# Oxytocin-dependent Social Salience Network Activity evoked by targeting melanocortin receptors

> **NIH NIH P50** · EMORY UNIVERSITY · 2020 · $412,690

## Abstract

PROJECT SUMMARY (Project 1, Young)
Evidence from animal studies suggests that oxytocin (OT) plays an important role in facilitating social behavior.
It is hypothesized that the influence of OT on social cognition is facilitated by increasing the salience and
rewarding value of social stimuli. Human studies, inspired by the work in animal models, have investigated the
effects of intranasal (IN) administration of OT on a wide range of human social behaviors, including psychiatric
outcomes such as social functioning in individuals with autism spectrum disorder (ASD). The clinical efficacy of
IN-OT is however questionable because of limited blood-brain-barrier penetration and diffusion within the brain.
Stimulating endogenous OT release would circumvent these issues. Studies investigating the effects of targeting
the melanocortin system have shown that melanocortin 4 receptors (MC4Rs) interact with several neurochemical
systems known to modulate social behavior including OT. Work in our laboratory has shown that peripheral
injection of melanotan II (MTII), a brain penetrant small-molecule selective MC4R agonist, facilitates partner
preference formation in monogamous prairie voles. This effect is blocked by central infusion of an OT receptor
(OXTR) antagonist (OTA). Further, MTII selectively activates hypothalamic OT neurons and potentiates OT
release in the nucleus accumbens (NAc). MTII does not have a direct effect on OT release at projection terminals
but is thought to result in local release of OT in the paraventricular nucleus of the hypothalamus (PVN) and
thereby priming OT neurons in this region to be more responsive to stimuli. We have shown that MTII alone does
not increase OT release outside of the PVN, but when combined with a hypertonic osmotic challenge, a potent
stimulus for terminal OT release, results in approximately a 2-fold increase in OT release in the NAc. In line with
this finding, preliminary data from our laboratory suggests that MTII combined with social exposure, also known
to stimulate OT release, results in robust brain activation. This effect is absent under non-social conditions and
blocked by central injection of an OTA. The aim of this project is to further investigate the mechanisms through
which MTII affects brain circuitry by studying how this compound influences activation across multiple nodes in
a brain network involved in social salience processing. Our hypothesis is that MTII paired with social interaction
will result in increased activation of nodes in the network and coordinated activity across nodes. We further
hypothesize that the effect of MTII on brain activity is mediated through the OT system and will therefore be
attenuated by administration of an OTA, as well as in animals carrying alleles associated with low brain OXTR
density. Finally, we will directly investigate if the effect of MTII is mediated through OXTRs in the PVN, through
autoregulation on OT neurons, by using a viral vector mediated CRISPR-...

## Key facts

- **NIH application ID:** 9851936
- **Project number:** 5P50MH100023-08
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Larry J Young
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,690
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851936

## Citation

> US National Institutes of Health, RePORTER application 9851936, Oxytocin-dependent Social Salience Network Activity evoked by targeting melanocortin receptors (5P50MH100023-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9851936. Licensed CC0.

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