Genetic and pharmacological mouse models of chronic melanocortin activation show enhanced baroreflex control of heart rate.

The central melanocortin system is an important regulator of energy homeostasis and cardiovascular functions. Although the acute effects of melanocortins on central blood pressure regulation are well-established, their long-term effects on autonomic balance and baroreflex function remain largely unexplored. Here we investigated the impact of chronic melanocortin activation on cardiovascular and autonomic nervous system functions by studying α- and γ-MSH overexpressing (MSH-OE) mice and, as pharmacological model, mice treated with the stable α-MSH analogue melonotan-II (MT-II, 0.3 mg/kg/day for 7 days, i.p.). Mean arterial pressure (MAP) and heart rate (HR) were measured in conscious mice by radiotelemetry. MSH-OE mice did not differ from their wild-type littermates in terms of MAP, but displayed reduced HR under physiological baseline conditions. To evaluate the relative activities of sympathetic and parasympathetic nervous systems, we applied autonomic receptor blockers and found an enhanced HR response to atropine in MSH-OE mice, indicating increased cardiac vagal activity. The compensatory increase in HR after drug-evoked vasodilatation was also augmented in MSH-OE mice. Exposure to a high-sodium diet (8% NaCl) markedly reduced HR in MSH-OE mice without concomitant changes in blood pressure, suggesting improved reflex regulation of HR. Chronic treatment with MT-II did not change 24-h MAP or HR regardless of the acute pressor and tachycardic actions of MT-II. Consistent with the finding in MSH-OE mice, MT-II-treated mice showed an enhanced HR response to vasodilatation. These observations suggest that chronic melanocortin activation may provide cardioprotective regulation by enhancing vagal nerve activity and baroreflex control of heart rate.

Central melanocortins modulate mesocorticolimbic activity and food seeking behavior in the rat.

The hypothalamic melanocortin system is known for its role in regulating energy homeostasis through it actions within hypothalamic brain centers. However, emerging evidence suggests that this system regulates addictive behaviors through signaling within mesolimbic neurons. Here, we hypothesized the melanocortin system modulates feeding behavior through its actions on mesolimbic neurons. In particular, we predicted that central administration of the melanocortin antagonist agouti-related peptide (AgRP) would activate midbrain dopamine neurons, increase mesolimbic dopamine turnover, and alter food seeking behaviors. We found that intraventricular administration of agouti-related peptide increased neuronal activation within midbrain dopamine neurons in addition to increasing dopamine turnover in the medial prefrontal cortex. Additionally, using the conditioned place preference paradigm to assay food seeking behavior, we report that central injection of agouti-related peptide attenuates the acquisition of a conditioned place preference for sucrose, but not high fat diet. These results suggest that the melanocortin system is capable of regulating mesocorticolimbic activity and food seeking behavior.