Distinct neural mechanisms for the prosocial and rewarding properties of MDMA

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Science Translational Medicine  11 Dec 2019:
Vol. 11, Issue 522, eaaw6435
DOI: 10.1126/scitranslmed.aaw6435

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Dissecting MDMA

MDMA, commonly known as ecstasy, is a psychoactive drug primarily used for recreational purposes. Because of its prosocial effects, MDMA is currently being evaluated for the treatment of psychiatric disorders. Unfortunately, the rewarding addictive properties hinder the therapeutic use. Now, Heifets et al. investigated the mechanisms mediating the effects of MDMA in rodents and found that the prosocial and the rewarding effects are mediated by independent mechanisms. The prosocial effects are mediated by activation of the serotoninergic system, whereas the rewarding effect requires the activation of the dopaminergic signaling. The results pave the way for the development of more specific therapeutic intervention with less side effects.


The extensively abused recreational drug (±)3,4-methylenedioxymethamphetamine (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 modeled both the prosocial and nonsocial drug reward of MDMA in mice and investigated the mechanism of these processes using brain region–specific pharmacology, transgenic manipulations, electrophysiology, and in vivo calcium imaging. 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.

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