Melanocortin-5 receptor deficiency promotes defensive behavior in male mice.

The endogenous melanocortin, alpha-melanocyte-stimulating hormone (alpha-MSH), is a neurohormone secreted by the neurointermediate lobe of the pituitary. Alpha-MSH promotes intermale aggression in mice by influencing pheromone secretion, but the role of specific melanocortin receptors has not been determined. We assessed mice made deficient in the gene for the melanocortin-5 receptor (MC5R) to determine its role in pheromone-regulated behavior. In heterotypic pairs assessed in the social interaction test (SIT), MC5R-deficient mice exhibited less aggressive behavior and more defensive behavior than their wild-type opponents. By contrast, when assessed in homotypic pairs and against stimulus animals in the SIT, MC5R-deficient and wild-type mice behaved similarly. Moreover, urine from MC5R deficient mice stimulated more aggression than did urine from wild-type mice. The results suggest that MC5R deficiency disinhibits an aggression-suppressing pheromonal signal.