Pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid N-arachidonoylethanolamine (or anandamide, AEA), exerts favourable effects in rodent models of stress-related depression. Yet although depression seems to be more common among women than men and in spite of some evidence of sex differences in treatment efficacy, preclinical development of FAAH inhibitors for the pharmacotherapy of stress-related depression has been predominantly conducted in male animals. Here, adult female rats were exposed to six weeks of social isolation and, starting from the second week, treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle. Compared to pair-housed females, socially isolated female rats treated with vehicle developed behavioral (mild anhedonia, passive stress coping) and physiological (reduced body weight gain, elevated plasma corticosterone levels) alterations. Moreover, prolonged social isolation provoked a reduction in brain-derived neurotrophic factor (BDNF) and AEA levels within the hippocampus. Together, these changes are indicative of an increased risk of developing a depressive-like state. Conversely, pharmacological inhibition of FAAH activity with URB694 restored both AEA and BDNF levels within the hippocampus of socially isolated rats and prevented the development of behavioral and physiological alterations. These results suggest a potential interplay between AEA-mediated signaling and hippocampal BDNF in the pathogenesis of depression-relevant behaviors and physiological alterations and antidepressant action of FAAH inhibition in socially isolated female rats.

中文翻译：

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药理抑制 FAAH 活性对社会隔离雌性大鼠的抗抑郁样作用

脂肪酸酰胺水解酶 (FAAH) 的药理学抑制作用可终止内源性大麻素 N-花生四烯酰乙醇胺（或花生四烯酸乙醇胺，AEA）的信号传导，在压力相关抑郁的啮齿动物模型中发挥有利作用。然而，尽管抑郁症似乎在女性中比男性更常见，并且尽管有一些证据表明治疗效果存在性别差异，但用于压力相关抑郁症药物治疗的 FAAH 抑制剂的临床前开发主要在雄性动物中进行。在这里，成年雌性大鼠接受六周的社会隔离，并从第二周开始，用 FAAH 抑制剂 URB694（0.3 毫克/公斤/天，腹腔注射）或载体治疗。与成对饲养的雌性相比，用载体治疗的社会孤立雌性大鼠出现了行为（轻度快感缺乏、被动应对压力）和生理（体重增加减少，血浆皮质酮水平升高）改变。此外，长期的社会隔离会导致海马体内脑源性神经营养因子 (BDNF) 和 AEA 水平降低。总之，这些变化表明患抑郁症的风险增加。相反，用 URB694 对 FAAH 活性的药理学抑制恢复了社会隔离大鼠海马内的 AEA 和 BDNF 水平，并防止了行为和生理改变的发展。这些结果表明，AEA 介导的信号传导与海马 BDNF 之间在与社会隔离的雌性大鼠的抑郁相关行为和生理改变以及 FAAH 抑制的抗抑郁作用的发病机制中存在潜在的相互作用。