FAAH inhibition as a pharmacological strategy to promote stress resilience: insights from rodent studies

Our view of the endocannabinoid system has evolved, encompassing not only its classical components like anandamide but also a plethora of related non-cannabinoid mediators and alternative signaling routes. A noteworthy illustration of this versatility is exemplified by Fatty Acid Amide Hydrolase (FAAH), a key enzyme responsible for the degradation of the endocannabinoid anandamide and its bioactive congeners within the fatty acid ethanolamide (FAE) family, including the "anti-inflammatory" N-palmitoylethanolamide and the "satiety factor" N-oleylethanolamide. Pharmacological inhibition of FAAH activity has exhibited promise in enhancing stress resilience, ameliorating or preventing symptoms associated with a variety of stress-related disorders, such as depression and post-traumatic stress disorder. This thesis investigates putative “non conventional” pathways (both central and peripheral) by which increased FAE tone promotes stress resilience, such as the gut microbiota and lipidome or inflammatory processes. Significantly, all these diverse pathways have been extensively implicated in stress-related psychopathologies, yet the impact of FAAH inhibitors on them is often overlooked. In the first study, male rats were subjected to chronic social stress and administered with a systemic FAAH inhibitor (URB694) to evaluate its effects on the gut microbial and lipidic profiles. Notably, this research reveals that systemic FAAH inhibition not only normalized stress induced behavioral and neuroendocrine changes but also stabilized gut microbiota and lipidome. In the second investigation, a peripherally restricted FAAH inhibitor (URB937) was administered in male rats to assess its effects on behavioral responses and pro-inflammatory cytokines levels following acute social stress. The results demonstrate the potential of peripheral FAAH inhibition in mitigating stress-related consequences, including the normalization of behavior and pro-inflammatory cytokine response. These studies challenge the traditional brain-centric view of psychopathologies by highlighting the intricate bidirectional communication between the brain and periphery. The multifaceted impact of FAAH inhibition, particularly on non-cannabinoid FAEs, like palmitoylethanolamide and oleoylethanolamide, underscores the complexity of the endocannabinoid system and its interconnected pathways.