

项目摘要

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is characterized by a significant impairment in mood and motivation. It exhibits a chronic, relapsing course and is associated with high morbidity and mortality worldwide. Currently available antidepressants are inadequate for many patients, suggesting the potential existence of other biological substrate(s) that could be a therapeutic target in the treatment of depressive illness. Neurochemical basis in multiple signaling pathways has been considered to be associated with the pathophysiology of MDD. The G-protein coupled receptor (GPCR) mediated signaling is believed to be the most widely used mechanism in cells for various physiological and behavioral processes. The CB1 receptor, a GPCR, has recently been shown to play a critical role in neural circuitries mediating mood, motivation, and emotional behavior. Depressive disorder is a complex and multifactorial trait with important genetic and environmental contributing factors. Several genetic animal models have recently been developed and are critical in identifying factors underlying predisposition to depression. Extensive behavioral and biochemical studies have established the Wistar Kyoto (WKY) rat as a genetic animal model of depression. The mood altering ability of cannabinoids, and reported changes in the CB1 receptor density in the postmortem brain of depressed suicide victims led us to explore the role of the endocannabinoid system in the neurobiology of depression. We propose here to investigate the status of the central endocannabinoid system and to further examine whether the endocannabinoid-based drugs exhibit antidepressant properties in WKY rat. This study will further our understanding the mechanism underlying the genetic predisposition to depressive illness and may potentially aid in developing a novel therapeutic target for the treatment of depressive disorder. PUBLIC HEALTH RELEVANCE: Given the significance of acute and chronic burden associated with depressive disorder, understanding of its pathophysiological basis and development of an effective drug treatment is of paramount importance. The long-term goal of this study is to understand the cellular and molecular mechanisms of depressive behavior and to examine possible utility of the endocannabinoid system as potential therapeutic target for the treatment of depressive disorder.

描述（由申请人提供）：重度抑郁症（MDD）的特征是情绪和动机的重大损害。它表现出慢性，复发的过程，并与全球发病率高和死亡率有关。目前可用的抗抑郁药对于许多患者而言不足，这表明其他生物底物的可能存在可能是治疗抑郁疾病的治疗靶点。多个信号通路中的神经化学基础被认为与MDD的病理生理有关。 G蛋白偶联受体（GPCR）介导的信号传导被认为是各种生理和行为过程中最广泛使用的机制。 CB1受体（GPCR）最近被证明在介导情绪，动机和情感行为的神经循环中起关键作用。抑郁症是一个复杂而多因素的特征，具有重要的遗传和环境促成因素。最近已经开发了几种遗传动物模型，对于识别抑郁症易感性的因素至关重要。广泛的行为和生化研究已将Wistar京都（WKY）大鼠建立为抑郁症的遗传动物模型。大麻素的情绪改变能力，并报道了自杀受害者死后大脑中CB1受体密度的变化，这使我们探索了内源性大麻素系统在抑郁症神经生物学中的作用。我们在这里建议研究中央内源性大麻素系统的状态，并进一步检查基于内源性大麻素的药物是否在WKY大鼠中表现出抗抑郁特性。这项研究将进一步理解抑郁疾病遗传易感性的基础机制，并有可能有助于开发一种用于治疗抑郁症的新型治疗靶标。公共卫生相关性：鉴于与抑郁症的急性和慢性负担的重要性，对其病理生理基础的理解以及对有效药物治疗的发展至关重要。这项研究的长期目标是了解抑郁行为的细胞和分子机制，并检查内源性大麻素系统作为治疗抑郁症的潜在治疗靶点的可能效用。