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

A R Tejeda-Martínez,V Chaparro-Huerta,E Pardo-González,M E Flores-Soto,G V Hidalgo-Franco,J M Viveros-Paredes,R E González-Castañeda,Giuseppe Biagini

doi:10.1155/2021/6651492

A R Tejeda-Martínez, V Chaparro-Huerta + Show 6 more

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https://doi.org/10.1155/2021/6651492

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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.

Highlights

Clinical depression is widespread and debilitating; it is characterized by the presence of symptoms such as anhedonia and despair [1]
We see an urgent need to develop more effective and safer pharmacological treatments for depression through the modulation of various neurotransmission systems such as the endocannabinoid system. This system consists of its specific receptors, type 1 and type 2 cannabinoid receptors (CB1R and CB2R, respectively); its endogenous ligands, 2-arachidonoylglycerol (2-AG) and anandamide (AEA); its recapture system; and the enzymes that participate in the synthesis: N-acyltransferase and phospholipase D, and degradation: fatty acid amide hydrolase (FAAH) and monoacyl-glycerol lipase (MAGL) of endogenous endocannabinoids [12]
This study was aimed at evaluating if the effects of chronic inhibition of FAAH could be capable of restoring neurogenesis and behavioral impairment in mice subjected to a depression model by chronic unpredictable stress model (CUS)

Summary

Introduction

Clinical depression is widespread and debilitating; it is characterized by the presence of symptoms such as anhedonia and despair [1]. We see an urgent need to develop more effective and safer pharmacological treatments for depression through the modulation of various neurotransmission systems such as the endocannabinoid system This system consists of its specific receptors, type 1 and type 2 cannabinoid receptors (CB1R and CB2R, respectively); its endogenous ligands, 2-arachidonoylglycerol (2-AG) and anandamide (AEA); its recapture system; and the enzymes that participate in the synthesis: N-acyltransferase and phospholipase D, and degradation: fatty acid amide hydrolase (FAAH) and monoacyl-glycerol lipase (MAGL) of endogenous endocannabinoids [12]. There is evidence for CB1R-mediated hippocampal neurogenesis in vivo in C57 mice subjected to the CB1 synthetic agonist arachidonyl-2-chloroethylamide administration [16] For his part, stimulation of CB2R has been capable of generating neural progenitor cell proliferation in healthy mouse hippocampus through the activation of the mTOR1 signaling pathway [17].

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