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Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview

Molecular Neurobiology volume 39, pages 210–271 (2009)Cite this article

Abstract

“Ecstasy” [(±)-3,4-methylenedioxymethamphetamine, MDMA, XTC, X, E] is a psychoactive recreational hallucinogenic substance and a major worldwide drug of abuse. Several reports raised the concern that MDMA has the ability to induce neurotoxic effects both in laboratory animals and humans. Despite more than two decades of research, the mechanisms by which MDMA is neurotoxic are still to be fully elucidated. MDMA induces serotonergic terminal loss in rats and also in some mice strains, but also a broader neuronal degeneration throughout several brain areas such as the cortex, hippocampus, and striatum. Meanwhile, in human “ecstasy” abusers, there are evidences for deficits in seronergic biochemical markers, which correlate with long-term impairments in memory and learning. There are several factors that contribute to MDMA-induced neurotoxicity, namely, hyperthermia, monoamine oxidase metabolism of dopamine and serotonin, dopamine oxidation, the serotonin transporter action, nitric oxide, and the formation of peroxinitrite, glutamate excitotoxicity, serotonin 2A receptor agonism, and, importantly, the formation of MDMA neurotoxic metabolites. The present review covered the following topics: history and epidemiology, pharmacological mechanisms, metabolic pathways and the influence of isoenzyme genetic polymorphisms, as well as the acute effects of MDMA in laboratory animals and humans, with a special focus on MDMA-induced neurotoxic effects at the cellular and molecular level. The main aim of this review was to contribute to the understanding of the cellular and molecular mechanisms involved in MDMA neurotoxicity, which can help in the development of therapeutic approaches to prevent or treat the long-term neuropsychiatric complications of MDMA abuse in humans.

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Abbreviations

Amph:

Amphetamine

AMPT:

α-Methyl-p-tyrosine

ATP:

Adenosine triphosphate

AUC:

Area under the curve

C max :

Maximum concentration

CNS:

Central nervous system

COMT:

Catechol-O-methyltransferase

CSF:

Cerebrospinal fluid

CTX:

Cortex

CYP:

Cytochrome P450

DA:

Dopamine

DAT:

Dopamine transporter

DHT:

Dihydroxytriptamine

DOI:

(±)-2,5-Dimethoxy-4-iodoamphetamine

EC50 :

Effective concentration 50%

EU:

European Union

GABA:

Gamma-aminobutyric acid

GFAP:

Glial fibrillary acidic protein

GLU:

Glutamate

GSH:

Glutathione

GST:

Glutathione S-transferase

γ-GT:

gamma-glutamyl transpeptidase or gamma-glutamyltransferase

5-HIAA:

5-Hydroxyindoleacetic acid

HIP:

Hippocampus

HMA:

4-Hydroxy-3-methoxyamphetamine, 3-O-Me-α-MeDA

HMMA:

4-Hydroxy-3-methoxymethamphetamine, 3-O-Me-N-Me-α-MeDA

HO● :

Hydroxyl radical

H2O2 :

Hydrogen peroxide

5-HT:

5-Hydroxytriptamine, serotonin

5-HTT:

Serotonin transporter

HVA:

4-Hydroxy-3-methoxyphenylacetic acid, homovanillic acid

i.p.:

Intraperitoneal

i.v.:

Intravenous

iCa2+ :

Intracellular calcium

ICV:

Intracerebroventricular

K e :

Elimination constant

KO:

Knockout

MAO:

Monoamine oxidase

MDA:

(±)-3,4-Methylenedioxyamphetamine

MDMA:

(±)-3,4-Methylenedioxymethamphetamine, “ecstasy”

α-MeDA:

α-Methyldopamine, 3,4-Dihydroxyamphetamine, HHA

N-Me-α-MeDA:

N-methyl-α-methyldopamine, 3,4-Dihydroxymethamphetamine, HHMA

Meth:

Methamphetamine

MK-801:

Dizocilpine

NAC:

N-acetylcysteine

NE:

Norepinephrine

NET:

Norepinephrine transporter

NMDA:

N-methyl-d-aspartic acid

l-NAME:

\(N_\omega \)-nitro-l-arginine methyl ester

l-NNA:

\(N_\omega \)-nitro-l-arginine

NO:

Nitric oxide

NO● :

Nitric oxide radical

O2 ●− :

Superoxide anion

ONOO− :

Peroxynitrite

p.o.:

Per os

PBN:

α-Phenyl-N-tert-butyl nitrone

PND:

Postnatal day

PET:

Positron emission tomography

PKC:

Protein kinase C

R-96544:

(2R,4R)-5-[2-[2-[2-(3-Methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3-pyrrolidinol hydrochloride

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

s.c.:

Subcutaneous

–SH:

Sulfhydryl

SPECT:

Single photon emission computed tomography

SULT:

Sulfotransferase

t 1/2 :

Elimination half-life

T max :

Median time to maximum concentration

T-4,5-D:

Tryptamine-4,5-dione

TPH:

Tryptophan hydroxylase

UGT:

UDP-glucuronosyltransferase

VMAT:

Vesicular monoamine transporter

WT:

Wild type

References

  1. Freudenmann RW, Öxler F, Bernschneider-Reif S (2006) The origin of MDMA (ecstasy) revisited: the true story reconstructed from the original documents. Addiction 101:1241–1245

