5-HT2A receptor in medial prefrontal cortex mediates pain-related empathic responses in rats

Using a dyadic social interaction (DSI) paradigm, we have validated a scenario of pain-related empathic responses in rats and mice during which socially transferred pain can be identified in naïve observers who have been spontaneously engaging the caring behavior (allolicking and allogrooming, ALAG) toward a familiar pain-sufferer. Although 5-hydroxytryptamine (5-HT) and its receptor subtype 5-HT2AR are major players in mammalian social behaviors, whether (if any, where) they have specific modulatory actions in the above processes is unknown. Here, by genetic and pharmacological depletion of central 5-HT, we demonstrated that observers lacking 5-HT showed deficiencies in not only the empathic responses but also sniffing, huddling and self-grooming during DSI with a familiar pain-sufferer. However, bilateral intra-mPFC microinjections of M100907, a selective 5-HT2AR antagonist, or down-regulation of 5-HT2AR expression in bilateral mPFC, selectively inhibited socially transferred pain and ALAG but without affecting other behaviors in observers. More interestingly, systemic or intra-mPFC administration of 25CN-NBOH, a high affinity and selective 5-HT2AR agonist, selectively promoted observers to express the empathic responses toward a stranger pain-sufferer in an antagonist reversible manner, that rarely happened under naïve-pain DSI paradigm. Finally, 5-HT2AR down-regulation in bilateral mPFC disabled the empathic responsiveness induced by 25CN-NBOH (i.p.) in stranger observers. Hereby we provide with a strong line of evidence showing activation of 5-HT2AR in the mPFC selectively mediates empathic responses in rat bystanders when socially interacting with a familiar or an unfamiliar pain-sufferer, by endogenous or exogenous 5-HT2AR agonist.