PMID- 31826983
OWN - NLM
STAT- MEDLINE
DCOM- 20200911
LR  - 20240425
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Print)
IS  - 1946-6234 (Linking)
VI  - 11
IP  - 522
DP  - 2019 Dec 11
TI  - Distinct neural mechanisms for the prosocial and rewarding properties of MDMA.
LID - 10.1126/scitranslmed.aaw6435 [doi]
LID - eaaw6435
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.
CI  - Copyright (c) 2019 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works.
FAU - Heifets, Boris D
AU  - Heifets BD
AUID- ORCID: 0000-0003-1474-0379
AD  - Department of Anesthesiology, Perioperative and Pain Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA.
AD  - Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, 
      Stanford University, Stanford, CA 94305, USA.
FAU - Salgado, Juliana S
AU  - Salgado JS
AUID- ORCID: 0000-0002-3687-846X
AD  - Department of Anesthesiology, Perioperative and Pain Medicine, Stanford 
      University School of Medicine, Stanford, CA 94305, USA.
AD  - Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, 
      Stanford University, Stanford, CA 94305, USA.
FAU - Taylor, Madison D
AU  - Taylor MD
AUID- ORCID: 0000-0002-8092-3029
AD  - Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, 
      Stanford University, Stanford, CA 94305, USA.
FAU - Hoerbelt, Paul
AU  - Hoerbelt P
AUID- ORCID: 0000-0002-8707-5376
AD  - Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, 
      Stanford University, Stanford, CA 94305, USA.
FAU - Cardozo Pinto, Daniel F
AU  - Cardozo Pinto DF
AUID- ORCID: 0000-0002-6104-4643
AD  - Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, 
      Stanford University, Stanford, CA 94305, USA.
FAU - Steinberg, Elizabeth E
AU  - Steinberg EE
AD  - Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, 
      Stanford University, Stanford, CA 94305, USA.
FAU - Walsh, Jessica J
AU  - Walsh JJ
AD  - Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, 
      Stanford University, Stanford, CA 94305, USA.
FAU - Sze, Ji Y
AU  - Sze JY
AD  - Department of Molecular Pharmacology and Rose F. Kennedy Intellectual and 
      Developmental Disabilities Center, Albert Einstein College of Medicine, Bronx, NY 
      10461, USA.
FAU - Malenka, Robert C
AU  - Malenka RC
AUID- ORCID: 0000-0002-5428-5211
AD  - Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, 
      Stanford University, Stanford, CA 94305, USA. malenka@stanford.edu.
LA  - eng
GR  - K08 MH110610/MH/NIMH NIH HHS/United States
GR  - P50 DA042012/DA/NIDA NIH HHS/United States
GR  - R56 MH105839/MH/NIMH NIH HHS/United States
GR  - R01 MH105839/MH/NIMH NIH HHS/United States
GR  - F32 MH115668/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Dopamine Plasma Membrane Transport Proteins)
RN  - 0 (Receptors, Oxytocin)
RN  - 0 (Receptors, Serotonin)
RN  - 0 (Serotonin Plasma Membrane Transport Proteins)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - Brain/*physiology
MH  - Dopamine/metabolism
MH  - Dopamine Plasma Membrane Transport Proteins/metabolism
MH  - Female
MH  - Male
MH  - Mice, Inbred C57BL
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*pharmacology
MH  - Nucleus Accumbens/drug effects/physiology
MH  - Receptors, Oxytocin/metabolism
MH  - Receptors, Serotonin/metabolism
MH  - *Reward
MH  - Serotonin Plasma Membrane Transport Proteins/metabolism
MH  - *Social Behavior
PMC - PMC7123941
MID - NIHMS1565640
COIS- Competing interests: R.C.M. is on the scientific advisory boards of MapLight 
      Therapeutics Inc., Cerevance, Cognition Therapeutics Inc., and the Brave 
      Neuroscience Company.
EDAT- 2019/12/13 06:00
MHDA- 2020/09/12 06:00
PMCR- 2020/04/03
CRDT- 2019/12/13 06:00
PHST- 2019/01/11 00:00 [received]
PHST- 2019/08/01 00:00 [revised]
PHST- 2019/10/15 00:00 [accepted]
PHST- 2019/12/13 06:00 [entrez]
PHST- 2019/12/13 06:00 [pubmed]
PHST- 2020/09/12 06:00 [medline]
PHST- 2020/04/03 00:00 [pmc-release]
AID - 11/522/eaaw6435 [pii]
AID - 10.1126/scitranslmed.aaw6435 [doi]
PST - ppublish
SO  - Sci Transl Med. 2019 Dec 11;11(522):eaaw6435. doi: 10.1126/scitranslmed.aaw6435.