5-HT_2A receptor in medial prefrontal cortex mediates pain-related empathic responses in rats

Using a dyadic social interaction (DSI) paradigm, we validated a scenario of pain-related empathic responses in rats and mice, during which socially transferred pain was identified in naïve observers spontaneously engaging in caring behavior (allolicking and allogrooming, ALAG) toward a familiar pain sufferer. Although 5-hydroxytryptamine (5-HT) and its receptor subtype 5-HT_2AR are major players in mammalian social behaviors, whether they have specific modulatory actions in these processes remains unknown. Here, by genetic and pharmacological depletion of central 5-HT, we demonstrated that observers lacking 5-HT showed deficiencies not only in empathic responses but also in sniffing, huddling, and self-grooming during DSI with a familiar pain sufferer. However, bilateral intra-mPFC microinjections of M100907, a selective 5-HT_2AR antagonist, or downregulation of 5-HT_2AR expression in the bilateral mPFC, selectively inhibited socially transferred pain and ALAG without affecting other behaviors in observers. Moreover, systemic or intra-mPFC administration of 25CN-NBOH, a high-affinity and selective 5-HT_2AR agonist, selectively promoted empathic responses in observers toward a stranger pain sufferer in an antagonist-reversible manner, a phenomenon rarely observed under the naïve-pain DSI paradigm. Finally, 5-HT_2AR downregulation in the bilateral mPFC abolished the empathic responsiveness induced by 25CN-NBOH (i.p.) in stranger observers. Collectively, our findings establish that 5-HT_2AR activation in the mPFC is both necessary and sufficient for selectively mediating empathic responses in bystanders toward individuals in pain, identifying 5-HT_2AR as a promising therapeutic target for alleviating prosocial and empathic impairments seen in disorders, such as autism spectrum disorder.