Melanocortin-5 receptor deficiency in mice blocks a novel pathway influencing pheromone-induced aggression

The rodent preputial gland secretes aggression-promoting pheromones and expresses melanocortin-5 receptor (MC5R), but the functional relationship is poorly understood. We investigated whether MC5R deficiency in male mice alters stimulatory melanocortin influences on preputial growth and pheromone-induced aggression. In wild-type (MC5R(+/+)) pairs, repeated NDP-MSH injection decreased attack latency and increased aggression in initial attackers. Similar NDP-MSH treatment in MC5R-deficient (MC5R(-/-)) pairs failed to alter attack latency or aggression frequency, but aggression increased in vehicle-injected opponents. NDP-MSH treatment promoted preputial hypertrophy, and in MC5R(+/+) mice paired against non-aggressive stimulus opponents it decreased attack latency and increased aggression. MC5R(-/-) mice were insensitive to behavioral and physiological effects of NDP-MSH, and preputialectomized mice were insensitive to behavioral effects of NDP-MSH. The results suggest that MC5R inactivation reduced a pheromonal signal for aggression that acts on donors, rather than their opponents.