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Cited by 108Psychedelics and Drug StudiesMemory and Neural MechanismsPosttraumatic Stress Disorder Research

Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA)

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Young, Matthew B., Norrholm, Seth D., Khoury, Lara M., Jovanovic, Tanja, Rauch, Sheila A.M., Reiff, Collin M., Dunlop, Boadie W., Rothbaum, Barbara O. +1 more·2017·Psychopharmacology
DOI 10.1007/s00213-017-4684-8PMC PMC5693755
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Abstract

Rationale 3,4-Methylenedioxymethamphetamine (MDMA) persistently improves symptoms of post-traumatic stress disorder (PTSD) when combined with psychotherapy. Studies in rodents suggest that these effects can be attributed to enhancement of fear memory extinction. Therefore, MDMA may improve the effects of exposure-based therapy for PTSD, particularly in treatment-resistant patients. However, given MDMA's broad pharmacological profile, further investigation is warranted before moving to a complex clinical population. Objectives We aimed to inform clinical research by providing a translational model of MDMA's effect, and elucidating monoaminergic mechanisms through which MDMA enhances fear extinction. Methods We explored the importance of monoamine transporters targeted by MDMA to fear memory extinction, as measured by reductions in conditioned freezing and fear-potentiated startle (FPS) in mice. Mice were treated with selective inhibitors of individual monoamine transporters prior to combined MDMA treatment and fear extinction training. Results MDMA enhanced the lasting extinction of FPS. Acute and chronic treatment with a 5-HT transporter (5-HTT) inhibitor blocked MDMA's effect on fear memory extinction. Acute inhibition of dopamine (DA) and norepinephrine (NE) transporters had no effect. 5-HT release alone did not enhance extinction. Blockade of MDMA's effect by 5-HTT inhibition also downregulated 5-HT 2A-mediated behavior, and 5-HT 2A antagonism disrupted MDMA's effect on extinction. Conclusions We validate enhancement of fear memory extinction by MDMA in a translational behavioral model, and reveal the importance of 5-HTT and 5-HT 2A receptors to this effect. These observations support future clinical research of MDMA as an adjunct to exposure therapy, and provide important pharmacological considerations for clinical use in a population frequently treated with 5-HTT inhibitors.

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Authors
Young, M. B., Norrholm, S. D., Khoury, L. M., Jovanovic, T., Rauch, S. A. M., Reiff, C. M., Dunlop, B. W., Rothbaum, B. O., & Howell, L. L.
Affiliations
Emory University (US)
Corresponding author
Howell, Leonard L.
ORCID
Venue
Psychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2017-07-24
Volume
234
Issue
19
Pages
2883-2895
ISSN
  • 0033-3158 (ISSN-L)
  • 1432-2072
DOI
10.1007/s00213-017-4684-8
PMC
PMC5693755
OpenAlex
W2739337936
Cited by
108
References
79
Citations by year
2026: 13 · 2025: 12 · 2024: 18 · 2023: 15 · 2022: 11 · 2021: 10 · 2020: 11 · 2019: 8 · 2018: 6 · 2017: 3
FWCI
9.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Psychopharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Drug Abuse (K05 DA031246)
  • National Institute of General Medical Sciences (K21 GM000680)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
Keywords
MDMA, fear extinction, serotonin transporter, 5-HT2A receptor, post-traumatic stress disorder, exposure therapy, monoamine transporters, fear-potentiated startle, conditioned freezing, serotonin release, monoaminergic mechanisms
MeSH terms
Animals, Dose-Response Relationship, Drug, Extinction, Psychological, Fear, Male, Memory, Mice, Inbred C57BL, Stress Disorders, Post-Traumatic, Selective Serotonin Reuptake Inhibitors, N-Methyl-3,4-methylenedioxyamphetamine, Serotonin Plasma Membrane Transport Proteins, Mice

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