3,4-Methylenedioxymethamphetamine induces monoamine release, but not toxicity, when administered centrally at a concentration occurring following a peripherally injected neurotoxic dose

Esteban, Basilio Moreno; O’Shea, Esther; Camarero, Jorge; Sánchez, Verónica; Green, A. Richard; Colado, M. Isabel

doi:10.1007/s002130000645

Cited by 142 publications

(125 citation statements)

References 26 publications

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“…At least fourteen metabolites are produced in vivo from MDMA [58]. Interestingly, direct administration of MDMA into the rat brain does not cause enduring neurochemical changes [43] suggesting that peripheral metabolism is necessary and that one or more metabolites cause neurotoxic effects. The identity of the presumed "neurotoxic metabolite" is uncertain as it has been difficult to identify a single metabolite with the same neurochemical profile as MDMA [68].…”

Section: Pharmacokineticsmentioning

confidence: 99%

A developmental comparison of the neurobehavioral effects of ecstasy (MDMA)

Piper

2007

Neurotoxicology and Teratology

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The entactogen ±3,4-methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug among college, high school, and, occasionally, middle school students. Preclinical research examining the acute and long-term effects of MDMA has predominately been conducted in reproductively mature subjects but there has been increasing interest in adolescent and in utero exposure. This review examines the acute and long-term responses to MDMA during perinatal, adolescent, and adult periods. The ability of MDMA to alter core body temperature emerges gradually during ontogeny while a reduction in body weight is evident at all ages. Learning and workingmemory are also altered independent of the developmental stage of exposure. Current evidence suggests adults are more sensitive to the long-term serotonin depletions following MDMA but younger ages also exhibit substantial and rapid neuroplasticity. Sexually dimorphic MDMA responses have been identified for the acute hyperthermic and motoric effects of MDMA with pubescent males being especially susceptible. Several physiological, behavioral, and neurochemical MDMA issues requiring further study are also outlined. Keywords±3; 4-methylenedioxymethamphetamine; Adolescence; Anxiety; Depression; Learning; SerotoninThe phenylethylamine ±3,4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug best known as ecstasy. MDMA has several other street names including Adam, baby slits, chocolate chips, clarity, doctor, essence, kleenex, and roll [77]. Although ecstasy has some similarities with both stimulants and hallucinogens, MDMA is an entactogen. Entactogen means "touching within" based on the drug's subjective effects [110]. MDMA also causes long term changes in several markers of the integrity of the serotonin (5-HT) neurotransmitter system [58]. There have been several excellent recent reviews on MDMA toxicology, pharmacokinetics, pharmacodynamics, and neurobehavioral consequences [30,37,113,157], but none have systematically addressed the intricate effects of MDMA during development.Ecstasy use is not restricted to limited subpopulations, that is fans of techno music and "raves" [173] or male homosexuals [73,81], as MDMA has expanded into the general population [124,148,170] and especially young people [52,78,170,172]. Over one hundred pregnant women in Toronto called a substance abuse helpline between 1998 and 2000 to inquire Corresponding Author: Brian J. Piper, Neuroscience and Behavior Program, University of Massachusetts, Amherst, MA 01003-7710, Tel: (413) 545-0996, bpiper@nsm.umass.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers...

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Section: Pharmacokineticsmentioning

confidence: 99%

A developmental comparison of the neurobehavioral effects of ecstasy (MDMA)

Piper

2007

Neurotoxicology and Teratology

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“…Dissociation between the effects of MDMA and its metabolites has not been demonstrated for behavioral or physiological variables, but were described for toxicity vs 5-HT release. Indeed, direct injection of MDMA into the hippocampus increases 5-HT release without any toxicity to serotonergic terminals (Esteban et al, 2001). Further experiments are needed to understand the mechanism(s) involved in ethanol-induced alterations of MDMA actions.…”

Section: Acute Effects Of Etoh And/or Mdma Intoxicationsmentioning

confidence: 99%

Ethanol, 3,4-Methylenedioxymethamphetamine (Ecstasy) and Their Combination: Long-Term Behavioral, Neurochemical and Neuropharmacological Effects in the Rat

Cassel

Riegert

Rutz³

et al. 2005

Neuropsychopharmacol

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This study investigated long-term behavioral, neurochemical, and neuropharmacological effects of ethanol-(7)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) combinations. Over 4 consecutive days, male Long-Evans rats received 1.5 g/kg ethanol and/or 10 mg/kg MDMA, or saline. Rectal temperatures were taken in some rats. Starting 4 days after the last injection, we tested working memory, sensory-motor coordination, and anxiety. Subsequently, we measured cortical, striatal, septal, and hippocampal monoamines (last MDMA injection-euthanasia delay: 20 days), or electrically evoked release of serotonin (5-HT) in cortical and hippocampal slices, and its modulation in the presence of CP 93,129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrollo[3,2-b]pyrid-5-one) or methiotepin (last MDMA injection-euthanasia delays: 3-6 weeks). Ethanol attenuated the MDMA-induced hyperthermia, but only on the first day. In the longterm, MDMA reduced 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content in most brain regions. The behavioral and neurochemical effects of the ethanol-MDMA combination were comparable to those of MDMA alone; sensory-motor coordination was altered after ethanol and/or MDMA. In hippocampal slices from rats given ethanol and MDMA, the CP 93,129-induced inhibition and methiotepininduced facilitation of 5-HT release were stronger and weaker, respectively, than in the other groups. This is the first study addressing long-term effects of repeated MDMA and EtOH combined treatments in experimental animals. Whereas the drug combination produced the same behavioral and neurochemical effects as MDMA alone, our neuropharmacological results suggest that MDMA-EtOH interactions may have specific long-term consequences on presynaptic modulation of hippocampal 5-HT release, but not necessarily related to MDMA-induced depletion of 5-HT. Thus, it is likely that the psycho(patho)logical problems reported by ecstasy users drinking alcohol are not solely due to the consumption of MDMA.

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“…A role for systemically formed MDMA metabolites is often inferred from the observation that direct injection of MDMA into brain fails to reproduce the 5-HT neurotoxic effects of peripherally administered MDMA (Schmidt and Taylor, 1988;Esteban et al, 2001). A report that cytochrome P450 modulators (SKF-525A and phenobarbital) influence MDMA-induced 5-HT depletions (Gollamudi et al, 1989) is also often cited to support the role of a drug metabolite.…”

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confidence: 99%

Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity

Mueller¹,

Yuan²,

Felim³

et al. 2009

Drug Metab Dispos

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3,4-Methylenedioxymethamphetamine induces monoamine release, but not toxicity, when administered centrally at a concentration occurring following a peripherally injected neurotoxic dose

Abstract: These data demonstrate that MDMA when injected directly into the brain produces 5-HT release but no neurotoxicity, suggesting that it must be metabolised peripherally in order to produce compounds that induce free radical formation and neurotoxicity in the brain.

Cited by 142 publications

References 26 publications

A developmental comparison of the neurobehavioral effects of ecstasy (MDMA)

A developmental comparison of the neurobehavioral effects of ecstasy (MDMA)

Ethanol, 3,4-Methylenedioxymethamphetamine (Ecstasy) and Their Combination: Long-Term Behavioral, Neurochemical and Neuropharmacological Effects in the Rat

Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity

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