Previous studies have indicated that type 3 or 4 melanocortin receptors (MCR) are downstream of the critical anorectic action of drugs that stimulate 5-HT2C receptors. To characterize further the receptor types involved, we have studied the effect of serotonergic anorectics in mice with genomic disruption of either MC3R or MC4R, or their combined knockout. In a first experiment, we showed that wild type (WT) and MC4R-/- mice showed comparable inhibition of food intake following acute treatment with dexnorfenfluramine. In a second experiment using WAY-161503, a 5-HT receptor full agonist with selectivity for 2B and 2C subtypes, we found that MC4R-/- responded comparably to WT, while MC3R-/- had reduced sensitivity. Double receptor knockout (DKO) mice responded comparably to WT and MC4R-/-Surprisingly, brain Fos-ir was not strongly induced in any brain region by WAY-16103 with the exception of the paraventricular nucleus of DKO. These data suggest that MC3Rs may be involved in the response to serotonergic anorectic agents, and more generally in control of food intake.
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