Distinct neural mechanisms for the prosocial and rewarding properties of MDMA

The extensively abused recreational drug MDMA has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMA’s prosocial effect. MDMA’s acute rewarding properties, in contrast, require dopaminergic signaling. MDMA’s prosocial effect requires 5-HT1b receptor activation and is mimicked by d-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMA’s prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability. One Sentence Summary MDMA, which has both therapeutic and abuse potential, engages a brain region-specific serotonergic pathway to produce its prosocial effect.