Abstract
The central melanocortin (MC) system has been widely studied for its
effects on food intake and sexual behavior. However, the MC system, and
more specifically the MC4 receptor (MC4R), also interacts with
neurochemical systems that regulate socioemotional behaviors, including
oxytocin (OT) and dopamine. In monogamous prairie voles, OT and dopamine
interact to promote partner preference formation, a laboratory measure
of an enduring social bond between mates. Here we investigated the
effects of MC receptor activation on partner preference formation in
prairie voles, as well as the interaction between the MC and OT systems
during this process. Peripheral administration of the brain penetrant
MC3/4R receptor peptide agonist, Melanotan II (MTII), and the highly
selective, small-molecule MC4R agonist, Pf-446687, enhanced partner
preference formation in the prairie vole, but not in the non-monogamous
meadow vole. MTII-induced partner preferences were enduring, as they
were present 1 week after drug manipulation. The prosocial effects of
MCR agonists may be mediated, in part, through modulation of OT, as
coadministration of an OT receptor antagonist prevented MTII-induced
partner preferences. MTII also selectively activated hypothalamic OT
neurons and potentiated central OT release. As OT has been shown to
enhance some aspects of social cognition in humans, our data suggest
that the MC4R may be a viable therapeutic target for enhancing social
function in psychiatric disorders, including autism spectrum disorders
and schizophrenia, potentially through activation of the OT system.