How brain cannabinoids control the breeding-vs-feeding switch

The mechanisms regulating seasonal transitions between reproduction and feeding behavior are not well understood. Endocannabinoids modulate neuronal signaling in reproductive, metabolic and locomotive control centers and are widely distributed throughout the vertebrate nervous system, making them a strong candidate for facilitating seasonal transitions. Using liquid chromatography tandem mass spectrometry, we asked if brain endocannabinoid concentrations in wild red-sided garter snakes (Thamnophis sirtalis parietalis) vary with behavioral phenotype, migratory status or sex. We found that levels of 2-arachidonoylglycerol (2-AG) in the reptilian homologue of the mammalian hippocampus decreased significantly as male and female snakes began their migration to feeding grounds. To further evaluate if endocannabinoids mediate seasonal behavior, we manipulated endocannabinoid signaling for 14 days in males with daily intraperitoneal injections of vehicle control or two different doses of cannabinoid-1 receptor antagonist (AM251), cannabinoid receptor agonist (CP-55940), or an inhibitor of the 2-AG degradative enzyme monoglyceride lipase (JZL184). We found that blocking cannabinoid-1 receptor with AM251 (15 ug per snake; approximately 0.5 mg/kg) significantly reduced male courtship behavior, but not locomotor activity, after 7 days of treatment. Despite 8 months of hibernation-induced aphagia, increasing endogenous levels of 2-AG with JZL184 (48 ug per snake; approximately 1.6 mg/kg) delayed the onset of food-motivated behavior and extended reproductive behavior in males. Our results support a role for 2-AG in the seasonal maintenance and termination of reproductive behavior. Because the endocannabinoid system is evolutionarily conserved across vertebrates, these data are broadly applicable to understanding the neuroendocrine mechanisms that mediate trade-offs between reproduction and self-maintenance.