Selective antagonist for the melanocortin 4 receptor (HS014) increases food intake in free-feeding rats

Recently, we discovered a cyclic analogue of MSH (melanocyte stimulating hormone), HS014, which is the first selective antagonist of the MC4 receptor. We have here studied the effects of this peptide on food intake in non-deprived male rats. Vehicle or five doses of HS014 (0.1-10 nmol) were administered ICV at midday. HS014 (0.33-3.3 nmol) significantly and in a dose-dependent manner increased food intake for the first 1 h. At 4 h after the injections, food intake was also significantly increased in rats treated with 1 and 3.3 nmol of HS014, whereas the lowest dose tested (0.1 nmol) was without effect. Cumulative food intake increased to 100% at 4 h after the injections. The highest dose of HS014 (10 nmol) induced sedation and inhibited feeding for first hour of testing. However, this dose also increased food consumption later. These data demonstrate that attenuation of central melanocortinergic tone with HS014 induces disinhibition of feeding and provides additional evidence for the hypothesis that activation of the MC4 receptor inhibits food intake. HS014 may be a useful tool for elucidating the role of the MC receptor subtypes in vivo. This is the first report demonstrating an increase in daytime food intake in free-feeding animals caused by a MC receptor active agent.