Review
Methylenedioxymethamphetamine (MDMA, Ecstasy) neurotoxicity: cellular and molecular mechanisms

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Abstract

Methylenedioxymethamphetamine (MDMA, Ecstasy) is a very popular drug of abuse. This has led to new intense concerns relevant to its nefarious neuropsychiatric effects. These adverse events might be related to the neurotoxic effects of the drug. Although the mechanisms of MDMA-induced neurotoxicity remain to be fully characterized, exposure to the drug can cause acute and long-term neurotoxic effects in animals and nonhuman primates. Recent studies have also documented possible toxic effects in the developing fetus. Nevertheless, there is still much debate concerning the effects of the drug in humans and how to best extrapolate animal and nonhuman primate data to the human condition. Herein, we review the evidence documenting the adverse effects of the drug in some animal models. We also discuss possible mechanisms for the development of MDMA neurotoxicity. Data supporting deleterious effects of this drug on the developing fetus are also described. Much remains to be done in order to clarify the molecular and biochemical pathways involved in the long-term neuroplastic changes associated with MDMA abuse.

Introduction

3,4-Methylenedioxy-N-methamphetamine (MDMA, Ecstasy) is a semi-synthetic compound that can be derived from an essential oil of plants including nutmeg, mace, sassafras, saffron, parsley, dill, and vanilla beans. MDMA was first synthesized by Merck Pharmaceuticals and patented in 1914 [19]. MDMA is a ring-substituted derivative of phenylisopropylamine, structurally similar to methamphetamine and the hallucinogen, mescaline (Fig. 1) [19], [61], [103]. MDMA affects peripheral and central nervous system (CNS) functions by acting mainly on the serotonergic system. The drug is reported to have sympathomimetic properties [161], and to modulate psychomotor [6] and neuroendocrine functions [45], [115]. MDMA acts as an indirect monoaminergic agonist [155] and displays relatively high, similar affinities for α2-adrenoceptors, 5-HT2 serotonin (5-HT) receptors, M-1 muscarinic receptors, and H-1 histamine receptors. MDMA binds with less affinity to dopamine (DA) and norepinephrine (NE) uptake sites, M-2 muscarinic receptors, α1-adrenoceptors, β-adrenoceptors, 5-HT1 receptors, and D1 and D2 DA receptors [7]. Neurochemical studies performed in vitro [102], [117], [155] and/or in laboratory animals [37], [50], [78], [155], [165], [167] demonstrate that MDMA blocks 5-HT reuptake and induces 5-HT release and, to a lesser extent, also causes DA [38], [102] and NE [52] release. MDMA releases 5-HT from striatal slices at concentrations that are ∼10-fold lower than concentrations required for stimulating DA release [144], [155]. The calcium-independent 5-HT release appears to be related to MDMA action on the 5-HT transporter (5-HTT) as demonstrated by in vitro studies in which the release is blocked by fluoxetine or imipramine, drugs that inhibit the 5-HTT [5], [188]. In addition to its inhibition of monoamine re-uptake, MDMA might also increase extracellular levels of monoamines by inhibiting brain monoamine oxidase activity [187], [193].

Section snippets

Acute effects of MDMA

The deleterious effects of MDMA on brain serotonergic systems have been studied extensively using rats [37], [91], [92], [122], [123], guinea pigs [7], dogs [54], [118], nonhuman primates [53], [70], [76], [136], [137], [139], chickens [18] as well as pigeons [83]. In mice, however, MDMA appears to affect mainly the nigrastriatal dopaminergic system [22], [23]. MDMA toxicity is affected by doses [46], [131], routes of administration, as well as by treatment regimens [7], [103], [124], [136]. In

Neurotoxicity in rats

Neurotoxic effects of MDMA appear between 24 h and 1 week following MDMA administration [150]. Neurochemical and anatomical studies initially reported long-term reductions in markers of 5-HT systems in rats [37], [107], [122], [150], [158], [181]. These include decreased levels of 5-HT and of its major metabolite, 5-HIAA [37], [107], [149], [155], decreased number of 5-HT transporters [10], [37], [46], and decreased activity of the rate-limiting enzyme of 5-HT synthesis, TPH [46], [107]. Other

Mechanisms of toxicity

In spite of two decades of studies on MDMA toxicity, the mechanisms underlying its effects remain to be fully elucidated. In what follows, we provide an overview of some of the ideas that have been put forward to explain the neurotoxic effects of MDMA.

