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

Abstract

Melanocortin receptor 4 (MCR4) and CB(1) 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 CB(1) 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 CB(1) receptor agonist Delta(9)-tetrahydrocannabinol, the MCR4 receptor agonist alpha-MSH, or the cannabinoid CB(1) receptor antagonist SR 141716. Food intake and locomotor activity were then recorded for 120 min. When administrated alone, SR 141716 and alpha-MSH dose-dependently attenuated baseline feeding, whereas sub-anorectic doses of SR 141716 and alpha-MSH synergistically attenuated baseline feeding when combined. Delta(9)-Tetrahydrocannabinol-induced feeding was not blocked by alpha-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 CB(1) receptors are located downstream from melanocortin receptors and CB(1) receptor signaling is necessary to prevent the melanocortin system from altering food intake.

Peripheral, but Not Central, CB1 Antagonism Provides Food Intake–Independent Metabolic Benefits in Diet-Induced Obese Rats

“…For peripheral delivery of the CB1 antagonist, we performed daily intraperitoneal injection of SR141716 at a dose of 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 for 6 days. This dose has been extensively used in previous work (19,37,38). For both treatments, control rats received vehicle (NaCl 0.9% plus 0.3% Tween 80).…”

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

“…The observations that SR141716 inhibits the feeding response induced by blocking MC-4 receptors, whereas ␣-MSH does not affect THC-induced feeding, suggest that CB 1 receptors are downstream from MC-4 receptors and have an obligatory role in ␣-MSH effects on food intake (Verty et al, 2004). The peptide product of CART is also a tonically active anorectic mediator (Kristensen et al, 1998) and, unlike ␣-MSH, may be a downstream mediator of the effect of endocannabinoids.…”

Effects of intracerebroventricular and intra-accumbens melanin-concentrating hormone agonism on food intake and energy expenditure

“…In line with what was reported in similar experimental designs with orexigenic or anorexigenic drugs (41,42), a 48-h washout period was chosen between test days, as such period allowed body weight and food intake (measured before the test days) to return to stable and normal values. Furthermore, to reduce the variability between the data collected in the different conditions, the rats were assigned to the test conditions in a randomized order, according to a counterbalanced design.…”