Methamphetamine, amphetamine, MDMA ('ecstasy'), MDA and mCPP modulate electrical and cholinergic input in PC12 cells.
Laura Hondebrink, Jan Meulenbelt, Saskia J. Rietjens, Marieke Meijer, Remco H S Westerink
Neurotoxicology March 2012 DOI: 10.1016/j.neuro.2011.09.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro experimental study Peer reviewed |
|---|---|
| Population | PC12 cells (a dopaminergic cell model) |
| Interventions | Methamphetamine Amphetamine MDMA MDA mCPP |
| Dose | 1-1000 μM; 0.1 mM; 1 mM; 10 μM |
| Measures | Fura 2 calcium imaging |
| Topics | MDMA |
| Key findings | At high concentrations (1 mM), all tested drugs inhibited ACh-evoked intracellular calcium increases by 80-97% and also reduced depolarization-evoked calcium increases, suggesting reduced dopaminergic output via electrical and cholinergic input. Low concentrations (10 μM) of methamphetamine or amphetamine potentiated ACh-evoked calcium increases, which the authors propose may contribute to drug-induced dopamine increases in vivo. High MDMA and mCPP increased basal calcium after ACh stimulation, likely increasing dopaminergic output. mCPP was the most potent drug across the endpoints examined. |
Abstract
Reversal of the dopamine (DA) membrane transporter is the main mechanism through which many drugs of abuse increase DA levels. However, drug-induced modulation of exocytotic DA release by electrical (depolarization) and neurochemical inputs (e.g., acetylcholine (ACh)) may also contribute. We therefore investigated effects of methamphetamine, amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and meta-chlorophenylpiperazine (mCPP) (1-1000 μM) on these inputs by measuring drug-induced changes in basal, depolarization- and ACh-evoked intracellular calcium concentrations ([Ca(2+)](i)) using a dopaminergic model (PC12 cells) and Fura 2 calcium imaging. The strongest drug-induced effects were observed on cholinergic input. At 0.1mM all drugs inhibited the ACh-evoked [Ca(2+)](i) increases by 40-75%, whereas ACh-evoked [Ca(2+)](i) increases were nearly abolished following higher drug exposure (1mM, 80-97% inhibition). Additionally, high MDMA and mCPP concentrations increased basal [Ca(2+)](i), but only following prior stimulation with ACh. Interestingly, low concentrations of methamphetamine or amphetamine (10 μM) potentiated ACh-evoked [Ca(2+)](i) increases. Depolarization-evoked [Ca(2+)](i) increases were also inhibited following exposure to high drug concentrations, although drugs were less potent on this endpoint. Our data demonstrate that at high drug concentrations all tested drugs reduce stimulation-evoked increases in [Ca(2+)](i), thereby probably reducing dopaminergic output through inhibition of electrical and cholinergic input. Furthermore, the increases in basal [Ca(2+)](i) at high concentrations of MDMA and mCPP likely increases dopaminergic output. Similarly, the increases in ACh-evoked [Ca(2+)](i) upon cholinergic stimulation following exposure to low concentrations of amphetamines can contribute to drug-induced increases in DA levels observed in vivo. Finally, this study shows that mCPP, which is regularly found in ecstasy tablets, is the most potent drug regarding the investigated endpoints.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 5
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- 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
- Neuropharmacological characterization of the new psychoactive substance methoxetamine Neuropharmacology September 1, 2017
- Additive inhibition of human α1β2γ2 GABAA receptors by mixtures of commonly used drugs of abuse. Neurotoxicology March 2013
Cites 6
- Non‐linear pharmacokinetics of MDMA (‘ecstasy’) in humans British Journal of Clinical Pharmacology February 1, 2000
- High concentrations of MDMA ('ecstasy') and its metabolite MDA inhibit calcium influx and depolarization-evoked vesicular dopamine release in PC12 cells. Neuropharmacology 2011
- mCPP: an undesired addition to the ecstasy market. Journal of Psychopharmacology September 2010
- Further studies on the role of metabolites in (+/-)-3,4-methylenedioxymethamphetamine-induced serotonergic neurotoxicity. Drug Metabolism and Disposition October 2009
- Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview Molecular Neurobiology June 1, 2009
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