MDMA (ecstasy) effects on cultured serotonergic neurons: evidence for Ca2+-dependent toxicity linked to release

E. C. Azmitia, R. B. Murphy, P. M. Whitaker-Azmitia

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Animal studies have established a correlation between release of 5-hydroxytryptamine (5-HT) and the long-term reduction of 5-HT (toxicity) by 3,4-methylenedioxymethamphetamine (MDMA) with the S(+) enantiomer being more active than the R(-). Using a microculture system of fetal raphe neurons, the enantiomers of MDMA were tested to determine if a similar difference in potency existed. The results showed that the development of the uptake capacity of [3H]5-HT in 4-day cultures was half-maximally inhibited by a single application at time of plating of 5 × 10-6 M S(+)-MDMA and 5 × 10-5 M R(-)-MDMA. In order to determine if the Ca2+-independent release (chemically induced through the transporter protein and inhibited by reuptake blockers) or the Ca2+-dependent release (K+-induced and inhibited by presynaptic receptors) contributed to the toxicity, fluoxetine and D1 and α2 agonists were studied. The results showed that both forms of release were involved in the loss of [3H]5-HT uptake capacity, with the direct MDMA-induced Ca2+-independent (fluoxetine-sensitive) release being the first step. Evidence from binding studies indicates that MDMA has a micromolar affinity for the 5-HT2 receptor, and our studies in culture showed that ketanserin, a specific 5-HT2 antagonist, was effective at attenuating the effects of S(+)-MDMA on the development of the [3H]5-HT uptake capacity by the cultured raphe neurons. The 5-HT2 receptor is linked to increased intracellular Ca2+ through a second messenger phosphatidylinositol (PI)-hydrolysis mechanism. Since increases in Ca2+ intracellular levels have been shown to be a key step in neuronal death, the interaction between MDMA and caffeine (stimulates release of Ca2+ from intracellular stores) and nimodipine (a Ca2+ channel blocker) were studied. The results showed that caffeine (10-6 M) potentiated aand nimodipine (10-9 M) attenuated the inhibitory effects of MDMA. Our results are consistent with both types of 5-HT release being involved in producing a Ca2+-dependent toxicity induced by MDMA on cultured serotonergic fetal neurons.

Original languageEnglish (US)
Pages (from-to)97-103
Number of pages7
JournalBrain Research
Issue number1
StatePublished - Feb 26 1990


  • 3,4-Methylenedioxymethamphetamine
  • Fluoxetine
  • Nimodipine
  • Presynaptic receptor
  • Serotonin
  • Tissue culture
  • Toxicity
  • Transmitter release

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology


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