Mechanistic studies of 2-AG inactivation inhibitors as antidepressants

2-AG失活抑制剂作为抗抑郁药的机制研究

• 批准号: 8384921
• 负责人: Qing-song Liu
• 金额: $ 22.95万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-11 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384921
• 关键词: 2-arachidonylglycerol; Action Potentials; Address; Affect; Agonist; Animal Model; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Brain; CNR1 gene; Cannabinoids; Cannabis; Case Study; Chronic; Clinical; Clinical Treatment; Clinical Trials; Coronary Arteriosclerosis; Depressed mood; Development; Disease; Disease remission; Effectiveness; Endocannabinoids; Enzymes; Epidemiologic Studies; Etiology; Exhibits; Genetic; High Prevalence; Hippocampus (Brain); Human; Hydrolase; Impairment; Incidence; Intervention; Investigation; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Left; Life; Ligands; Long-Term Depression; Mediating; Mental Depression; Mind; Modeling; Monoacylglycerol Lipases; Moods; Morbidity - disease rate; Mus; Obesity; Parahippocampal Gyrus; Patients; Pharmacotherapy; Phenotype; Population; Psychiatrist; Receptor Activation; Reporting; Research; Rewards; Serine Hydrolase; Signal Transduction; Stress; Suicide; Swimming; System; Testing; Therapeutic; Therapeutic Agents; Validation; World Health Organization; dentate gyrus; feeding; functional status; improved; in vivo; inhibitor/antagonist; monoamine; mood regulation; mortality; new therapeutic target; peace; positive emotional state; receptor; research study; response; rimonabant; synaptic depression; transmission process

DESCRIPTION (provided by applicant): Depression is a debilitating and life-threatening disease that affects millions of people worldwide. The clinically available antidepressants share the same core mechanisms of enhancing monoamine transmission in the brain. The high prevalence of the disease and limited effectiveness of current treatments indicate the importance and urgency to find novel therapeutic targets for the treatment of depression. Clinical and laboratory observations over the last decade indicate that the endocannabinoid (eCB) system represents a promising target for the pharmacotherapy of depression. The CB1 cannabinoid receptor antagonist rimonabant increases the incidence of anxiety and depression in clinical trials for the treatment of obesity, whereas cannabis improves mood in humans and CB1 agonists produce antidepressant-like effects in animal models of depression. Inhibitors of eCB inactivation amplify endogenous eCB activity in a temporal- and spatial-specific manner and should be superior to direct CB1 receptor agonists as therapeutic agents. The eCB ligand 2- arachidonoylglycerol (2-AG) is inactivated by monoacylglycerol lipase (MAGL) and serine hydrolase alpha- beta-hydrolase domain 6 and 12 (ABHD6/12). However, it remains unknown whether inhibition of MAGL or ABHD6/12 produces antidepressant effects in animal models of depression. Addressing this important question became possible now with the recent synthesis of selective and potent MAGL inhibitor JZL184 and ABHD6 inhibitor WWL123. Using chronic mild unpredictable stress (CUS) as an animal model for depression, we test the hypothesis that the 2-AG signaling is impaired in depression and the blockade of 2-AG inactivation with MAGL or ABHD6 inhibitors produces antidepressant-like effects by rescuing the deficiency in 2-AG signaling. We will test this hypothesis through two specific aims: (1) Test the hypothesis that 2-AG signaling is impaired in CUS model of depression; and (2) Test the hypothesis that MAGL or ABHD6 blockade produces antidepressant-like effects by rescuing CUS-induced impairment of 2-AG signaling. Under the first Aim, we will record 2-AG-mediated electrophysiological responses to interrogate ongoing status of 2-AG signaling in the hippocampus in a CUS model of depression. Under the second aim, we will examine whether in vivo chronic or subchronic administration of JZL184 or WWL123 produces antidepressant-like effects by rescuing CUS- induced deficiency in eCB signaling. We will also examine whether MAGL knockout mice exhibit antidepressant-like phenotypes. Completion of this investigation will lead to the identification and validation of new therapeutic targets for pharmacotherapy of depression and will provide an improved understanding of the mechanisms of mood regulation and the etiology of depression. PUBLIC HEALTH RELEVANCE: The proposed research investigates the antidepressant effects of inhibitors of endocannabinoid inactivation in an animal model of depression. Completion of this project will contribute knowledge at both mechanistic and practical levels for the development and testing of therapeutic strategies for pharmacological intervention of depression.

描述（由申请人提供）：抑郁症是一种使人衰弱且危及生命的疾病，影响着全世界数百万人。临床上可用的抗抑郁药具有相同的增强大脑中单胺传输的核心机制。该疾病的高患病率和当前治疗的有限有效性表明寻找治疗抑郁症的新治疗靶点的重要性和紧迫性。过去十年的临床和实验室观察表明，内源性大麻素（eCB）系统是抑郁症药物治疗的一个有希望的目标。在治疗肥胖的临床试验中，CB1 大麻素受体拮抗剂利莫那班会增加焦虑和抑郁的发生率，而大麻可以改善人类的情绪，CB1 激动剂在抑郁症动物模型中产生类似抗抑郁的作用。 eCB 失活抑制剂以时间和空间特异性方式放大内源性 eCB 活性，并且作为治疗剂应优于直接 CB1 受体激动剂。 eCB 配体 2-花生四烯酰甘油 (2-AG) 被单酰基甘油脂肪酶 (MAGL) 和丝氨酸水解酶 α-β-水解酶结构域 6 和 12 (ABHD6/12) 灭活。然而，目前尚不清楚 MAGL 或 ABHD6/12 的抑制是否会在抑郁动物模型中产生抗抑郁作用。随着最近合成的选择性强效 MAGL 抑制剂 JZL184 和 ABHD6 抑制剂 WWL123，解决这个重要问题成为可能。使用慢性轻度不可预测应激（CUS）作为抑郁症动物模型，我们测试了这样的假设：2-AG信号传导在抑郁症中受损，并且用MAGL或ABHD6抑制剂阻断2-AG失活可通过挽救2-AG信号传导的缺陷而产生抗抑郁样作用。我们将通过两个具体目标来检验这一假设：（1）检验2-AG信号在抑郁症CUS模型中受损的假设； (2) 检验 MAGL 或 ABHD6 阻断通过挽救 CUS 诱导的 2-AG 信号传导损伤而产生抗抑郁样作用的假设。在第一个目标下，我们将记录 2-AG 介导的电生理反应，以询问 CUS 抑郁症模型中海马中 2-AG 信号传导的持续状态。在第二个目标下，我们将检查 JZL184 或 WWL123 体内慢性或亚慢性给药是否通过挽救 CUS 诱导的 eCB 信号传导缺陷而产生抗抑郁样作用。我们还将检查 MAGL 基因敲除小鼠是否表现出抗抑郁药样表型。这项研究的完成将导致抑郁症药物治疗新治疗靶点的识别和验证，并将加深对情绪调节机制和抑郁症病因学的理解。 公共健康相关性：拟议的研究调查了抑郁症动物模型中内源性大麻素失活抑制剂的抗抑郁作用。该项目的完成将为抑郁症药物干预治疗策略的开发和测试提供机械和实践层面的知识。