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 be a key link between energy-state cues, sensory cues, and food intake. 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 this amplification. We are developing C. elegans as a model in which to investigate the neurophysiology and genetics 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 the C. elegans gene
npr-19, a CB1 homolog, eliminates hedonic amplification, which can be rescued not only by expression of the wild type
npr-19 gene, but the human CB1 gene, establishing a humanized worm for cannabinoid signaling studies. Further, deletion of the olfactory neuron AWC, which directs chemotaxis to food, abolished hedonic amplification. Consistent with this finding, calcium imaging revealed that AEA bidirectionally modulates AWC, increasing its responses to strongly preferred food and decreasing its response for weakly preferred food. In a GFP expression analysis, we found that
npr-19 is expressed 20 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 the mutation
unc-13(
e51), had no effect on modulation. We are now testing the hypothesis that AEA modulates AWC by activating one or more NPR-19-expressing neurons that release a diffusible neuromodulator to which AWC is sensitive.