    PubMed  Google Scholar 

  2. Pentney AR (2001) An exploration of the history and controversies surrounding MDMA and MDA. J Psychoactive Drugs 33:213–221

    PubMed  CAS  Google Scholar 

  3. Shulgin AT, Nichols DE (1978) Characterization of three new psychotomimetics. Pergamon, New York

    Google Scholar 

  4. Greer G, Strassman RJ (1985) Information on “ecstasy”. Am J Psychiatry 142:1391

    PubMed  CAS  Google Scholar 

  5. Grinspoon L, Bakalar JB (1986) Can drugs be used to enhance the psychotherapeutic process. Am J Psychotherapy 40:393–404

    CAS  Google Scholar 

  6. Great Britain (2008) The misuse of drugs Act 1971 (amendment) order 2008. The Stationery Office

  7. Saunders N (1993) E for ecstasy. Saunders, London, UK

    Google Scholar 

  8. DEA (2008) Orange book. US Department of Justice, Drug Enforcement Administration (DEA)

  9. Check E (2004) Psychedelic drugs: the ups and downs of ecstasy. Nature 429:126–128

    PubMed  CAS  Google Scholar 

  10. Doblin R (2002) A clinical plan for MDMA (ecstasy) in the treatment of posttraumatic stress disorder (PTSD): partnering with the FDA. J Psychoactive Drugs 34:185–194

    PubMed  Google Scholar 

  11. Sessa B (2005) Can psychedelics have a role in psychiatry once again. Br J Psychiatry 186:457–458

    PubMed  Google Scholar 

  12. Parrott AC (2007) The psychotherapeutic potential of MDMA (3,4-methylenedioxymethamphetamine): an evidence-based review. Psychopharmacology 191:181–193

    PubMed  CAS  Google Scholar 

  13. Morton J (2005) Ecstasy: pharmacology and neurotoxicity. Curr Opin Pharmacol 5:79–86

    PubMed  CAS  Google Scholar 

  14. EMCDDA (2007) Annual report 2007: the state of the drugs problem in Europe. European Monitoring Centre for Drugs and Drug Addiction, Lisbon

    Google Scholar 

  15. UNODC (2007) World drug report. United Nations Office on Drugs and Crime, Vienna

    Google Scholar 

  16. Cole JC, Sumnall HR (2003) Altered states: the clinical effects of ecstasy. Pharmacol Ther 98:35–58

    PubMed  CAS  Google Scholar 

  17. Parrott AC (2004) Is ecstasy MDMA? A review of the proportion of ecstasy tablets containing MDMA, their dosage levels, and the changing perceptions of purity. Psychopharmacology 173:234–241

    PubMed  CAS  Google Scholar 

  18. Johnston LD, O'Malley PM, Bachman JG, Schulenberg JE (2008) Monitoring the future national survey results on drug use, 1975–2007, vol I: secondary school students.. National Institute on Drug Abuse, Bethesda, MD

    Google Scholar 

  19. Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE (2008) Monitoring the future national survey results on drug use, 1975–2007, vol ii: college students and adults ages 19–45. National Institute on Drug Abuse, Bethesda, MD

    Google Scholar 

  20. Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE (2008) Monitoring the future national results on adolescent drug use: overview of key findings, 2007. National Institute on Drug Abuse, Bethesda, MD

    Google Scholar 

  21. Schmidt CJ, Levin JA, Lovenberg W (1987) In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on striatal monoaminergic systems in the rat brain. Biochem Pharmacol 36:747–755

    PubMed  CAS  Google Scholar 

  22. Johnson MP, Hoffman AJ, Nichols DE (1986) 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 132:269–276

    PubMed  CAS  Google Scholar 

  23. Berger UV, Gu XF, Azmitia EC (1992) The substituted amphetamines 3,4-methylenedioxymethamphetamine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine. Eur J Pharmacol 215:153–160

    PubMed  CAS  Google Scholar 

  24. Crespi D, Mennini T, Gobbi M (1997) Carrier-dependent and Ca(2+)-dependent 5-HT and dopamine release induced by (+)-amphetamine, 3,4-methylendioxymethamphetamine, p-chloroamphetamine and (+)-fenfluramine. Br J Pharmacol 121:1735–1743

    PubMed  CAS  Google Scholar 

  25. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39:32–41

    PubMed  CAS  Google Scholar 

  26. Montgomery T, Buon C, Eibauer S, Guiry PJ, Keenan AK, McBean GJ (2007) Comparative potencies of 3,4-methylenedioxymethamphetamine (MDMA) analogues as inhibitors of [3H]noradrenaline and [3H]5-HT transport in mammalian cell lines. Br J Pharmacol 152:1121–1130

    PubMed  CAS  Google Scholar 

  27. Han D, Gu H (2006) Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol 6:6

    PubMed  Google Scholar 

  28. Baumann MH, Clark RD, Budzynski AG, Partilla JS, Blough BE, Rothman RB (2005) N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or “ecstasy”). Neuropsychopharmacology 30:550–560

    PubMed  CAS  Google Scholar 

  29. Yamamoto BK, Spanos LJ (1988) The acute effects of methylenedioxymethamphetamine on dopamine release in the awake-behaving rat. Eur J Pharmacol 148:195–203

