TY - JOUR
T1 - Distinct neural mechanisms for the prosocial and rewarding properties of MDMA
AU - Heifets, Boris D.
AU - Salgado, Juliana S.
AU - Taylor, Madison D.
AU - Hoerbelt, Paul
AU - Cardozo Pinto, Daniel F.
AU - Steinberg, Elizabeth E.
AU - Walsh, Jessica J.
AU - Sze, Ji Y.
AU - Malenka, Robert C.
N1 - Publisher Copyright:
Copyright © 2019 The Authors.
PY - 2019/12/11
Y1 - 2019/12/11
N2 - 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.
AB - 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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U2 - 10.1126/scitranslmed.aaw6435
DO - 10.1126/scitranslmed.aaw6435
M3 - Article
C2 - 31826983
AN - SCOPUS:85076423351
SN - 1946-6234
VL - 11
JO - Science translational medicine
JF - Science translational medicine
IS - 522
M1 - eaaw6435
ER -