Distinct neural mechanisms for the prosocial and rewarding properties of MDMA
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Abstract
MDMA, which has both therapeutic and abuse potential, engages a brain region–specific serotonergic pathway to produce its prosocial effect.
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The prosocial effect of systemic MDMA on sociability was blocked by direct infusion into the nucleus accumbens of a 5-HT1b receptor antagonist.
“In mice, systemic administration of a prosocial dose of MDMA enhanced sociability in the three-chamber assay, an effect that was mimicked by direct infusion of MDMA into the NAc, prevented by pharmacological inhibition of the 5-HT transporter (SERT) or its genetic deletion, and blocked by direct infusion into the NAc of a 5-HT1b receptor antagonist [51].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [51]
The prosocial effect of systemic MDMA on sociability was mimicked by direct infusion of MDMA into the nucleus accumbens.
“In mice, systemic administration of a prosocial dose of MDMA enhanced sociability in the three-chamber assay, an effect that was mimicked by direct infusion of MDMA into the NAc, prevented by pharmacological inhibition of the 5-HT transporter (SERT) or its genetic deletion, and blocked by direct infusion into the NAc of a 5-HT1b receptor antagonist [51].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [51]
In mice, systemic administration of a prosocial dose of MDMA enhanced sociability in the three-chamber assay.
“In mice, systemic administration of a prosocial dose of MDMA enhanced sociability in the three-chamber assay, an effect that was mimicked by direct infusion of MDMA into the NAc, prevented by pharmacological inhibition of the 5-HT transporter (SERT) or its genetic deletion, and blocked by direct infusion into the NAc of a 5-HT1b receptor antagonist [51].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [51]
The prosocial effect of systemic MDMA on sociability was prevented by pharmacological inhibition of the serotonin transporter or its genetic deletion.
“In mice, systemic administration of a prosocial dose of MDMA enhanced sociability in the three-chamber assay, an effect that was mimicked by direct infusion of MDMA into the NAc, prevented by pharmacological inhibition of the 5-HT transporter (SERT) or its genetic deletion, and blocked by direct infusion into the NAc of a 5-HT1b receptor antagonist [51].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [51]
Administration of methamphetamine, a potent dopamine releaser, did not enhance sociability.
“Furthermore, administration of methamphetamine, a potent DA releaser, did not enhance sociability [51].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [51]
This 5-HT1b receptor-triggered synaptic plasticity was subsequently found to be generated by bath application of oxytocin or MDMA.
“This simple form of 5-HT1b receptor-triggered synaptic plasticity was subsequently found to be generated by bath application of OXT or MDMA [41,51], results consistent with the 5-HT releasing properties of these agents.”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [51]
The actions of MDMA on the dopamine transporter were not required for its prosocial effect, as prior administration of a DAT inhibitor did not influence MDMA's effects in the three-chamber assay.
“In contrast, the actions of MDMA on the DA transporter (DAT) were not required for this prosocial effect, as prior administration of a DAT inhibitor did not influence MDMA's effects in the three-chamber assay.”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [51]
It is unlikely that MDMA itself can ever be used as a daily treatment for sociability deficits because of its abuse potential and potential toxicity.
“Because of its abuse potential and potential toxicity [51,177], it is unlikely that MDMA itself can ever be used as a daily treatment for sociability deficits.”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [51]
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Generalizable Molecular Switch Designs for In Vivo Continuous Biosensing
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5-HT2C receptors in the nucleus accumbens constrain the rewarding effects of MDMA
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Bioisosteric analogs of MDMA : Improving the pharmacological profile?
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The serotonin 1B receptor is required for some of the behavioral effects of psilocybin in mice
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Continuous optical detection of small-molecule analytes in complex biomatricesPreprint
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A Systematic Review of the MDMA Model to Address Social Impairment in Autism
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Stereoselective, sex-dependent 5-HT2A receptor modulation of cortical plasticity by MDMA in mice
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Self-citationCocaine restricts nucleus accumbens feedforward drive through a monoamine-independent mechanism
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History, pharmacology and therapeutic mechanisms of 3,4‐methylenedioxymethamphetamine (MDMA)
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Serotonin modulates nucleus accumbens circuits to suppress aggression in mice
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Post-traumatic stress disorder in psychedelic research
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Pharmacological Evaluation of Tropane Analogues at the Serotonin Transporter
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Timing is key for behavioural benefits of psychedelics
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MDMA for treatment of PTSD and neurorehabilitation in military populations
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R -MDDMA is a Safer Analogue of MDMA with Therapeutic Potential
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Medical Use of Cannabinoids and Psychedelic Compounds
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3,4-Methylenedioxymethamphetamine (MDMA) and Synaptic Dopamine
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3,4-Methylenedioxymethamphetamine (MDMA) and Synaptic Dopamine
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Mind the gap: A systematic review and meta-analysis of how social memory is studiedPreprint
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Self-citationHyperactivity of the Amygdala Mediates Depressive-Like Phenotypes and Decreased Serotonin ReleasePreprint
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- Authors
- Heifets, B. D., Salgado, J. S., Taylor, M. D., Hoerbelt, P., Cardozo Pinto, D. F., Steinberg, E. E., Walsh, J. J., Sze, J. Y., & Malenka, R. C.
- Affiliations
- Stanford Medicine (US)
- Stanford University (US)
- Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
- Albert Einstein College of Medicine (US)
- Corresponding author
- Malenka, Robert C.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2019-12-11
- Volume
- 11
- Issue
- 522
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC7123941
- OpenAlex
- W2994786945
- Cited by
- 120
- References
- 42
- Citations by year
- 2026: 12 · 2025: 25 · 2024: 25 · 2023: 12 · 2022: 17 · 2021: 18 · 2020: 10
- FWCI
- 13.14
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Science Translational Medicine (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (MH110610, MH115668, MG105839)
- National Institute on Drug Abuse (DA042012)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- MDMA, ecstasy, prosocial behavior, reward, addiction, abuse liability, serotonin release, fenfluramine, neural pathways, treatment development
- MeSH terms
- Animals, Brain, Dopamine, Female, Male, Mice, Inbred C57BL, Nucleus Accumbens, Receptors, Serotonin, Reward, Social Behavior, Receptors, Oxytocin, N-Methyl-3,4-methylenedioxyamphetamine, Dopamine Plasma Membrane Transport Proteins, Serotonin Plasma Membrane Transport Proteins
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