    PubMed  CAS  Google Scholar 

  30. Gudelsky GA, Nash JF (1996) Carrier-mediated release of serotonin by 3,4-methylenedioxymethamphetamine: implications for serotonin–dopamine interactions. J Neurochem 66:243–249

    PubMed  CAS  Google Scholar 

  31. Ramamoorthy S, Blakely RD (1999) Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science 285:763–766

    PubMed  CAS  Google Scholar 

  32. Kahlig KM, Binda F, Khoshbouei H, Blakely RD, McMahon DG, Javitch JA, Galli A (2005) Amphetamine induces dopamine efflux through a dopamine transporter channel. Proc Natl Acad Sci 102:3495–3500

    PubMed  CAS  Google Scholar 

  33. Sulzer D, Chen TK, Lau YY, Kristensen H, Rayport S, Ewing A (1995) Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci 15:4102–4108

    PubMed  CAS  Google Scholar 

  34. Azmitia EC, Murphy RB, Whitaker-Azmitia PM (1990) MDMA (ecstasy) effects on cultured serotonergic neurons: evidence for CA2(+)-dependent toxicity linked to release. Brain Res 26:97–103

    Google Scholar 

  35. Wichems CH, Hollingsworth CK, Bennett BA (1995) Release of serotonin induced by 3,4-methylenedioxymethamphetamine (MDMA) and other substituted amphetamines in cultured fetal raphe neurons: further evidence for calcium-independent mechanisms of release. Brain Res 695:10–18

    PubMed  CAS  Google Scholar 

  36. Partilla JS, Dempsey AG, Nagpal AS, Blough BE, Baumann MH, Rothman RB (2006) Interaction of amphetamines and related compounds at the vesicular monoamine transporter. J Pharmacol Exp Ther 319:237–246

    PubMed  CAS  Google Scholar 

  37. Fleckenstein AE, Hanson GR (2003) Impact of psychostimulants on vesicular monoamine transporter function. Eur J Pharmacol 479:283–289

    PubMed  CAS  Google Scholar 

  38. Leonardi ET, Azmitia EC (1994) MDMA (ecstasy) inhibition of MAO type A and type B: comparisons with fenfluramine and fluoxetine (Prozac). Neuropsychopharmacology 10:231–238

    PubMed  CAS  Google Scholar 

  39. Cervinski MA, Foster JD, Vaughan RA (2005) Psychoactive substrates stimulate dopamine transporter phosphorylation and down-regulation by cocaine-sensitive and protein kinase C-dependent mechanisms. J Biol Chem 280:40442–40449

    PubMed  CAS  Google Scholar 

  40. Jayanthi LD, Samuvel DJ, Blakely RD, Ramamoorthy S (2005) Evidence for biphasic effects of protein kinase C on serotonin transporter function, endocytosis, and phosphorylation. Mol Pharmacol 67:2077–2087

    PubMed  CAS  Google Scholar 

  41. O'Shea E, Esteban B, Camarero J, Green AR, Colado MI (2001) Effect of GBR 12909 and fluoxetine on the acute and long term changes induced by MDMA (“ecstasy”) on the 5-HT and dopamine concentrations in mouse brain. Neuropharmacology 40:65–74

    PubMed  Google Scholar 

  42. Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181

    PubMed  CAS  Google Scholar 

  43. Sadzot B, Baraban JM, Glennon RA, Lyon RA, Leonhardt S, Jan CR, Titeler M (1989) Hallucinogenic drug interactions at human brain 5-HT2 receptors: implications for treating LSD-induced hallucinogenesis. Psychopharmacology 98:495–499

    PubMed  CAS  Google Scholar 

  44. Battaglia G, Brooks BP, Kulsakdinun C, De Souza EB (1988) Pharmacologic profile of MDMA (3,4-methylenedioxymethamphetamine) at various brain recognition sites. Eur J Pharmacol 149:159–163

    PubMed  CAS  Google Scholar 

  45. Nash JF, Roth BL, Brodkin JD, Nichols DE, Gudelsky GA (1994) Effect of the r(2) and s(1) isomers of MDA and MDMA on phosphatidyl inositol turnover in cultured cells expressing 5-HT2a or 5-HT2c receptors. Neurosci Lett 177:111–115

    PubMed  CAS  Google Scholar 

  46. Baker LE, Broadbent J, Michael EK, Matthews PK, Metosh CA, Saunders RB, West WB, Appel JB (1995) Assessment of the discriminative stimulus effects of the optical isomers of ecstasy (3,4-methylenedioxymethamphetamine; MDMA). Behav Pharmacol 6:263–275

    PubMed  CAS  Google Scholar 

  47. Callahan PM, Appel JB (1988) Differences in the stimulus properties of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine in animals trained to discriminate hallucinogens from saline. J Pharmacol Exp Ther 246:866–870

    PubMed  CAS  Google Scholar 

  48. Broadbent J, Appel JB, Michael EK, Ricker JH (1992) Discriminative stimulus effects of the optical isomers of 3,4-methylenedioxyamphetamine (MDA). Behav Pharmacol 3:443–454

    PubMed  CAS  Google Scholar 

  49. Baker LE, Taylor MM (1997) Assessment of the MDA and MDMA optical isomers in a stimulant–hallucinogen discrimination. Pharmacol Biochem Behav 57:737–748

