Novel approaches to enhance social cognition by stimulating central oxytocin release.
Basic & Clinical
In humans, intranasal oxytocin (OT) enhances many aspects of social cognition, including increasing gazing to the eyes, inferring the emotions of others, socially reinforced learning, and empathy. Intranasal OT also enhances some aspects of social cognition and social functioning is subjects with autism spectrum disorder (ASD). While these findings are promising, there are limitations to intranasal delivery, including poor penetration of the blood brain barrier. The study will utilize an alternative approach to stimulate the OT system. Melanocortin 4 receptors (MC4R) are concentrated in brain regions that synthesize OT and MC4R agonists stimulate central, but not peripheral release of OT in rats. Social bonding in the monogamous prairie vole is an OT-dependent form of social learning that may be useful for screening drugs to enhance social cognition. Melanotan II (MT II), an MC4R agonist greatly enhances social bonding in prairie voles. The investigators will explore the mechanisms by which MTII, and a small molecule MC4 agonist from Pfizer, enhance social bonding. MTII is currently being used in humans for other indications, enabling an immediate translational application of this work for enhancing social cognition in ASD. However, before clinical trials can be initiated with MC4R agonists, the mechanisms of action must be documented. The investigators hypothesize that MC4 agonist will promote OT-dependent social bonding in the prairie vole by acting directly on OT neurons in the hypothalamus and stimulating OT release. This study will test this hypothesis with four Specific Aims that determine whether: 1) MC4R receptors are expressed on OT neurons; 2) MC4 agonists induce immediate-early gene activation in OT neurons and induce OT release in the prairie vole brain using in vivo microdialysis; 3)the facilitation of social bonding in prairie voles requires activation of OT receptors in the nucleus accumbens; and 44) the site of action of the MC4R agonist is directly on OT neurons in the hypothalamus. Together these aims promise to provide critical mechanistic information that will be critical for drug development targeting the MC4R and the initiation of studies in humans. This study directly addresses the priority area of evaluating novel treatments that can address the core symptoms and associated medical conditions throughout the lifespan.