Arachidonoyl serotonin (AA-5-HT) modulates general fear-like behavior and inhibits mesolimbic dopamine release.

Cannabinergic and vanilloidergic signaling are potential mechanisms for the treatment of anxiety symptoms because of the anxiolytic properties of cannabinoid type 1 receptor (CB1R) activation and transient potential vanilloid type 1 channel (TRPV1) inhibition. Arachidonoyl serotonin (AA-5-HT), a fatty acid amide hydrolase and TRPV1 inhibitor provides a means of modulating these systems. We examined the effects of AA-5-HT on anxiety- and fear-like behaviors in male low (C57BL/6 J; [B6]) and high (BALB/cJ; [BCJ]) anxiety mice in light/dark box (LDB), open-field (OF), and fear extinction (FE) paradigms. AA-5-HT (1 mg/kg) did not affect anxiety-related behaviors in the LDB or OF in B6 mice. However, AA-5-HT attenuated generalized fear compared to vehicle treated B6s. AA-5-HT increased rearing and locomotion in the LDB in BCJ mice but did not affect fear-related behaviors. in vivo amperometry was used to determine the effects of AA-5-HT on dopamine release in the basolateral amygdala (BLA) and nucleus accumbens (NAc). AA-5-HT inhibited dopamine release in the BLA of BCJs and the NAc of B6s. Our results indicate that context interacts with basal anxiety levels to modulate the effects of AA-5-HT on some anxiety- and fear-related behaviors. We also provide evidence of cannabinergic and dopaminergic interactions in the BLA which could affect anxiety and fear. We suggest that this dose of AA-5-HT exhibits limited utility as a treatment for anxiety symptoms because it affects only some aspects of anxiety- and fear-related behavior in a manner dependent on baseline anxiety and environmental context.