Neonatal Melanotan-II reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner

The melanocortin receptor (MCR) system is well-known for its roles in feeding and sexual behavior, but its influence on broader social behaviors remains under-explored. This system, involving peptides like α-MSH, interacts significantly with key neural circuits governing sociality, including the oxytocin, dopamine, and opioid systems. Previous research has shown that acute administration of the MC3/4R agonist Melanotan-II can enhance brain oxytocin release and promote partner preference formation in socially monogamous prairie voles. However, the long-term, developmental consequences of stimulating this system early in life are unknown. This study investigates whether neonatal exposure to MCR agonists can induce lasting changes in social development and the underlying neural circuits.

Male and female prairie voles received daily subcutaneous injections of 10 mg/kg Melanotan-II (MTII) or saline from postnatal day (PND) 1 to 7. Researchers observed juvenile social behavior by measuring initiated play fighting bouts. Adult social attachment was assessed by testing for partner preference formation after a brief cohabitation period. In a separate experiment, a more selective MC4R agonist, PF44687 (1 mg/kg), was administered daily during the same neonatal period to both sexes. To examine acute neural effects, another group of PND 6-7 animals received a single MTII injection, and their hypothalamic neurons were analyzed for EGR-1 immunoreactivity, an immediate early gene marker for neuronal activity.

Neonatal MTII treatment led to sex-specific long-term behavioral changes. Treated males initiated significantly fewer play fighting bouts as juveniles compared to control males. In adulthood, neonatal MTII exposure facilitated partner preference formation in females, but not in males, following a brief cohabitation. Acute MTII injection in PND 6-7 voles caused a significant burst of EGR-1 immunoreactivity, indicating increased neuronal activity in hypothalamic oxytocin (OT), vasopressin (AVP), and corticotrophin releasing factor (CRF) neurons. This suggests a direct, immediate impact on key social-neuroendocrine circuits.

In contrast to the sex-specific effects of the non-selective agonist MTII, daily neonatal treatment with 1 mg/kg of the selective MC4R agonist PF44687 successfully promoted adult partner preferences in both females and males compared to vehicle controls. This points to MC4R as a key mediator of these developmental effects.