Electronic Theses and Dissertations
Arachidonoyl Serotonin (AA-5-HT) Modulates Exploratory Anxiety-Related Behavior and Tunes Mesolimbic Dopamine Transmission
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Abstract
Cannabinergic and vanilloidergic signaling are mechanisms of interest for the treatment of anxiety symptoms due to 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 dual fatty acid amide hydrolase and TRPV1 inhibitor provides an efficient means of modulating these systems. We therefore examined the effects of AA-5-HT on anxiety- and fear-like behaviors in male low (C57BL/6J; [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) administration did not affect anxiety-related behaviors in the LDB or OF in B6 mice. However, AA-5-HT treatment attenuated generalized fear compared to vehicl treated B6s. AA-5-HT administration increased rearing and locomotion in the LDB in BCJ mice but did not affect fear-related behaviors. In vivo fixed potential amperometry was used to determine whether AA-5-HT administration modulates phasic dopamine release in the basolateral amygdala (BLA) and nucleus accumbens (NAc) of mice. AA-5-HT treatment inhibited phasic dopamine release in the BLA of BCJs and the NAc of B6s. Our results suggest that contextual factors interact with basal anxiety levels to modulate the effects of cannabinergic signaling on anxiety-related behaviors. We also provide evidence of cannabinergic and dopaminergic interactions in the BLA which could affect anxiety and fear. The lack of elevated subsecond dopamine release observed in the NAc following systemic AA-5-HT administration suggests that the drug may not produce rewarding effect by enhancing peak dopamine release in this region. Ultimately, our findings imply that the utility of AA-5-HT as an anxiolytic drug may limited by individual differences in contextual factors and basal anxiety symptoms in humans.
