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Submitted on January 19, 2004
Accepted on March 9, 2004
School of Psychologyand School of Biological, Biomedical & Molecular Science, University of New England, Armidale, NSW 2351, Australia. School of Psychology, University of Sydney, NSW 2006, Australia.
* To whom correspondence should be addressed. E-mail: paul.mallet{at}une.edu.au.
Melanocortin receptor 4 (MCR4) and CB1 cannabinoid receptors independently modulate food intake. Although an interaction between 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 (ICV) injections of various combinations of the MCR4 receptor antagonist JKC-363, the CB1 receptor agonist 
9-tetrahydrocannabinol (THC), 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, while sub-anorectic doses of SR 141716 and -MSH synergistically attenuated baseline feeding when combined. THC-induced feeding was not blocked by -MSH, while SR 141716 dose-dependently attenuated JKC-363-induced feeding. Locomotor activity was not significantly gaffected by any drug treatment, suggesting that the observed effects on feeding were not due to a non-specific reduction in motivated behavior. These findings reveal a synergistic interaction between cannabinoid and melanocortin systems in feeding behavior. These results further suggest 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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