Inhibiting the enzyme fatty-acid amide hydrolase (FAAH) with URB597, which prevents the breakdown of the endocannabinoid anandamide, produces antidepressant-like effects in mice and rats. URB597 reduced immobility in the tail-suspension and forced-swim tests, and increased firing of serotonin and norepinephrine neurons in brain regions linked to mood. These effects required CB1 receptor activation and were accompanied by higher brain anandamide levels. Unlike direct THC-like drugs, URB597 showed no rewarding or abuse-related effects. The findings suggest FAAH inhibition as a potential target for antidepressant drugs without the psychotropic side effects of cannabis.
Three novel phenethylamine derivatives—25C-NBF, 25B-NBF, and 25I-NBF—show high affinity and selectivity for the 5-HT2A receptor, with signaling bias toward Gq over β-arrestin pathways similar to serotonin. In mice, they cause moderate head-twitch responses without affecting movement or sensorimotor gating. No rewarding or reinforcing effects were observed, and accumbal dopamine levels in rats remained unchanged. 25C-NBF promotes dendritogenesis, spinogenesis, and increased Bdnf mRNA in vitro and in vivo, reduces despair-like behavior after acute stress, and produces rapid antidepressant effects in a chronic corticosterone model of anhedonia. These findings suggest 25C-NBF may offer a fast-acting antidepressant with no abuse potential or sensorimotor deficits.