Distinct neural mechanisms for the prosocial and rewarding properties of MDMA

Boris D. Heifets, Juliana S. Salgado, Madison D. Taylor, Paul Hoerbelt, Daniel F. Cardozo Pinto, Elizabeth E. Steinberg, Jessica J. Walsh, Ji Y. Sze, Robert C. Malenka

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbereaaw6435
JournalScience translational medicine
Volume11
Issue number522
DOIs
StatePublished - Dec 11 2019

Fingerprint

N-Methyl-3,4-methylenedioxyamphetamine
Fenfluramine
Serotonin Plasma Membrane Transport Proteins
Electrophysiology
Nucleus Accumbens
Street Drugs
Therapeutic Uses
Reward
Psychotherapy
Psychiatry
Serotonin
Pharmacology
Calcium
Brain
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Heifets, B. D., Salgado, J. S., Taylor, M. D., Hoerbelt, P., Cardozo Pinto, D. F., Steinberg, E. E., ... Malenka, R. C. (2019). Distinct neural mechanisms for the prosocial and rewarding properties of MDMA. Science translational medicine, 11(522), [eaaw6435]. https://doi.org/10.1126/scitranslmed.aaw6435

Distinct neural mechanisms for the prosocial and rewarding properties of MDMA. / Heifets, Boris D.; Salgado, Juliana S.; Taylor, Madison D.; Hoerbelt, Paul; Cardozo Pinto, Daniel F.; Steinberg, Elizabeth E.; Walsh, Jessica J.; Sze, Ji Y.; Malenka, Robert C.

In: Science translational medicine, Vol. 11, No. 522, eaaw6435, 11.12.2019.

Research output: Contribution to journalArticle

Heifets, BD, Salgado, JS, Taylor, MD, Hoerbelt, P, Cardozo Pinto, DF, Steinberg, EE, Walsh, JJ, Sze, JY & Malenka, RC 2019, 'Distinct neural mechanisms for the prosocial and rewarding properties of MDMA', Science translational medicine, vol. 11, no. 522, eaaw6435. https://doi.org/10.1126/scitranslmed.aaw6435
Heifets BD, Salgado JS, Taylor MD, Hoerbelt P, Cardozo Pinto DF, Steinberg EE et al. Distinct neural mechanisms for the prosocial and rewarding properties of MDMA. Science translational medicine. 2019 Dec 11;11(522). eaaw6435. https://doi.org/10.1126/scitranslmed.aaw6435
Heifets, Boris D. ; Salgado, Juliana S. ; Taylor, Madison D. ; Hoerbelt, Paul ; Cardozo Pinto, Daniel F. ; Steinberg, Elizabeth E. ; Walsh, Jessica J. ; Sze, Ji Y. ; Malenka, Robert C. / Distinct neural mechanisms for the prosocial and rewarding properties of MDMA. In: Science translational medicine. 2019 ; Vol. 11, No. 522.
@article{3792ba0585d34c868e09b1380c564304,
title = "Distinct neural mechanisms for the prosocial and rewarding properties of MDMA",
abstract = "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.",
author = "Heifets, {Boris D.} and Salgado, {Juliana S.} and Taylor, {Madison D.} and Paul Hoerbelt and {Cardozo Pinto}, {Daniel F.} and Steinberg, {Elizabeth E.} and Walsh, {Jessica J.} and Sze, {Ji Y.} and Malenka, {Robert C.}",
year = "2019",
month = "12",
day = "11",
doi = "10.1126/scitranslmed.aaw6435",
language = "English (US)",
volume = "11",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "522",

}

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85076423351&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85076423351&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aaw6435

DO - 10.1126/scitranslmed.aaw6435

M3 - Article

C2 - 31826983

AN - SCOPUS:85076423351

VL - 11

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 522

M1 - eaaw6435

ER -