The endocannabinoid-inactivating enzyme, fatty acid amide hydrolase (FAAH), and the transient receptor potential vanilloid type-1 (TRPV1) channel are new targets for the development of anxiolytic drugs. We studied the effect on anxiety-like behavior in the elevated plus maze of a dual FAAH/TRPV1 blocker, N-arachidonoyl-serotonin (AA-5-HT). In male C57BL/6J mice, acute intraperitoneal administration of AA-5-HT (0.1-2.5 mg/kg) increased both the time spent and the number of entries in the open arm, while being inactive at the highest dose tested (5 mg/kg). AA-5-HT was more potent than selective blockers of FAAH or TRPV1 (URB597 and SB366791, respectively). In male Swiss mice, AA-5-HT had to be administered chronically to observe an anxiolytic effect at an intermediate dose (2.5 mg/kg), the highest dose (5 mg/kg) being anxiogenic, and 1 mg/kg being ineffective. In both strains, the anxiolytic effects of AA-5-HT were paralleled by elevation of brain endocannabinoid levels and were reversed by per se inactive doses of the cannabinoid receptors of type-1 (CB 1 ) receptor antagonist AM251, or the TRPV1 agonist, olvanil. Immunohistochemical localization of CB 1 and TRPV1 receptors was observed in mouse prefrontal cortex, nucleus accumbens, amygdala, and hippocampus. Simultaneous 'indirect' activation of CB 1 receptors following FAAH inhibition, and antagonism at TRPV1 receptors might represent a new therapeutic strategy against anxiety.

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