Differential long-term effects of MDMA on the serotoninergic system and hippocampal cell proliferation in 5-HTT knock-out vs. wild-type mice
Thibault Renoir, Eleni Païzanis, Malika El Yacoubi, Françoise Saurini, Naı̈ma Hanoun, Maxette Melfort, Klaus‐peter Lesch, M. Hamon, Laurence Lanfumey
The International Journal of Neuropsychopharmacology July 9, 2008 DOI: 10.1017/s1461145708009048 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with in-vitro and in-vivo approaches Peer reviewed |
|---|---|
| Population | 5-HTT wild-type and knock-out mice |
| Intervention | MDMA |
| Dose | 20 mg/kg b.i.d for 4 d |
| Duration | 4-week post-treatment assessment |
| Topics | MDMA Serotonin |
| Keywords | Autoreceptor Agonist Pharmacology Hippocampal formation 5-HT Receptor Dorsal raphe nucleus Endocrinology |
| Citations | 58 |
| Key findings | MDMA administration in mice induced delayed adaptive supersensitivity of 5-HT1A autoreceptors in the dorsal raphe nucleus, a deficit in hippocampal cell proliferation, and depressive-like behavior, all dependent on the serotonin transporter. |
Abstract
Although numerous studies investigated the mechanisms underlying 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity, little is known about its long-term functional consequences on 5-HT neurotransmission in mice. This led us to evaluate the delayed effects of MDMA exposure on the 5-HT system, using in-vitro and in-vivo approaches in both 5-HTT wild-type and knock-out mice. Acute MDMA in-vitro application on slices of the dorsal raphe nucleus (DRN) induced concentration-dependent 5-HT release and 5-HT cell firing inhibition. Four weeks after MDMA administration (20 mg/kg b.i.d for 4 d), a 2-fold increase in the potency of the 5-HT1A receptor agonist ipsapirone to inhibit the discharge of DRN 5-HT neurons and a larger hypothermic response to 8-OH-DPAT were observed in MDMA- compared to saline-treated mice. This adaptive 5-HT1A autoreceptor supersensitivity was associated with decreases in 5-HT levels but no changes of [3H]citalopram binding in brain. Long-term MDMA treatment also induced a 30% decrease in BrdU labelling of proliferating hippocampal cells and an increased immobility duration in the forced swim test suggesting a depressive-like behaviour induced by MDMA treatment. All these effects were abolished in 5-HTT-/- knock-out mice. These data indicated that, in mice, MDMA administration induced a delayed adaptive supersensitivity of 5-HT1A autoreceptors in the DRN, a deficit in hippocampal cell proliferation and a depressive-like behaviour. These 5-HTT-dependent effects, opposite to those of antidepressants, might contribute to MDMA-induced mood disorders.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 14
- Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[11C]DASB and structural brain imaging study Brain May 17, 2010
- Psilocybin as a lead candidate molecule in preclinical therapeutic studies of psychiatric disorders: A systematic review Journal of Neurochemistry November 29, 2023
- Mice lacking the serotonin transporter do not respond to the behavioural effects of psilocybin. European Journal of Pharmacology March 15, 2025
- Cocaine and MDMA Induce Cellular and Molecular Changes in Adult Neurogenic Systems: Functional Implications Pharmaceuticals June 17, 2011
- Neuroadaptive Changes in 5-HT1A Autoreceptor Sensitivity Following High-Dose MDMA Treatment 2011
and 9 more in the library
Cites 14
- Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings The Lancet October 1, 1998
- The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Proceedings of the National Academy of Sciences March 1, 1992
- Carrier‐Mediated Release of Serotonin by 3,4‐Methylenedioxymethamphetamine: Implications for Serotonin‐Dopamine Interactions Journal of Neurochemistry 1996
- Cortical Serotonin Transporter Density and Verbal Memory in Individuals Who Stopped Using 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") Archives of General Psychiatry October 1, 2001
- Ecstasy/MDMA attributed problems reported by novice, moderate and heavy recreational users Human Psychopharmacology: Clinical and Experimental July 12, 2002
and 9 more in the library