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

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
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