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Evidence for an Interaction between CB₁ Cannabinoid and Melanocortin MCR-4 Receptors in Regulating Food Intake

Schools of Psychology (A.N.A.V., P.E.M.) and Biological, Biomedical and Molecular Science (J.R.M.), University of New England, Armidale, New South Wales 2351; and School of Psychology (I.S.M.), University of Sydney, New South Wales 2006, Australia

Address all correspondence and requests for reprints to: Dr. Paul Mallet, School of Psychology, University of New England, Armidale, New South Wales 2351, Australia. E-mail: paul.mallet{at}une.edu.au.

Melanocortin receptor 4 (MCR4) and CB₁ cannabinoid receptors independently modulate food intake. Although an interaction between the cannabinoid and melanocortin systems has been found in recovery from hemorrhagic shock, the interaction between these systems in modulating food intake has not yet been examined. The present study had two primary purposes: 1) to examine whether the cannabinoid and melanocortin systems act independently or synergistically in suppressing food intake; and 2) to determine the relative position of the CB₁ receptors in the chain of control of food intake in relation to the melanocortin system. Rats were habituated to the test environment and injection procedure and then received intracerebroventicular injections of various combinations of the MCR4 receptor antagonist JKC-363, the CB₁ receptor agonist ⁹-tetrahydrocannabinol, the MCR4 receptor agonist -MSH, or the cannabinoid CB₁ receptor antagonist SR 141716. Food intake and locomotor activity were then recorded for 120 min. When administrated alone, SR 141716 and -MSH dose-dependently attenuated baseline feeding, whereas sub-anorectic doses of SR 141716 and -MSH synergistically attenuated baseline feeding when combined. ⁹-Tetrahydrocannabinol-induced feeding was not blocked by -MSH, whereas SR 141716 dose-dependently attenuated JKC-363-induced feeding. Locomotor activity was not significantly affected by any drug treatment, suggesting that the observed effects on feeding were not due to a nonspecific reduction in motivated behavior. These findings revealed a synergistic interaction between the cannabinoid and melanocortin systems in feeding behavior. These results further suggested that CB₁ receptors are located downstream from melanocortin receptors and CB₁ receptor signaling is necessary to prevent the melanocortin system from altering food intake.

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