    PubMed  CAS  Google Scholar 

  50. Chu T, Kumagai Y, DiStefano EW, Cho AK (1996) Disposition of methylenodioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion. Biochem Pharmacol 51:789–796

    PubMed  CAS  Google Scholar 

  51. Johnson EA, O’Callaghan JP, Miller DB (2004) Brain concentrations of d-MDMA are increased after stress. Psychopharmacology 173:278–286

    PubMed  CAS  Google Scholar 

  52. Lavelle A, Honner V, Docherty JR (1999) Investigation of the prejunctional [alpha]2-adrenoceptor mediated actions of MDMA in rat atrium and vas deferens. Br J Pharmacol 128:975–980

    PubMed  CAS  Google Scholar 

  53. Fischer HS, Zernig G, Schatz DS, Humpel C, Saria A (2000) MDMA (‘ecstasy’) enhances basal acetylcholine release in brain slices of the rat striatum. Eur J Neurosci 12:1385–1390

    PubMed  CAS  Google Scholar 

  54. Garcia-Ratés S, Camarasa J, Escubedo E, Pubill D (2007) Methamphetamine and 3,4-methylenedioxymethamphetamine interact with central nicotinic receptors and induce their up-regulation. Toxicol Appl Pharmacol 223:195–205

    PubMed  Google Scholar 

  55. de la Torre R, Farré M, Navarro M, Pacifici R, Zuccaro P, Pichini S (2004) Clinical pharmacokinetics of amfetamine and related substances monitoring in conventional and non-conventional matrices. Clin Pharmacokinet 43:157–185

    PubMed  Google Scholar 

  56. de la Torre R, Farre M, Ortuno J, Mas M, Brenneisen R, Roset PN, Segura J, Cami J (2000) Non-linear pharmacokinetics of MDMA (“ecstasy”) in humans. Br J Clin Pharmacol 49:104–109

    PubMed  Google Scholar 

  57. Delaforge M, Jaouen M, Bouille G (1999) Inhibitory metabolite complex formation of methylenedioxymethamphetamine with rat and human cytochrome p450: particular involvement of cyp2d. Environ Pharmacol Toxicol 7:153–158

    CAS  Google Scholar 

  58. Wu D, Otton SV, Inaba T, Kalow W, Sellers EM (1997) Interactions of amphetamine analogs with human liver cyp2d6. Biochem Pharmacol 53:1605–1612

    PubMed  CAS  Google Scholar 

  59. Heydari A, Yeo KR, Lennard MS, Ellis SW, Tucker GT, Rostami-Hodjegan A (2004) Mechanism-based inactivation of cyp2d6 by methylenedioxymethamphetamine. Drug Metab Dispos 32:1213–1217

    PubMed  CAS  Google Scholar 

  60. Farré M, Torre R, Mathúna B, Roset PN, Peiró AM, Torrens M, Ortuño J, Pujadas M, Camí J (2004) Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics. Psychopharmacology 173:364–375

    PubMed  Google Scholar 

  61. Segura M, Farre M, Pichini S, Peiro AM, Roset PN, Ramirez A, Ortuno J, Pacifici R, Zuccaro P, Segura J, de la Torre R (2005) Contribution of cytochrome p450 2d6 to 3,4-methylenedioxymethamphetamine disposition in humans: use of paroxetine as a metabolic inhibitor probe. Clin Pharmacokinet 44:649–660

    PubMed  CAS  Google Scholar 

  62. Colado M, Williams J, Green A (1995) The hyperthermic and neurotoxic effects of “ecstasy” (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the dark agouti (DA) rat, a model of the cyp2d6 poor metabolizer phenotype. Br J Pharmacol 115:1281–1289

    PubMed  CAS  Google Scholar 

  63. Koenig J, Lazarus C, Jeltsch H, Ben Hamida S, Riegert C, Kelche C, Jones BC, Cassel J-C (2005) MDMA (ecstasy) effects in pubescent rats: males are more sensitive than females. Pharmacol Biochem Behav 81:635–644

    PubMed  CAS  Google Scholar 

  64. Fonsart J, Menet M-C, Declèves X, Galons H, Crété D, Debray M, Scherrmann J-M, Noble F (2008) Sprague–Dawley rats display metabolism-mediated sex differences in the acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Toxicol Appl Pharmacol 230:117–125

    PubMed  CAS  Google Scholar 

  65. Fallon JK, Kicman AT, Henry JA et al (1999) Stereospecific analysis and enantiomeric disposition of 3,4-methylenedioxymethamphetamine (ecstasy) in humans. Clin Chem 45:1058–1069

    PubMed  CAS  Google Scholar 

  66. Pizarro N, Farre M, Pujadas M, Peiro AM, Roset PN, Joglar J, de la Torre R (2004) Stereochemical analysis of 3,4-methylenedioxymethamphetamine and its main metabolites in human samples including the catechol-type metabolite (3,4-dihydroxymethamphetamine). Drug Metab Dispos 32:1001–1007

    PubMed  CAS  Google Scholar 

  67. Meyer MR, Peters FT, Maurer HH (2008) The role of human hepatic cytochrome p450 isozymes in the metabolism of racemic MDMA and its enantiomers. Drug Metab Dispos 36:2345–2354

    PubMed  CAS  Google Scholar 

  68. Kreth K, Kovar K, Schwab M, Zanger UM (2000) Identification of the human cytochromes p450 involved in the oxidative metabolism of “ecstasy”-related designer drugs. Biochem Pharmacol 59:1563–1571

