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

    Research output: Contribution to journalArticleAcademicpeer-review

    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.

    Original languageEnglish
    Pages (from-to)255-260
    Number of pages6
    JournalNeuroToxicology
    Volume33
    Issue number2
    DOIs
    Publication statusPublished - 2012

    Keywords

    • 3,4-Methylenedioxyamphetamine
    • Adrenergic Agents
    • Amphetamine
    • Animals
    • Calcium
    • Cholinergic Agents
    • Dose-Response Relationship, Drug
    • Membrane Potentials
    • Methamphetamine
    • N-Methyl-3,4-methylenedioxyamphetamine
    • PC12 Cells
    • Piperazines
    • Potassium Chloride
    • Rats
    • Serotonin Receptor Agonists

    Fingerprint

    Dive into the research topics of 'Methamphetamine, amphetamine, MDMA ('ecstasy'), MDA and mCPP modulate electrical and cholinergic input in PC12 cells'. Together they form a unique fingerprint.

    Cite this