The mammalian endocannabinoid system, comprised of the endocannabinoids AEA (N-arachidonoyl-ethanolamine) and 2-AG (2-Arachidonoylglycerol), their receptors, CB1 and CB2, and their metabolic enzymes, is thought to integrate internal energy state and sensory food cues to modulate feeding. For example, cannabinoids, acting on CB1, can increase preference for more palatable, calorically dense food: a response called hedonic amplification, colloquially known as "the munchies." In mammals, cannabinoids can increase sensitivity to odors and sweet tastes, which may underlie hedonic amplification. We are developing C. elegans as a model in which to investigate the neurogenetics of hedonic amplification. We have found that exposure to AEA, an endocannabinoid common to mammals and C. elegans, increases the worm's preference for strongly preferred (more palatable) bacteria over weakly preferred (less palatable) bacteria, mimicking hedonic amplification in mammals. Furthermore, AEA acts bidirectionally, increasing consumption of strongly preferred bacteria while decreasing consumption of weakly preferred bacteria. We also found that deletion of the CB1 ortholog, NPR-19, eliminates hedonic amplification, which can be rescued by expression of the human CB1 receptor, establishing a humanized worm for cannabinoid signaling studies. Deletion of the olfactory neuron AWC, which directs chemotaxis to food, abolishes hedonic amplification. Consistent with this finding, calcium imaging revealed that AEA bidirectionally modulates AWC's activity, increasing its responses to strongly preferred food and decreasing its response for weakly preferred food. Furthermore, AEA's effect on AWC requires NPR-19. However, GFP expression analysis revealed that NPR-19 is expressed ~21 neuron classes but, surprisingly, not in AWC. Although AEA's effect could be mediated by NPR-19-expressing neurons presynaptic to AWC, nearly complete elimination of fast synaptic transmission, via a mutation in
unc-13, has no effect on modulation. Instead, AEA's effect on AWC is mediated via
unc-31-dependent dense-core vesicle release. We are now working to identify the NPR-19-expressing neurons that pass the cannabinoid signal down to AWC, thereby modulating chemosensation and leading to hedonic amplification.