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bioRxiv · 10.1101/2025.09.17.676826

Pharmacological Modulation of MC4R in the Periaqueductal Gray Does Not Alter Social Behavior

Ruan, N.·Ng, A. J.·Christianson, J. P.
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Abstract

Competing motivational drives are integral to survival and encompass a spectrum of internal physiological needs such as hunger to external goals like social connection. Elucidating how these motivational states interact at the neural level is critical to our understanding of adaptive behavior. Hunger-driven behaviors are primarily initiated by agouti-related peptide (AgRP), an inverse agonist of the melanocortin 4 receptor (MC4R), which acts to promote feeding by suppressing MC4R signaling. MC4R is present in the periaqueductal gray (PAG), a midbrain region involved in pain, appetite, and social behavior. A pilot study found a dense concentration of AgRP fibers in the PAG of male rats, suggesting a potential link between hunger-related signaling and social behavior in this region. To investigate the role of AgRP and MC4R in the PAG on social interaction, we conducted a within-subject dose-response experiment using male rats. Subjects received bilateral microinjections (0.5 {micro}L/side) of either vehicle, an MC4R agonist (THIQ), or an antagonist (HS014) into the PAG prior to a five-minute social exploration (SE) test with a novel juvenile conspecific. Contrary to our hypothesis, pharmacological manipulation of MC4R activity in the PAG did not produce significant changes in social interaction time, suggesting that MC4R in the PAG may not directly play a major role in modulating social behavior in rodents. These results highlight the complexity of the neural circuitry involved in social motivation, hunger, and other competing motivational states.

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Ruan, N., Ng, A. J., Christianson, J. P.. 2025-09-17. Pharmacological Modulation of MC4R in the Periaqueductal Gray Does Not Alter Social Behavior. https://doi.org/10.1101/2025.09.17.676826

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