Toxicity in fetal development

In spite of the multiple reports of MDMA neurotoxicity in mature animals, studies on the effects of MDMA on the developing fetus are scarce. This is an area of great concern because MDMA abusers are young and of childbearing ages. In addition, the drug is known to produce a feeling of closeness towards others and sexual arousal [30], [31], [32]. Therefore, it is not far-fetched to presume that young MDMA abusers might be prone to get pregnant. It is thus of paramount importance to generate more

Conclusion

Ecstasy is a popular recreational drug among young adults and even teenagers. The evidence is overwhelming that MDMA produces acute and long-lasting neurotoxic effects in animals. There is a growing consensus that MDMA might also cause neurodegenerative effects in the human brain. Nevertheless, it is still not clear how the animal literature might completely relate to the human condition. Because of the pervasive abuse of MDMA among young people, who are of childbearing age, it is of paramount

Acknowledgements

Johnalyn Lyles is supported by the NIH/NIDA Intramural Research Program and the David and Lucille Packard Foundation. We thank Dr. Ning-sheng Cai for her helpful comments on the manuscript. We also wish to thank two anonymous reviewers for their constructive criticism and comments that helped to improve the manuscript.

References (194)

  • R.S. Cohen

    Adverse symptomatology and suicide associated with the use of methylenedioxymethamphetamine (MDMA; ‘Ecstasy’)

    Biol. Psychiatry

    (1996)
  • R.S. Cohen

    Subjective reports on the effects of the MDMA (‘ecstasy’) experience in humans

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (1995)
  • R.S. Cohen et al.

    Neuropsychiatric manifestations following the use of 3,4-methylenedioxymethamphetamine (MDMA: ‘Ecstasy’)

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (1997)
  • M.I. Colado et al.

    The spin trap reagent alpha-phenyl-N-tert-butyl nitrone prevents ‘ecstasy’-induced neurodegeneration of 5-hydroxytryptamine neurones

    Eur. J. Pharmacol.

    (1995)
  • R.I. Dafters

    Hyperthermia following MDMA administration in rats: effects of ambient temperature, water consumption, and chronic dosing

    Physiol. Behav.

    (1995)
  • G.M. Farfel et al.

    The N-methyl-d-aspartate antagonist MK-801 protects against serotonin depletions induced by methamphetamine, 3,4-methylenedioxymethamphetamine and p-chloroamphetamine

    Brain Res.

    (1992)
  • K.T. Finnegan et al.

    Orally administered MDMA causes a long-term depletion of serotonin in rat brain

    Brain Res.

    (1988)
  • J.L. Fitzgerald et al.

    Effects of methylenedioxymethamphetamine on the release of monoamines from rat brain slices

    Eur. J. Pharmacol.

    (1990)
  • D.L. Frederick et al.

    Behavioral and neurochemical effects of chronic methylenedioxymethamphetamine (MDMA) treatment in rhesus monkeys

    Neurotoxicol. Teratol.

    (1995)
  • C.H. Frith et al.

    Toxicity of methylenedioxymethamphetamine (MDMA) in the dog and the rat

    Fundam. Appl. Toxicol.

    (1987)
  • G. Gerra et al.

    Long-lasting effects of (+/−)3,4-methylenedioxymethamphetamine (ecstasy) on serotonin system function in humans

    Biol. Psychiatry

    (2000)
  • C.J. Gordon

    Twenty-four hour rhythms of selected ambient temperature in rat and hamster

    Physiol. Behav.

    (1993)
  • C.J. Gordon et al.

    Effects of 3,4-methylenedioxymethamphetamine on autonomic thermoregulatory responses of the rat

    Pharmacol. Biochem. Behav.

    (1991)
  • B. Gough et al.

    Acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on monoamines in rat caudate

    Pharmacol. Biochem. Behav.

    (1991)
  • X.F. Gu et al.

    Integrative transporter-mediated release from cytoplasmic and vesicular 5-hydroxytryptamine stores in cultured neurons

    Eur. J. Pharmacol.

    (1993)
  • G.A. Gudelsky et al.

    Potentiation of 3,4-methylenedioxymethamphetamine-induced dopamine release and serotonin neurotoxicity by 5-HT2 receptor agonists

    Eur. J. Pharmacol.

    (1994)
  • J.D. Higley et al.

    CSF testosterone and 5-HIAA correlate with different types of aggressive behaviors

    Biol. Psychiatry

    (1996)
  • M. Johnson et al.