    PubMed  CAS  Google Scholar 

  69. Maurer HH, Bickeboeller-Friedrich J, Kraemer T, Peters FT (2000) Toxicokinetics and analytical toxicology of amphetamine-derived designer drugs (“ecstasy”). Toxicol Lett 113:133–142

    Google Scholar 

  70. Segura M, Ortuño J, Farré M, McLure JA, Pujadas M, Pizarro N, Llebaria A, Joglar J, Roset PN, Segura J, de la Torre R (2001) 3,4-Dihydroxymethamphetamine (HHMA). A major in vivo 3,4-methylenedioxymethamphetamine (MDMA) metabolite in humans. Chem Res Toxicol 14:1203–1208

    PubMed  CAS  Google Scholar 

  71. de la Torre R, Farre M, Mathuna BO, Roset PN, Pizarro N, Segura M, Torrens M, Ortuno J, Pujadas M, Cami J (2005) MDMA (ecstasy) pharmacokinetics in a cyp2d6 poor metaboliser and in nine cyp2d6 extensive metabolisers. Eur J Clin Pharmacol 61:551–554

    PubMed  Google Scholar 

  72. Hiramatsu M, Kumagai Y, Unger SE, Cho AK (1990) Metabolism of methylenedioxymethamphetamine: formation of dihydroxymethamphetamine and a quinone identified as its glutathione adduct. J Pharmacol Exp Ther 254:521–527

    PubMed  CAS  Google Scholar 

  73. Carvalho M, Hawksworth G, Milhazes N, Borges F, Monks TJ, Fernandes E, Carvalho F, Bastos ML (2002) Role of metabolites in MDMA (ecstasy)-induced nephrotoxicity: an in vitro study using rat and human renal proximal tubular cells. Arch Toxicol 76:581–588

    PubMed  CAS  Google Scholar 

  74. Carvalho M, Remiao F, Milhazes N, Borges F, Fernandes E, Carvalho F, Bastos ML (2004) The toxicity of N-methyl-alpha-methyldopamine to freshly isolated rat hepatocytes is prevented by ascorbic acid and N-acetylcysteine. Toxicology 200:193–203

    PubMed  CAS  Google Scholar 

  75. Carvalho M, Remião F, Milhazes N, Borges F, Fernandes E, Monteiro MC, Gonçalves MJ, Seabra V, Amado F, Carvalho F, Bastos ML (2004) Metabolism is required for the expression of ecstasy-induced cardiotoxicity in vitro. Chem Res Toxicol 17:623–632

    PubMed  CAS  Google Scholar 

  76. Capela JP, Meisel A, Abreu AR, Branco PS, Ferreira LM, Lobo AM, Remião F, Bastos ML, Carvalho F (2006) Neurotoxicity of ecstasy metabolites in rat cortical neurons, and influence of hyperthermia. J Pharmacol Exp Ther 316:53–61

    PubMed  CAS  Google Scholar 

  77. Capela JP, Macedo C, Branco PS, Ferreira LM, Lobo AM, Fernandes E, Remiao F, Bastos ML, Dirnagl U, Meisel A, Carvalho F (2007) Neurotoxicity mechanisms of thioether ecstasy metabolites. Neuroscience 146:1743–1757

    PubMed  CAS  Google Scholar 

  78. Jones DC, Duvauchelle C, Ikegami A, Olsen CM, Lau SS, de la Torre R, Monks TJ (2005) Serotonergic neurotoxic metabolites of ecstasy identified in rat brain. J Pharmacol Exp Ther 313:422–431

    PubMed  CAS  Google Scholar 

  79. Meisel C, Gerloff T, Kirchheiner J, Mrozikiewicz PM, Niewinski P, Brockmoller J, Roots I (2003) Implications of pharmacogenetics for individualizing drug treatment and for study design. J Mol Med 81:154–167

    PubMed  Google Scholar 

  80. Johne A, Kopke K, Gerloff T, Mai I, Rietbrock S, Meisel C, Hoffmeyer S, Kerb R, Fromm MF, Brinkmann U, Eichelbaum M, Brockmoller J, Cascorbi I, Roots I (2002) Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin Pharmacol Ther 72:584–594

    PubMed  CAS  Google Scholar 

  81. Evans WE, McLeod HL (2003) Pharmacogenomics—drug disposition, drug targets, and side effects. N Engl J Med 348:538–549

    PubMed  CAS  Google Scholar 

  82. Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286:487–491

    PubMed  CAS  Google Scholar 

  83. Anzenbacher P, Anzenbacherová E (2001) Cytochromes p450 and metabolism of xenobiotics. Cell Mol Life Sci 58:737–747

    PubMed  CAS  Google Scholar 

  84. Ingelman-Sundberg M, Oscarson M, McLellan RA (1999) Polymorphic human cytochrome p450 enzymes: an opportunity for individualized drug treatment. Trends Pharmacol Sci 20:342–349

    PubMed  CAS  Google Scholar 

  85. Tyndale R, Aoyama T, Broly F, Matsunaga T, Inaba T, Kalow W, Gelboin HV, Meyer UA, Gonzalez FJ (1991) Identification of a new variant cyp2d6 allele lacking the codon encoding lys-281: possible association with the poor metabolizer phenotype. Pharmacogenetics 1:26–32

