Chronic Inhibition of FAAH Reduces Depressive-Like Behavior and Improves Dentate Gyrus Proliferation after Chronic Unpredictable Stress Exposure

Abstract

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.

Gender variation in whole genome sequencing of susceptibility genes in a rat model of depression

“…Some studies have shown that the level of Sox2 expression was decreased in the depressed state (Tejeda-Martínez et al, 2021;Boehler et al, 2021). In this study, stop gained mutation was found in the Sox2 gene of our depressed female rat.…”

Effects of Fatty Acid Amide Hydroxylase Inhibitor URB597 on the Catecholaminergic Activity of the Adrenal Medulla in Stressed Male and Female Rats

“…McFadden et al [13] demonstrated that female adrenal weights were higher than males exposed to CUS for 21 days which is in agreement with our findings. On the other hand, Tejeda-Martinez et al [14] reported enlarged adrenal medulla in male mice exposed to CUS. We first demonstrated that treatment with URB597 reduced enlarged adrenals in stressed female rats.…”

Neurobiological Links between Stress, Brain Injury, and Disease

“…Oxidative stress eventually leads to the depression of animals after stress [ 47 , 54 , 55 ], and the symptoms of depression were significantly improved after using drugs that can increase the level of BDNF or show antioxidant effect in animals [ 47 , 51 , 52 , 54 ]. Inhibition of fatty acid amide hydrolase (FAAH) can also be antidepressant through promoting neural progenitor proliferation and BDNF expression and reducing adrenal gland weight and oxidative stress in mice under the CUMS model [ 49 ].…”