Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay.
Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay.
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DOI：
10.1016/j.pbb.2010.12.002
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发表时间：
2011-03
影响因子：
3.6
通讯作者：
Lichtman, Aron H.
中科院分区：
文献类型：
--
作者：
Kinsey, Steven G.;O'Neal, Scott T.;Long, Jonathan Z.;Cravatt, Benjamin F.;Lichtman, Aron H.
关键词：
大麻素长期以来被证明具有一系列潜在的治疗作用，包括止吐作用、镇痛和抗焦虑作用。然而，精神拟态和记忆破坏性的副作用，以及滥用和依赖的可能性，限制了它们的临床发展。内源性大麻素（即，内源性大麻素; eCB），如花生四烯酸（AEA）和2-花生四烯酸甘油（2-AG），在整个边缘系统和与情绪相关的其他大脑区域产生，并被认为调节对压力相关条件的行为反应。AEA和2-AG分别被脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL）快速代谢。因此，每种酶的抑制都会增加适当eCB的大脑水平。虽然FAAH抑制已被确定为减少焦虑样行为，但2-AG的作用一直难以确定，直到最近合成了JZL 184，一种有效的和选择性的MAGL抑制剂。在本研究中，我们研究了抑制FAAH或MAGL对大理石埋葬中焦虑样行为的影响，这是一种与焦虑症如强迫症密切相关的重复强迫行为模型。FAAH抑制剂PF-3845、MAGL抑制剂JZL 184和苯二氮卓类地西泮在不影响自发活动的剂量下降低了大理石掩埋。相比之下，大麻的主要精神活性成分Δ9-四氢大麻酚（THC）并没有持续减少大理石埋葬，也没有引起运动行为的深刻减少。CB 1大麻素受体拮抗剂利莫那班阻断了FAAH和MAGL抑制剂引起的大理石掩埋减少，但没有地西泮，表明CB 1受体的作用机制。这些数据表明，AEA或2-AG的升高降低了大理石掩埋行为，并表明它们的分解代谢酶代表了开发新型药物治疗焦虑相关疾病的潜在靶点。
Cannabinoids have long been shown to have a range of potential therapeutic effects, including antiemetic actions, analgesia, and anxiolysis. However, psychomimetic and memory disruptive side effects, as well as the potential for abuse and dependence, have restricted their clinical development. Endogenous cannabinoids (i.e., endocannabinoids; eCBs), such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are produced throughout the limbic system and other brain regions associated with emotionality and are believed to modulate behavioral responses to stress-related conditions. AEA and 2-AG are rapidly metabolized by the respective enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Accordingly, inhibition of each enzyme increases brain levels of the appropriate eCB. Although FAAH inhibition has been established to decrease anxiety-like behavior, the role of 2-AG has been difficult to ascertain until the recent synthesis of JZL184, a potent and selective MAGL inhibitor. In the present study, we investigated the effects of inhibiting FAAH or MAGL on anxiety-like behavior in marble burying, a model of repetitive, compulsive behaviors germane to anxiety disorders such as obsessive-compulsive disorder. The FAAH inhibitor PF-3845, the MAGL inhibitor JZL184, and the benzodiazepine diazepam decreased marble burying at doses that did not affect locomotor activity. In contrast, Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana, did not consistently reduce marble burying without also eliciting profound decreases in locomotor behavior. The CB1 cannabinoid receptor antagonist rimonabant blocked the reduction in marble burying caused by FAAH and MAGL inhibitors, but not by diazepam, indicating a CB1 receptor mechanism of action. These data indicate that elevation of AEA or 2-AG reduces marble burying behavior and suggest that their catabolic enzymes represent potential targets for the development of new classes of pharmacotherapeutics to treat anxiety-related disorders.
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