    PubMed  CAS  Google Scholar 

  86. Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman-Sundberg M (1994) Genetic analysis of the Chinese cytochrome p4502d locus: characterization of variant cyp2d6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 46:452–459

    PubMed  CAS  Google Scholar 

  87. Raimundo S, Fischer J, Eichelbaum M, Griese EU, Schwab M, Zanger UM (2000) Elucidation of the genetic basis of the common ‘intermediate metabolizer’ phenotype for drug oxidation by cyp2d6. Pharmacogenetics 10:577–581

    PubMed  CAS  Google Scholar 

  88. Ramamoorthy Y, Yu A, Suh N, Haining RL, Tyndale RF, Sellers EM (2002) Reduced (±)-3,4-methylenedioxymethamphetamine (“ecstasy”) metabolism with cytochrome p450 2d6 inhibitors and pharmacogenetic variants in vitro. Biochem Pharmacol 63:2111–2119

    PubMed  CAS  Google Scholar 

  89. Sachse C, Brockmoller J, Bauer S, Roots I (1997) Cytochrome p450 2d6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 60:284–295

    PubMed  CAS  Google Scholar 

  90. Masimirembwa C, Persson I, Bertilsson L, Hasler J, Ingelman-Sundberg M (1996) A novel mutant variant of the cyp2d6 gene (cyp2d6*17) common in a black African population: association with diminished debrisoquine hydroxylase activity. Br J Clin Pharmacol 42:713–719

    PubMed  CAS  Google Scholar 

  91. Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F, Ingelman-Sundberg M (1996) Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional cyp2d6 alleles. J Pharmacol Exp Ther 278:441–446

    PubMed  CAS  Google Scholar 

  92. Ingelman-Sundberg M (2004) Pharmacogenetics of cytochrome p450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci 25:193–200

    PubMed  CAS  Google Scholar 

  93. Tucker GT, Lennard MS, Ellis SW, Woods HF, Cho AK, Lin LY, Hiratsuka A, Schmitz DA, Chu TY (1994) The demethylenation of methylenedioxymethamphetamine (“ecstasy”) by debrisoquine hydroxylase (cyp2d6). Biochem Pharmacol 47:1151–1156

    PubMed  CAS  Google Scholar 

  94. Ramamoorthy Y, Tyndale RF, Sellers EM (2001) Cytochrome p450 2d6.1 and cytochrome p450 2d6.10 differ in catalytic activity for multiple substrates. Pharmacogenetics 11:477–487

    PubMed  CAS  Google Scholar 

  95. Easton N, Fry J, O'Shea E, Watkins A, Kingston S, Marsden CA (2003) Synthesis, in vitro formation, and behavioural effects of glutathione regioisomers of alpha-methyldopamine with relevance to MDA and MDMA (ecstasy). Brain Res 987:144–154

    PubMed  CAS  Google Scholar 

  96. de la Torre R, Farre M (2004) Neurotoxicity of MDMA (ecstasy): the limitations of scaling from animals to humans. Trends Pharmacol Sci 25:505–508

    PubMed  Google Scholar 

  97. Gilhooly TC, Daly AK (2002) Cyp2d6 deficiency, a factor in ecstasy related deaths. Br J Clin Pharmacol 54:69–70

    PubMed  CAS  Google Scholar 

  98. O’Donohoe A, O’Flynn K, Shields K, Hawi Z, Gill M (1998) MDMA toxicity: no evidence for a major influence of metabolic genotype at CYP2D6. Addict Biol 3:309–314

    Google Scholar 

  99. Schwab M, Seyringer E, Brauer RB, Hellinger A, Griese EU (1999) Fatal MDMA intoxication. Lancet 353:593–594

    PubMed  CAS  Google Scholar 

  100. Lima JJ, Thomason DB, Mohamed MH, Eberle LV, Self TH, Johnson JA (1999) Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharmacol Ther 65:519–525

    PubMed  CAS  Google Scholar 

  101. Zanger UM, Raimundo S, Eichelbaum M (2004) Cytochrome p450 2d6: overview and update on pharmacology, genetics, biochemistry. Naunyn-Schmiedebergs Arch Pharmacol 369:23–37

    PubMed  CAS  Google Scholar 

  102. Krebsfaenger N, Murdter TE, Zanger UM, Eichelbaum MF, Doehmer J (2003) V79 Chinese hamster cells genetically engineered for polymorphic cytochrome p450 2d6 and their predictive value for humans. ALTEX 20:143–154

    PubMed  Google Scholar 

  103. Carmo H, Brulport M, Hermes M, Oesch F, Silva R, Ferreira LM, Branco PS, Boer DD, Remiao F, Carvalho F, Schon MR, Krebsfaenger N, Doehmer J, Bastos MD, Hengstler JG (2006) Influence of cyp2d6 polymorphism on 3,4-methylenedioxymethamphetamine (“ecstasy”) cytotoxicity. Pharmacogenet Genomics 16:789–799

    PubMed  CAS  Google Scholar 

  104. Carmo H, Brulport M, Hermes M, Oesch F, deBoer D, Remião F, Carvalho F, Schön MR, Krebsfaenger N, Doehmer J, Bastos ML, Hengstler JG (2007) Cyp2d6 increases toxicity of the designer drug 4-methylthioamphetamine (4-MTA). Toxicology 229:236–244

