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.
Low doses of the cannabinoid CB1 receptor agonist WIN55,212-2 produce antidepressant-like effects in rats, as measured by the forced-swim test. This effect depends on CB1 receptors and the serotonin system, as it is blocked by the CB1 antagonist rimonabant and by serotonin depletion. Electrophysiology shows that low doses of WIN55,212-2 increase serotonin neuron firing in the dorsal raphe nucleus via a CB1-dependent mechanism, while high doses decrease firing through a CB1-independent mechanism and lack antidepressant effects. The enhancement of serotonin activity requires the ventromedial prefrontal cortex, as local microinjection there mimics the antidepressant effect, whereas lateral prefrontal cortex involvement is not needed.