High concentrations of MDMA ('ecstasy') and its metabolite MDA inhibit calcium influx and depolarization-evoked vesicular dopamine release in PC12 cells.
Laura Hondebrink, Jan Meulenbelt, Marieke Meijer, Martin Van den Berg, Remco H S Westerink
Neuropharmacology 2011 DOI: 10.1016/j.neuropharm.2011.03.028 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Laboratory study Peer reviewed |
|---|---|
| Population | PC12 cells |
| Interventions | MDMA MDA |
| Dose | 1 mM; 10-100 μM for MDA |
| Duration | 15-minute exposure |
| Measures | Fura-2 imaging, amperometry |
| Topics | MDMA |
| Key points | MDMA and MDA did not alter basal calcium or exocytosis but inhibited depolarization-evoked calcium influx and exocytosis after 15-minute exposure to 1 mM concentrations. MDA was more potent, inhibiting exocytosis at 10-100 μM without affecting calcium influx, suggesting indirect inhibition of calcium influx and additional effects on vesicle cycling. |
Abstract
The popular synthetic drug of abuse 3,4-methylenedioxymethampetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA) act mainly on the serotonergic system, though they also increase the amount of extracellular dopamine (DA) in the brain, presumably via reversal of the membrane dopamine transporter (DAT). As the involvement of exocytotic DA release is debated, we investigated if these drugs alter the intracellular calcium concentration ([Ca(2+)](i)) and subsequent DA exocytosis in single PC12 cells using respectively Fura-2 imaging and amperometry. MDMA and MDA did not change basal [Ca(2+)](i) or exocytosis, but inhibited depolarization-evoked increases in [Ca(2+)](i) and exocytosis following 15 min exposure to high concentrations of drugs (1 mM). Surprisingly, MDA was more potent in inhibiting exocytosis than MDMA and already inhibited exocytosis at concentrations that did not inhibit depolarization-evoked Ca(2+) influx (10-100 μM). Without 15 min pre-exposure, both drugs failed to inhibit depolarization-evoked Ca(2+) influx. These results indicate that at high concentrations both MDMA and MDA inhibit exocytosis via indirect inhibition of Ca(2+) influx, whereas at lower concentrations MDA may also reduce vesicle cycling. Our data suggest that the DAT-independent increase in extracellular DA in vivo is not due to direct stimulation of exocytosis, but rather to effects of these drugs on other neurotransmitter systems that innervate the dopaminergic system.
Comparable studies
Other experimental studies on MDMA, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| Oxytocin-dependent reopening of a social reward learning critical period with MDMA | 2019 | Experimental study | |
| Effects of certain hallucinogenic amphetamine analogs on the release of [3H]-serotonin from rat brain synaptosomes Rat whole brain synaptosomes | 1982 | Experimental study |
Citations in the library
Cited by 10
- Duloxetine Inhibits Effects of MDMA (“Ecstasy") In Vitro and in Humans in a Randomized Placebo-Controlled Laboratory Study PLoS One May 4, 2012
- Effect fingerprinting of new psychoactive substances (NPS): What can we learn from in vitro data? Pharmacology & Therapeutics February 1, 2018
- Measuring inhibition of monoamine reuptake transporters by new psychoactive substances (NPS) in real-time using a high-throughput, fluorescence-based assay. Toxicology in Vitro December 1, 2017
- Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug–drug interactions Critical Reviews in Toxicology October 3, 2012
- Constructing the ecstasy of MDMA from its component mental organs: Proposing the primer/probe method. Medical Hypotheses February 1, 2016
and 5 more in the library
Cites 15
- Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin Synapse 2000
- 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
- Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs BMC Pharmacology March 3, 2006
- Potentiation of 3,4-methylenedioxymethamphetamine-induced dopamine release and serotonin neurotoxicity by 5-HT2 receptor agonists. European Journal of Pharmacology November 3, 1994
- 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 10 more in the library