Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors
Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors
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DOI：
10.1016/j.neuropharm.2007.07.005
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发表时间：
2008-01-01
影响因子：
4.7
通讯作者：
Lutz, Beat
中科院分区：
文献类型：
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作者：
Moreira, Fabricio A.;Kaiser, Nadine;Lutz, Beat
Anandamide 和 2-花生四烯酰甘油，称为内源性大麻素 (eCB)，是 1 型大麻素受体 (CB1) 的内源性激动剂。一些证据支持 eCB 在减轻焦虑相关行为中的作用，尽管确切的机制仍不确定。脂肪酸酰胺水解酶 (FAAH) 是一种负责 eCB 降解的酶，它已成为焦虑相关疾病的一个有希望的靶标，因为 FAAH 抑制剂能够增加 anandamide 的水平，从而在啮齿动物中诱导抗焦虑样作用。本研究采用遗传和药理学方法，并测试了以下假设：FAAH 缺陷 (FAAH(-/-)) 小鼠以及用 FAAH 抑制剂 (URB597) 治疗的 C57BL/6N 小鼠会表现出减少的焦虑样反应。此外，众所周知，anandamide 可以结合 CB I 受体以外的其他几个靶点，我们研究了 FAAH 抑制是否通过 CB I 受体减少焦虑。 FAAH(-/-) 小鼠在高架十字迷宫和明暗测试中均表现出焦虑感降低。这些与基因型相关的差异可以通过 CB I 受体拮抗剂利莫那班（3 mg/kg）来预防。此外，URB597 (1 mg/kg) 在暴露于高架十字迷宫的 C57BL/6N 小鼠中诱导抗焦虑样作用，而利莫那班 (3 mg/kg) 可以阻止这种作用。目前的工作提供了遗传和药理学证据，支持抑制 FAAH 作为缓解焦虑的重要机制。此外，它表明 CBI 受体的激活增加是两种焦虑模型中 FAAH 抑制作用的潜在机制。 (c) 2007 Elsevier Ltd. 保留所有权利。
Anandamide and 2-arachidonoyl glycerol, referred to as endocannabinoids (eCBs), are the endogenous agonists for the cannabinoid receptor type 1 (CB1). Several pieces of evidence support a role for eCBs in the attenuation of anxiety-related behaviours, although the precise mechanism has remained uncertain. The fatty acid amid hydrolase (FAAH), an enzyme responsible for the degradation of eCBs, has emerged as a promising target for anxiety-related disorders, since FAAH inhibitors are able to increase the levels of anandamide and thereby induce anxiolytic-like effects in rodents. The present study adopted both genetic and pharmacological approaches and tested the hypothesis that FAAH-deficient (FAAH(-/-)) mice as well as C57BL/6N mice treated with an FAAH inhibitor (URB597) would express reduced anxiety-like responses. Furthermore, as it is known that anandamide can bind several other targets than CB I receptors, we investigated whether FAAH inhibition reduces anxiety via CB I receptors. FAAH(-/-) mice showed reduced anxiety both in the elevated plus maze and in the light-dark test. These genotype-related differences were prevented by the CB I receptor antagonist rimonabant (3 mg/kg). Moreover, URB597 (1 mg/kg) induced an anxiolytic-like effect in C57BL/6N mice exposed to the elevated plus maze, which was prevented by rimonabant (3 mg/kg). The present work provides genetic and pharmacological evidence supporting the inhibition of FAAH as an important rnechanism for the alleviation of anxiety. In addition, it indicates an increased activation of CBI receptors as a mechanism underlying the effects of FAAH inhibition in two models of anxiety. (c) 2007 Elsevier Ltd. All rights reserved.