MDMA enhances empathy-like behaviors in mice via 5-HT release in the nucleus accumbens.

MDMA, a psychoactive drug known for its prosocial effects, enhances empathy-like behaviors in mice by increasing serotonin signaling in the nucleus accumbens. The drug, whether given systemically or infused directly into this brain region, strengthens the social transfer of pain and analgesia, a behavioral test of empathy. Optogenetically stimulating serotonin release in the nucleus accumbens mimics MDMA's effects, confirming serotonin's role. MDMA also restores deficits in empathy-like behaviors in a mouse model of autism lacking the Shank3 gene. The findings indicate that serotonin signaling in the nucleus accumbens is a core mechanism underlying MDMA's empathogenic effects.

Study at a glance

Abstract

MDMA (3,4-methylenedioxymethamphetamine) is a psychoactive drug with powerful prosocial effects. While MDMA is sometimes termed an "empathogen," empirical studies have struggled to clearly demonstrate these effects or pinpoint underlying mechanisms. Here, we paired the social transfer of pain and analgesia-behavioral tests modeling empathy in mice-with region-specific neuropharmacology, optogenetics, and transgenic manipulations to explore MDMA's action as an empathogen. We report that MDMA, given intraperitoneally or infused directly into the nucleus accumbens (NAc), robustly enhances the social transfer of pain and analgesia. Optogenetic stimulation of 5-HT release in the NAc recapitulates the effects of MDMA, implicating 5-HT signaling as a core mechanism. Last, we demonstrate that systemic MDMA or optogenetic stimulation of NAc 5-HT inputs restores deficits in empathy-like behaviors in the Shank3-deficient mouse model of autism. These findings demonstrate enhancement of empathy-related behaviors by MDMA and implicate 5-HT signaling in the NAc as a core mechanism mediating MDMA's empathogenic effects.