Evidence for an Interaction between CB<sub>1</sub> Cannabinoid and Melanocortin MCR-4 Receptors in Regulating Food Intake

Melanocortin receptor 4 (MCR4) and CB₁ cannabinoid receptorsindependently modulate food intake. Although an interactionbetween the cannabinoid and melanocortin systemshas been found in recovery from hemorrhagic shock, the interactionbetween these systems in modulating food intakehas not yet been examined. The present study had two primarypurposes: 1) to examine whether the cannabinoid andmelanocortin systems act independently or synergistically insuppressing food intake; and 2) to determine the relative positionof the CB₁ receptors in the chain of control of foodintake in relation to the melanocortin system. Rats were habituatedto the test environment and injection procedure andthen received intracerebroventicular injections of variouscombinations of the MCR4 receptor antagonist JKC-363, thereceptor agonist Δ⁹-tetrahydrocannabinol, the MCR4 receptoragonist α-MSH, or the cannabinoid CB1 receptor antagonistSR 141716. Food intake and locomotor activity werethen recorded for 120 min. When administrated alone, SR141716 and α-MSH dose-dependently attenuated baselinefeeding, whereas sub-anorectic doses of SR 141716 and α-MSHsynergistically attenuated baseline feeding when combined.Δ⁹-Tetrahydrocannabinol-induced feeding was not blockedby α-MSH, whereas SR 141716 dose-dependently attenuatedJKC-363-induced feeding. Locomotor activity was not significantlyaffected by any drug treatment, suggesting that theobserved effects on feeding were not due to a nonspecificreduction in motivated behavior. These findings revealed asynergistic interaction between the cannabinoid and melanocortinsystems in feeding behavior. These results furthersuggested that receptors are located downstream frommelanocortin receptors and receptor signaling is necessaryto prevent the melanocortin system from altering foodintake.