Methylenedioxymethamphetamine-induced inhibition of neuronal firing in the nucleus accumbens is mediated by both serotonin and dopamine.
T Obradovic, K M Imel, S R White
Neuroscience September 1996 DOI: 10.1016/0306-4522(96)00135-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical electrophysiological study Peer reviewed |
|---|---|
| Population | Rat nucleus accumbens neurons |
| Interventions | MDMA serotonin 5-HT1B 5-HT2A/2C methysergide methiothepin fluoxetine 6-hydroxydopamine alpha-methyl-p-tyrosine |
| Dose | 30-60 nA, 60 s ejection currents for MDMA, serotonin, and agonists; 20-60 nA, 60 s for serotonin in dopamine-depleted experiments |
| Topics | MDMA Serotonin |
| Key points | MDMA inhibited glutamate-evoked firing of nucleus accumbens neurons, an effect mimicked by serotonin and serotonin agonists and partially blocked by serotonin antagonists and fluoxetine. Dopamine depletion blocked MDMA-induced inhibition at low ejection currents but not serotonin-induced inhibition, suggesting both dopamine release and an intermediate step of MDMA-induced serotonin release are necessary for MDMA's inhibitory effects. |
Abstract
Methylenedioxymethamphetamine (MDMA) is a mood-altering, legally restricted drug that has been reported to inhibit glutamate-evoked firing of cells in the nucleus accumbens. This study used extracellular recording combined with microiontophoresis to examine whether the inhibitory effect of MDMA on neuronal firing in the nucleus accumbens is mediated by serotonin and/or dopamine. Serotonin and serotonin agonists with relative selectivity for the receptor subtypes 5-HT1A, 5-HT1B, 5-HT2A/2C and 5-HT3 all significantly (P < 0.01) inhibited glutamate-evoked firing of cells in the nucleus accumbens compared to the effects of an acidic saline control solution (30-60 nA, 60 s ejection currents for all). The current (dose)-dependent inhibition produced by the serotonin agonists did not differ significantly from the inhibition produced by MDMA except for the 5-HT1A agonist 8-hydroxy-(2-di-n-propylamino) tetralin, which inhibited glutamate-evoked firing significantly more than MDMA or any of the other serotonin agonists. At the highest ejection current tested (60 nA, 60 s), glutamate-evoked firing was inhibited by MDMA in 94% of tested cells, by serotonin in 80% of tested cells and by the serotonin receptor subtype agonists in 95-100% of the tested cells. In addition to being mimicked by serotonin and serotonin agonists, MDMA-induced inhibition of glutamate-evoked firing in the nucleus accumbens was partially blocked by the serotonin antagonists ketanserin (100% of tested cells), methysergide (80% of tested cells), methiothepin (100% of tested cells) and WAY100135 (100% of tested cells). Furthermore, application of the serotonin uptake blocker fluoxetine, which prevents MDMA-induced serotonin release, also significantly attenuated MDMA-induced inhibition of glutamate-evoked firing in all of the cells that were tested. These observations suggest that MDMA-induced inhibition of nucleus accumbens cell firing is at least partially mediated by serotonin. Depletion of dopamine by pretreatment with the neurotoxin 6-hydroxydopamine and the synthesis inhibitor alpha-methyl-p-tyrosine blocked the inhibition of glutamate-evoked firing produced by MDMA applied with low ejection currents (30-40 nA, 60 s). However, this dopamine depletion had no effect on inhibition of glutamate-evoked firing produced by serotonin ejected with low or high currents (20-60 nA, 60 s). These results suggest that both dopamine release and an intermediate step of MDMA-induced serotonin release are necessary for the inhibitory effects of MDMA on neuronal excitability in the nucleus accumbens. The dopamine- and serotonin-mediated inhibitory effects of MDMA on glutamate-evoked firing of nucleus accumbens cells may play a role in the mood-altering properties of this increasingly popular drug.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
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- The effects of acute and repeated adolescent MDMA exposure on behavior, cognition, and the monoamine neurotransmitter systems: A review of human and pre-clinical research Behavioural Brain Research February 10, 2026
- Contribution of Impulsivity and Serotonin Receptor Neuroadaptations to the Development of an MDMA ('Ecstasy') Substance Use Disorder. Current Topics in Behavioral Neurosciences 2017
- Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview Molecular Neurobiology June 1, 2009
- Pre-treatment with 3,4-methylenedioxymethamphetamine (MDMA) causes long-lasting changes in 5-HT2A receptor-mediated glucose utilization in the rat brain. Journal of Psychopharmacology March 2006
and 3 more in the library
Cites 13
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- The substituted amphetamines 3,4-methylenedioxymethamphetamine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine European Journal of Pharmacology May 1, 1992
- Diversity of Psychopathology Associated with use of 3,4-Methylenedioxymethamphetamine (‘Ecstasy’) The British Journal of Psychiatry September 1, 1994
- Effects of certain hallucinogenic amphetamine analogs on the release of [3H]-serotonin from rat brain synaptosomes Journal of Medicinal Chemistry May 1, 1982
- Blockade of Striatal 5‐Hydroxytryptmine2Receptors Reduces the Increase in Extracellullar Concentrations of Dopamine Produced by the Amphhetamine analogue 3,4‐Methylenedioxymethamphetamine Journal of Neurochemistry April 1, 1994
and 8 more in the library