Symptoms of depressive disorders such as anhedonia and despair can be a product of an aberrant adaptation to stress conditions. Chronic unpredictable stress model (CUS) can generate an increase in the activity of the hypothalamic-pituitary-adrenal axis (HPA) and induce a reduction of neurotrophin signaling and the proliferation of neural progenitors in the adult dentate gyrus, together with increased oxidative stress. Levels of the endocannabinoid anandamide (AEA) seem to affect these depression-by-stress-related features and could be modulated by fatty acid amide hydrolase (FAAH). We aimed to evaluate the effects of FAAH inhibitor, URB597, on depressive-like behavior and neural proliferation of mice subjected to a model of CUS. URB597 was administered intraperitoneally at a dose of 0.2 mg/kg for 14 days after CUS. Depressive-like behaviors, anhedonia, and despair were evaluated in the splash and forced swimming tests, respectively. Alterations at the HPA axis level were analyzed using the relative weight of adrenal glands and serum corticosterone levels. Oxidative stress and brain-derived neurotrophic factor (BDNF) were also evaluated. Fluorescence immunohistochemistry tests were performed for the immunoreactivity of BrdU and Sox2 colabeling for comparison of neural precursors. The administration of URB597 was able to reverse the depressive-like behavior generated in mice after the model. Likewise, other physiological responses associated with CUS were reduced in the treated group, among them, increase in the relative weight of the adrenal glands, increased oxidative stress, and decreased BDNF and number of neural precursors. Most of these auspicious responses to enzyme inhibitor administration were blocked by employing a cannabinoid receptor antagonist. In conclusion, the chronic inhibition of FAAH generated an antidepressant effect, promoting neural progenitor proliferation and BDNF expression, while reducing adrenal gland weight and oxidative stress in mice under the CUS model.

中文翻译：

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FAAH 的慢性抑制可减少抑郁样行为并改善慢性不可预测的压力暴露后齿状回的增殖

抑郁症的症状，如快感缺乏和绝望，可能是对压力条件异常适应的产物。慢性不可预测压力模型 (CUS) 可以增加下丘脑 - 垂体 - 肾上腺轴 (HPA) 的活性，并诱导成年齿状回中神经营养蛋白信号传导的减少和神经祖细胞的增殖，同时增加氧化应激。内源性大麻素 anandamide (AEA) 的水平似乎会影响这些与压力相关的抑郁症特征，并且可以通过脂肪酸酰胺水解酶 (FAAH) 进行调节。我们旨在评估 FAAH 抑制剂 URB597 对 CUS 模型小鼠抑郁样行为和神经增殖的影响。URB597 在 CUS 后以 0.2 mg/kg 的剂量腹膜内给药 14 天。类似抑郁的行为，快感缺乏和绝望分别在飞溅和强迫游泳测试中进行评估。使用肾上腺的相对重量和血清皮质酮水平分析 HPA 轴水平的变化。还评估了氧化应激和脑源性神经营养因子 (BDNF)。对 BrdU 和 Sox2 共标记的免疫反应性进行了荧光免疫组织化学测试，以比较神经前体。URB597 的给药能够逆转模型后小鼠产生的抑郁样行为。同样，治疗组与 CUS 相关的其他生理反应减少，其中，肾上腺相对重量增加，氧化应激增加，BDNF 和神经前体数量减少。通过使用大麻素受体拮抗剂，大多数这些对酶抑制剂给药的吉祥反应被阻止了。总之，FAAH的慢性抑制产生抗抑郁作用，促进神经祖细胞增殖和BDNF表达，同时降低CUS模型下小鼠的肾上腺重量和氧化应激。