    PubMed  CAS  Google Scholar 

  105. Carvalho M, Carvalho F, Bastos ML (2001) Is hyperthermia the triggering factor for hepatotoxicity induced by 3,4-methylenedioxymethamphetamine (ecstasy)? An in vitro study using freshly isolated mouse hepatocytes. Arch Toxicol 74:789–793

    PubMed  CAS  Google Scholar 

  106. Carmo H, Boer DD, Remiao F, Carvalho F, Reys LAD, Bastos ML (2004) Metabolism of the designer drug 4-bromo-2,5-dimethoxyphenethylamine (2c-b) in mice, after acute administration. J Chromatogr B Analyt Technol Biomed Life Sci 811:143–152

    PubMed  CAS  Google Scholar 

  107. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM (1996) Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6:243–250

    PubMed  CAS  Google Scholar 

  108. Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J (1995) Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 34:4202–4210

    PubMed  CAS  Google Scholar 

  109. Lundstrom K, Tenhunen J, Tilgmann C, Karhunen T, Panula P, Ulmanen I (1995) Cloning, expression and structure of catechol-O-methyltransferase. Biochim Biophys Acta 1251:1–10

    PubMed  CAS  Google Scholar 

  110. Weinshilboum RM, Otterness DM, Szumlanski CL (1999) Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Annu Rev Pharmacol Toxicol 39:19–52

    PubMed  CAS  Google Scholar 

  111. Zhu BT (2002) Catechol-O-methyltransferase (COMT)-mediated methylation metabolism of endogenous bioactive catechols and modulation by endobiotics and xenobiotics: importance in pathophysiology and pathogenesis. Curr Drug Metab 3:321–349

    PubMed  CAS  Google Scholar 

  112. Ameyaw MM, Syvanen AC, Ulmanen I, Ofori-Adjei D, McLeod HL (2000) Pharmacogenetics of catechol-O-methyltransferase: frequency of low activity allele in a Ghanaian population. Hum Mutat 16:445–446

    PubMed  CAS  Google Scholar 

  113. McLeod HL, Fang L, Luo X, Scott EP, Evans WE (1994) Ethnic differences in erythrocyte catechol-O-methyltransferase activity in black and white Americans. J Pharmacol Exp Ther 270:26–29

    PubMed  CAS  Google Scholar 

  114. McLeod HL, Collie-Duguid ES, Vreken P, Johnson MR, Wei X, Sapone A, Diasio RB, Fernandez-Salguero P, vanKuilenberg AB, vanGennip AH, Gonzalez FJ (1998) Nomenclature for human DPYD alleles. Pharmacogenetics 8:455–459

    PubMed  CAS  Google Scholar 

  115. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR (2003) Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A 100:6186–6191

    PubMed  CAS  Google Scholar 

  116. Freimuth RR, Eckloff B, Wieben ED, Weinshilboum RM (2001) Human sulfotransferase sult1c1 pharmacogenetics: gene resequencing and functional genomic studies. Pharmacogenetics 11:747–756

    PubMed  CAS  Google Scholar 

  117. Nagata K, Yamazoe Y (2000) Pharmacogenetics of sulfotransferase. Annu Rev Pharmacol Toxicol 40:159–176

    PubMed  CAS  Google Scholar 

  118. Daly AK (2003) Pharmacogenetics of the major polymorphic metabolizing enzymes. Fundam Clin Pharmacol 17:27–41

    PubMed  CAS  Google Scholar 

  119. Monaghan G, Ryan M, Seddon R, Hume R, Burchell B (1996) Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert’s syndrome. Lancet 347:578–581

    PubMed  CAS  Google Scholar 

  120. Aono S, Adachi Y, Uyama E, Yamada Y, Keino H, Nanno T, Koiwai O, Sato H (1995) Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert’s syndrome. Lancet 345:958–959

    PubMed  CAS  Google Scholar 

  121. deMorais SM, Uetrecht JP, Wells PG (1992) Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert’s syndrome. Gastroenterology 102:577–586

    CAS  Google Scholar 

  122. Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, Coffman BL, Ratain MJ (1998) Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 101:847–854

    PubMed  CAS  Google Scholar 

  123. Miners JO, McKinnon RA, Mackenzie PI (2002) Genetic polymorphisms of UDP-glucuronosyltransferases and their functional significance. Toxicology 181–182:453–456

    PubMed  Google Scholar 

  124. Zheng Z, Park JY, Guillemette C, Schantz SP, Lazarus P (2001) Tobacco carcinogen-detoxifying enzyme UGT1a7 and its association with orolaryngeal cancer risk. J Natl Cancer Inst 93:1411–1418

    PubMed  CAS  Google Scholar 

  125. Pemble S, Schroeder KR, Spencer SR, Meyer DJ, Hallier E, Bolt HM, Ketterer B, Taylor JB (1994) Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem J 300:271–276

    PubMed  CAS  Google Scholar 

  126. Seidegard J, Vorachek WR, Pero RW, Pearson WR (1988) Hereditary differences in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion. Proc Natl Acad Sci U S A 85:7293–7297

    PubMed  CAS  Google Scholar 

  127. Ali-Osman F, Akande O, Antoun G, Mao JX, Buolamwini J (1997) Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase Pi gene variants. Evidence for differential catalytic activity of the encoded proteins. J Biol Chem 272:10004–10012