    Effect of MK-801 on the decrease in tryptophan hydroxylase induced by methamphetamine and its methylenedioxy analog

    Eur. J. Pharmacol.

    (1989)
  • M.P. Johnson et al.

    [3H]monoamine releasing and uptake inhibition properties of 3,4-methylenedioxymethamphetamine and p-chloroamphetamine analogues

    Eur. J. Pharmacol.

    (1991)
  • M.P. Johnson et al.

    Effects of the enantiomers of MDA, MDMA and related analogues on [3H]serotonin and [3H]dopamine release from superfused rat brain slices

    Eur. J. Pharmacol.

    (1986)
  • M.P. Johnson et al.

    Serotonin neurotoxicity in rats after combined treatment with a dopaminergic agent followed by a nonneurotoxic 3,4-methylenedioxymethamphetamine (MDMA) analogue

    Pharmacol. Biochem. Behav.

    (1991)
  • M.S. Kleven et al.

    Evidence that both intragastric and subcutaneous administration of methylenedioxymethylamphetamine (MDMA) produce serotonin neurotoxicity in rhesus monkeys

    Brain Res.

    (1989)
  • A. Klugman et al.

    Toxic effect of MDMA on brain serotonin neurons

    Lancet

    (1999)
  • H.K. Kramer et al.

    3,4-Methylenedioxymethamphetamine (‘Ecstasy’) promotes the translocation of protein kinase C (PKC): requirement of viable serotonin nerve terminals

    Brain Res.

    (1995)
  • M.E. Liechti et al.

    Acute psychological effects of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) are attenuated by the serotonin uptake inhibitor citalopram

    Neuropsychopharmacology

    (2000)
  • M.E. Liechti et al.

    Psychological and physiological effects of MDMA (‘Ecstasy’) after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans

    Neuropsychopharmacology

    (2000)
  • M.E. Liechti et al.

    Acute psychological and physiological effects of MDMA (‘Ecstasy’) after haloperidol pretreatment in healthy humans

    Eur. Neuropsychopharmacol.

    (2000)
  • A. Malpass et al.

    Acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA) in Sprague–Dawley and Dark Agouti rats

    Pharmacol. Biochem. Behav.

    (1999)
  • H.H. Maurer et al.

    Toxicokinetics and analytical toxicology of amphetamine-derived designer drugs (‘Ecstasy’)

    Toxicol. Lett.

    (2000)
  • U.D. McCann et al.

    Positron emission tomographic evidence of toxic effect of MDMA (‘Ecstasy’) on brain serotonin neurons in human beings

    Lancet

    (1998)
  • N. Aguirre et al.

    The role of dopaminergic systems in the perinatal sensitivity to 3,4-methylenedioxymethamphetamine-induced neurotoxicity in rats

    J. Pharmacol. Exp. Ther.

    (1998)
  • R.P. Allen et al.

    Persistent effects of (+/−)3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) on human sleep

    Sleep

    (1993)
  • M.G. Bankson et al.

    3,4-Methylenedioxymethamphetamine (MDMA) as a unique model of serotonin receptor function and serotonin–dopamine interactions

    J. Pharmacol. Exp. Ther.

    (2001)
  • G. Battaglia et al.

    Selective blockade of mGlu5 metabotropic glutamate receptors is protective against methamphetamine neurotoxicity

    J. Neurosci.

    (2002)
  • G. Battaglia et al.

    3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites

    J. Pharmacol. Exp. Ther.

    (1987)
  • K.I. Bolla et al.

    Memory impairment in abstinent MDMA (‘Ecstasy’) users

    Neurology

    (1998)
  • H.W. Broening et al.

    Age modulates the long-term but not the acute effects of the serotonergic neurotoxicant 3,4-methylenedioxymethamphetamine

    J. Pharmacol. Exp. Ther.

    (1994)
  • H.W. Broening et al.

    Age-dependent sensitivity of rats to the long-term effects of the serotonergic neurotoxicant (+/−)-3,4-methylenedioxymethamphetamine (MDMA) correlates with the magnitude of the MDMA-induced thermal response

    J. Pharmacol. Exp. Ther.

    (1995)
  • H.W. Broening et al.

    3,4-Methylenedioxymethamphetamine (ecstasy)-induced learning and memory impairments depend on the age of exposure during early development

    J. Neurosci.

    (2001)
  • E. Bruce
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