The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents

Guy Griebel,Valérie Fauchey,Mati Lopez-Grancha,Philippe Pichat,Franck Slowinski,Olivier E Bergis,Gihad Dargazanli,Caroline Cohen,Jeanne Stemmelin,Ahmed Abouabdellah

doi:10.1038/s41598-018-20895-z

Abstract

Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.

Highlights

The endocannabinoid system is formed by two G protein-coupled receptors, CB1 and CB2, and their main transmitters, N-arachidonoylethanolamine and 2-arachidonoyglycerol (2-AG)[1]
Inhibitors (e.g. BIA 10-2474, PF-04457845, JNJ-42165279) have entered into clinical trials to assess their potential efficacy in patients suffering from major depressive disorder (MDD), social anxiety or post-traumatic stress disorder (PTSD)
The cause of the clinical neurotoxicity is unknown, it has been postulated that off-target activities of BIA 10-2474 due to its irreversible nature may have played a role[15], suggesting that reversible Fatty acid amide hydrolase (FAAH) inhibitors may be safer

Summary

Introduction

The endocannabinoid (eCB) system is formed by two G protein-coupled receptors, CB1 and CB2, and their main transmitters, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoyglycerol (2-AG)[1]. Alterations in eCB signalling have been demonstrated in a wide range of pathological conditions including inflammation, immunological disorders, neurological and psychiatric conditions, obesity and metabolic syndromes and cancer (for recent reviews, see[6,7]) These findings have triggered significant interest in the development of eCB-interacting drugs, including direct-acting receptor ligands and catabolism inhibitors to treat these conditions[8]. Inhibitors (e.g. BIA 10-2474, PF-04457845, JNJ-42165279) have entered into clinical trials to assess their potential efficacy in patients suffering from major depressive disorder (MDD), social anxiety or post-traumatic stress disorder (PTSD) Several of these studies were either put on hold because of safety issues (e.g. BIA 10-2474) or terminated for strategic reasons (e.g. PF-04457845)[14], so that no definitive conclusion could be drawn on the therapeutic potential of FAAH inhibitors against stress-related disorders. A second objective was to evaluate possible behavioral side-effects of SSR411298, related to the modulation of the eCB system, i.e. impairment in motor activity and coordination, catalepsy, nociception, physical dependence, and deficits in learning and memory

Methods

Results

Discussion

Conclusion