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.
CB1 receptor antagonists rimonabant and AM251 reversed deficits in sensorimotor gating caused by phencyclidine in rats, an effect comparable to the atypical antipsychotic clozapine. Rimonabant also attenuated gating disruptions from dizocilpine and apomorphine. No augmentation was seen when rimonabant and clozapine were given together. The findings suggest that blocking CB1 receptors may help restore disrupted interactions between the endocannabinoid and glutamate systems implicated in schizophrenia.