Cannabinoids stimulate the TRP-channel dependent release of both serotonin and dopamine to modulate behavior in C. elegans

Cannabis sativa alters sensory perception and exhibits potential medicinal benefits. In mammals, cannabinoids activate two canonical receptors, CB 1 /CB 2 , as well additional receptors/ion channels whose overall contributions to cannabinoid signaling have yet to be fully assessed. In C. elegans , the endogenous cannabinoid receptor agonist, 2-arachidonoylglycerol (2-AG) activates a CB 1 orthologue, NPR-19, to modulate behavior (Oakes et al., 2017). In addition, 2-AG stimulates the NPR-19 independent release of both serotonin (5-HT) and dopamine (DA) from subsets of monoaminergic neurons to modulate locomotory behaviors through a complex monoaminergic signaling pathway involving multiple serotonin and dopamine receptors. 2-AG also inhibits locomotion in remodeled monoamine receptor mutant animals designed to measure the acute release of either 5-HT or DA, confirming the direct effects of 2-AG on monoamine release. 2-AG-dependent locomotory inhibition requires the expression of TRPV1 and TRPN-like channels in the serotonergic or dopaminergic neurons, respectively, and the acute pharmacological inhibition of the TRPV 1 -like channel abolishes both 2-AG dependent 5-HT release and locomotory inhibition, suggesting the 2-AG may activate the channel directly. This study highlights the advantages of identifying and assessing both CB 1 /CB 2 -dependent and independent cannabinoid signaling pathways in a genetically-tractable, mammalian predictive model, where cannabinoid signaling at the molecular/neuronal levels can be correlated directly with changes in behavior. SIGNIFICANCE STATEMENT This study is focused on assessing CB 1 /CB 2 -independent cannabinoid signaling in a genetically-tractable, whole animal, model where cannabinoid signaling at the molecular/neuronal levels can be correlated with behavioral change. C. elegans contains a cannabinoid signaling system mediated by a canonical cannabinoid receptor, NPR-19 with orthology to human CB 1 /CB 2 (Oakes et al., 2017). The present study has characterized and NPR-19-independent signaling pathway that involves the cannabinoid-dependent release of both serotonin and dopamine and the expression of distinct TRP-like channels on the monoaminergic neurons. Our work should be of interest to those studying the complexities of CB 1 /CB 2 -independent cannabinoid signaling, the role of TRP channels in the modulation of monoaminergic signaling and the cannabinoid-dependent modulation of behavior.