Altered responses of dopamine D3 receptor null mice to excitotoxic or anxiogenic stimuli: Possible involvement of the endocannabinoid and endovanilloid systems

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 elevatedplus maze of a dual FAAH/TRPV1 blocker, N-arachidonoyl-serotonin (AA-5-HT). In male C57BL/6J mice, acute intraperitonealadministration 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 beinginactive at the highest dose tested (5 mg/kg). AA-5-HT was more potent than selective blockers of FAAH or TRPV1 (URB597 andSB366791, respectively). In male Swiss mice, AA-5-HT had to be administered chronically to observe an anxiolytic effect at anintermediate dose (2.5 mg/kg), the highest dose (5 mg/kg) being anxiogenic, and 1 mg/kg being ineffective. In both strains, the anxiolyticeffects of AA-5-HT were paralleled by elevation of brain endocannabinoid levels and were reversed by per se inactive doses of thecannabinoid receptors of type-1 (CB1) receptor antagonist AM251, or the TRPV1 agonist, olvanil. Immunohistochemical localization ofCB1 and TRPV1 receptors was observed in mouse prefrontal cortex, nucleus accumbens, amygdala, and hippocampus. Simultaneous‘indirect’ activation of CB1 receptors following FAAH inhibition, and antagonism at TRPV1 receptors might represent a new therapeuticstrategy against anxiety.