The endocannabinoid system is involved in the regulation of the stress response, but the relative contribution of N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) and their mechanisms have to be elucidated. In this study, we compared the effects of the pharmacological inhibition of the two major endocannabinoid-degrading enzymes [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) for AEA and 2-AG, respectively] on stress-coping [forced swim test (FST) and tail suspension test (TST)] and anxiety-like [elevated-plus maze (EPM) and light-dark test (LDT)] behaviors in wild-type and FAAH knockout mice. In vivo microdialysis estimated the effects of FAAH and MAGL inhibition on dopamine (DA) and serotonin (5-HT) levels in the medial prefrontal cortex (mPFC) during an FST. Mice were treated with PF-3845 (FAAH inhibitor), JZL184 (MAGL inhibitor), JZL195 (dual FAAH/MAGL inhibitor) or vehicle. Our data showed that PF-3845 increased latency to immobility and decreased total immobility time in FST, but no effects were observed in TST compared with vehicle-treated wild-type mice. By contrast, JZL184 decreased latency and increased immobility in TST and FST. JZL195 in wild-type mice and JZL184 in FAAH knockout mice reproduced the same passive coping behaviors as JZL184 in wild-type mice in TST and FST. In the microdialysis experiment, FST was associated with increased DA and 5-HT levels in the mPFC. However, JZL184-treated wild-type mice displayed a significant attenuation of forced swim stress-induced DA release compared with vehicle-treated wild-type mice and PF-3845-treated wild-type mice. Finally, FAAH and/or MAGL inhibitors induced robust and consistent anxiolytic-like effects in EPM and LDT. These results suggested differences between FAAH and MAGL inhibition in stress-coping behaviors. Notably, MAGL inhibition induced a consistent avoidant coping behavior and attenuated the stress-induced mPFC DA response in FST. However, more investigation is needed to elucidate the functional association between DA and 2-AG signaling pathways, and the molecular mechanism in the regulation of passive coping strategies during inescapable stress.

内源性大麻素系统参与应激反应的调节，但必须阐明 N-花生四烯酰乙醇胺 (AEA) 和 2-花生四烯酰甘油 (2-AG) 的相对贡献及其机制。在这项研究中，我们比较了两种主要的内源性大麻素降解酶 [脂肪酸酰胺水解酶 (FAAH) 和单酰基甘油脂肪酶 (MAGL)，分别用于 AEA 和 2-AG] 对压力应对 [强迫游泳试验（FST）和悬尾试验（TST）]和焦虑样[高架十字迷宫（EPM）和明暗试验（LDT）]在野生型和FAAH基因敲除小鼠中的行为。体内微透析评估了 FST 期间 FAAH 和 MAGL 抑制对内侧前额叶皮层 (mPFC) 中多巴胺 (DA) 和血清素 (5-HT) 水平的影响。用PF-3845（FAAH抑制剂）、JZL184（MA​​GL抑制剂）、JZL195（FAAH/MAGL双重抑制剂）或载体治疗小鼠。我们的数据显示 PF-3845 增加了不动的潜伏期并减少了 FST 的总不动时间，但与载体处理的野生型小鼠相比，在 TST 中没有观察到影响。相比之下，JZL184 在 TST 和 FST 中减少了延迟并增加了不动。野生型小鼠中的 JZL195 和 FAAH 敲除小鼠中的 JZL184 在 TST 和 FST 中再现了与野生型小鼠中 JZL184 相同的被动应对行为。在微透析实验中，FST 与 mPFC 中 DA 和 5-HT 水平的增加有关。然而，与载体处理的野生型小鼠和 PF-3845 处理的野生型小鼠相比，JZL184 处理的野生型小鼠表现出强迫游泳应激诱导的 DA 释放的显着减弱。最后，FAAH 和/或 MAGL 抑制剂在 EPM 和 LDT 中诱导了强大且一致的抗焦虑样作用。这些结果表明 FAAH 和 MAGL 抑制在压力应对行为方面存在差异。值得注意的是，MAGL 抑制诱导了一致的回避应对行为，并减弱了 FST 中应激诱导的 mPFC DA 反应。然而，需要更多的研究来阐明 DA 和 2-AG 信号通路之间的功能关联，以及在不可避免的压力下被动应对策略调节的分子机制。