Role of the Endocannabinoid System in the Neurobiology of Depressive Behavior

描述（由申请人提供）：重度抑郁症（MDD）的特征是情绪和动机明显受损。它表现出慢性、复发性病程，并与全世界的高发病率和死亡率有关。目前可用的抗抑郁药对许多患者来说是不够的，这表明可能存在其他生物底物，这些底物可能是治疗抑郁症的治疗靶点。多个信号通路的神经化学基础被认为与MDD的病理生理学相关。G蛋白偶联受体（GPCR）介导的信号传导被认为是细胞中用于各种生理和行为过程的最广泛使用的机制。CB1受体是一种GPCR，最近已被证明在调节情绪、动机和情绪行为的神经回路中发挥关键作用。抑郁症是一种复杂的多因素特征，具有重要的遗传和环境影响因素。最近已经开发了几种遗传动物模型，这些模型在确定抑郁症易感因素方面至关重要。广泛的行为和生化研究已经建立了Wistar京都（WKY）大鼠作为抑郁症的遗传动物模型。大麻素的情绪改变能力，以及抑郁自杀受害者死后大脑中CB1受体密度的变化，使我们探索内源性大麻素系统在抑郁症神经生物学中的作用。我们建议在这里调查的地位，中央内源性大麻素系统，并进一步检查是否内源性大麻素为基础的药物表现出抗抑郁药的性质在WKY大鼠。这项研究将进一步了解抑郁症遗传易感性的机制，并可能有助于开发一种新的治疗抑郁症的治疗靶点。公共卫生相关性：鉴于抑郁症的急性和慢性负担的重要性，了解其病理生理基础和开发有效的药物治疗是至关重要的。本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。

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.