    PubMed  CAS  Google Scholar 

  128. McLellan RA, Oscarson M, Alexandrie AK, Seidegard J, Evans DA, Rannug A, Ingelman-Sundberg M (1997) Characterization of a human glutathione S-transferase mu cluster containing a duplicated GSTM1 gene that causes ultrarapid enzyme activity. Mol Pharmacol 52:958–965

    PubMed  CAS  Google Scholar 

  129. Hashimoto T, Hashimoto K, Matsuzawa D, Shimizu E, Sekine Y, Inada T, Ozaki N, IIwata N, Harano M, Komiyama T, Yamada M, Sora I, Ujike H, Iyo M (2005) A functional glutathione S-transferase P1 gene polymorphism is associated with methamphetamine-induced psychosis in Japanese population. Am J Med Genet B Neuropsychiatr Genet 135:5–9

    Google Scholar 

  130. Mueller M, Peters F, Maurer H, McCann U, Ricaurte GA (2008) Non-linear pharmacokinetics of MDMA (“ecstasy”) and its major metabolites in squirrel monkeys at plasma concentrations of MDMA that develop after typical psychoactive doses. J Pharmacol Exp Ther 327:38–44

    PubMed  CAS  Google Scholar 

  131. Bowyer JF, Young JF, Slikker JW, Itzak Y, Mayorga AJ, Newport GD, Ali SF, Frederick DL, Paule MG (2003) Plasma levels of parent compound and metabolites after doses of either d-fenfluramine or d-3,4-methylenedioxymethamphetamine (MDMA) that produce long-term serotonergic alterations. Neurotoxicology 24:379–390

    PubMed  CAS  Google Scholar 

  132. Lim HK, Su Z, Foltz RL (1993) Stereoselective disposition: enantioselective quantitation of 3,4-(methylenedioxy) methamphetamine and three of its metabolites by gas chromatography/electron capture negative ion chemical ionization mass spectrometry. Biol Mass Spectrom 22:403–411

    PubMed  CAS  Google Scholar 

  133. Carvalho M, Carvalho F, Pereira M, Pires-das-Neves R, Bastos M (2002) Effect of 3,4-methylenedioxymethamphetamine (“ecstasy”) on body temperature and liver antioxidant status in mice. Influence of ambient temperature. Arch Toxicol 76:166–172

    PubMed  CAS  Google Scholar 

  134. Miller DB, O’Callaghan JP (1995) The role of temperature, stress, and other factors in the neurotoxicity of the substituted amphetamines 3,4-methylenedioxymethamphetamine and fenfluramine. Mol Neurobiol 11:177–192

    PubMed  CAS  Google Scholar 

  135. Johnson EA, Sharp DS, Miller DB (2000) Restraint as a stressor in mice: against the dopaminergic neurotoxicity of d-MDMA, low body weight mitigates restraint-induced hypothermia and consequent neuroprotection. Brain Res 875:107–118

    PubMed  CAS  Google Scholar 

  136. Colado MI, Camarero J, Mechan AO, Sanchez V, Esteban B, Elliott JM, Green AR (2001) A study of the mechanisms involved in the neurotoxic action of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) on dopamine neurones in mouse brain. Br J Pharmacol 134:1711–1723

    PubMed  CAS  Google Scholar 

  137. Fantegrossi WE, Kiessel CL, De la Garza R, Woods JH (2005) Serotonin synthesis inhibition reveals distinct mechanisms of action for MDMA and its enantiomers in the mouse. Psychopharmacology 181:529–536

    PubMed  CAS  Google Scholar 

  138. Bexis S, Docherty JR (2005) Role of [alpha]2a-adrenoceptors in the effects of MDMA on body temperature in the mouse. Br J Pharmacol 146:1–6

    PubMed  CAS  Google Scholar 

  139. Mills EM, Banks ML, Sprague JE, Finkel T (2003) Uncoupling the agony from ecstasy. Nature 426:403–404

    PubMed  CAS  Google Scholar 

  140. Fantegrossi WE, Godlewski T, Karabenick RL, Stephens JM, Ullrich T, Rice KC, Woods JH (2003) Pharmacological characterization of the effects of 3,4-methylenedioxymethamphetamine (“ecstasy”) and its enantiomers on lethality, core temperature, and locomotor activity in singly housed and crowded mice. Psychopharmacology 166:202–211

    PubMed  CAS  Google Scholar 

  141. Pontes H, Duarte JA, de Pinho PG, Soares ME, Fernandes E, Dinis-Oliveira RJ, Sousa C, Silva R, Carmo H, Casal S, Remião F, Carvalho F, Bastos ML (2008) Chronic exposure to ethanol exacerbates MDMA-induced hyperthermia and exposes liver to severe MDMA-induced toxicity in CD1 mice. Toxicology 252:64–71

    PubMed  CAS  Google Scholar 

  142. Broening HW, Bowyer JF, Slikker WJ (1995) Age dependent sensitivity of rats to the long term effects of the serotonergic neurotoxicant (±)-3,4methylenedioxymethamphetamine (MDMA) correlates with the magnitude of the MDMA-induced thermal response. J Pharmacol Exp Ther 275:325–333

    PubMed  CAS  Google Scholar 

  143. Malberg J, