Stress Physiology Lab, Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 11/A, 43124 Parma, Italy.
Stress Physiology Lab, Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 11/A, 43124 Parma, Italy.
Eur Neuropsychopharmacol. 2020 Mar;32:77-87. doi: 10.1016/j.euroneuro.2019.12.119. Epub 2020 Jan 13.
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.
酶脂肪酸酰胺水解酶（FAAH）的药理学抑制作用可终止内源性大麻素 N-花生四烯酸乙醇胺（或大麻素，AEA）的信号传递，在与应激相关的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为常见，尽管在治疗效果方面有一些性别差异的证据，但 FAAH 抑制剂用于应激相关抑郁症的药物治疗的临床前开发主要在雄性动物中进行。在这里，成年雌性大鼠经历了六周的社交隔离，并且从第二周开始，用 FAAH 抑制剂 URB694（0.3mg/kg/天，ip）或载体处理。与配对饲养的雌性大鼠相比，用载体处理的社交隔离雌性大鼠表现出行为（轻度快感缺失，被动应激应对）和生理（体重增加减少，血浆皮质酮水平升高）改变。此外，长期社交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。这些变化共同表明发生抑郁样状态的风险增加。相反，用 URB694 抑制 FAAH 活性可恢复社交隔离大鼠海马体内的 AEA 和 BDNF 水平，并防止行为和生理改变的发生。这些结果表明，AEA 介导的信号传递和海马体 BDNF 之间可能存在相互作用，这与抑郁相关行为和生理改变的发病机制以及社交隔离雌性大鼠中 FAAH 抑制的抗抑郁作用有关。
