ReviewMethylenedioxymethamphetamine (MDMA, Ecstasy) neurotoxicity: cellular and molecular mechanisms
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.
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