Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA)
This mouse study (n=360) investigated the role of serotonergic neurotransmission in MDMA's (7.8 mg/kg) ability to extinguish fearful memories in mice and found that the selective inhibition of serotonin release via 5-HTT and the inhibition of neurotransmission via 5-HT2A receptors diminished this effect.
Authors
- Katharine Dunlop
- Boadie Dunlop
- Matthew Young
Published
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-HT2A-mediated behavior, and 5-HT2A 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-HT2A 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.
Research Summary of 'Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA)'
Introduction
For several decades MDMA has been investigated as an adjunct to psychotherapy because of acute mood-elevating and prosocial effects, and recent clinical work has reported long-term reductions in PTSD symptoms after only two MDMA-assisted psychotherapy sessions. Young and colleagues note that preclinical studies suggest MDMA enhances the extinction of fear memory, a learning process central to exposure-based therapies for PTSD, but that the pharmacological and psychological mechanisms underlying this effect remain incompletely understood. The introduction frames fear extinction as a targetable process where pharmacological adjuncts could improve exposure therapy outcomes, and highlights the need to characterise the monoaminergic mechanisms through which MDMA influences extinction before broader clinical application, especially because many PTSD patients are commonly treated with SSRIs. This study set out to identify which monoamine transporters and receptor mechanisms are required for MDMA's enhancement of fear memory extinction. Using auditory Pavlovian fear conditioning in mice, the investigators compared two behavioural readouts—conditioned freezing (a common rodent index) and fear‑potentiated startle (FPS, a cross‑species measure more directly comparable to human studies)—and tested whether pharmacological inhibition of serotonin (5-HT), norepinephrine (NE) or dopamine (DA) transporters, as well as manipulation of 5-HT2A receptors, alters MDMA's extinction‑enhancing effects.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Young, M. B., Norrholm, S. D., Khoury, L. M., Jovanovic, T., Rauch, S. A., Reiff, C. M., Dunlop, B. W., Rothbaum, B. O., & Howell, L. L. (2017). Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA). Psychopharmacology, 234(19), 2883-2895. https://doi.org/10.1007/s00213-017-4684-8
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