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
Brain Research February 1, 1990 DOI: 10.1016/0006-8993(90)90732-q (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro experimental study Peer reviewed |
|---|---|
| Population | Fetal rat raphe neurons in culture |
| Interventions | S(+)-MDMA R(-)-MDMA fluoxetine alpha-2 agonists ketanserin |
| Dose | 5 × 10⁻⁶ M S(+)-MDMA, 5 × 10⁻⁵ M R(-)-MDMA |
| Duration | 4-day cultures |
| Topics | MDMA Serotonin |
| Keywords | Pharmacology Toxicity Hallucinogen |
| Citations | 68 |
| Key findings | The S(+) enantiomer of MDMA is ten times more potent than the R(-) enantiomer at inhibiting serotonin uptake capacity in cultured raphe neurons, and both calcium-dependent and calcium-independent release mechanisms, along with 5-HT2 receptor activation, contribute to this toxicity. |
Abstract
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 X 10(-6) M S(+)-MDMA and 5 X 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 alpha 2 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 20
- Altered Serotonin Innervation Patterns in the Forebrain of Monkeys Treated with (±)3,4-Methylenedioxymethamphetamine Seven Years Previously: Factors Influencing Abnormal Recovery Journal of Neuroscience June 15, 1999
- 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
- The mechanisms involved in the long‐lasting neuroprotective effect of fluoxetine against MDMA (‘ecstasy’)‐induced degeneration of 5‐HT nerve endings in rat brain British Journal of Pharmacology September 1, 2001
- The abused drug MDMA (Ecstasy) induces programmed death of human serotonergic cells The FASEB Journal February 1, 1997
- Deconstructing Ecstasy: The Politics Of Mdma Research Addiction Research & Theory 2000
and 15 more in the library
Cites 7
- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
- Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Journal of Neuroscience August 1, 1988
- Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Journal of Pharmacology and Experimental Therapeutics 1987
- Hallucinogenic Amphetamine Selectively Destroys Brain Serotonin Nerve Terminals Science September 6, 1985
- The Background and Chemistry of MDMA Journal of Psychoactive Drugs October 1, 1986
and 2 more in the library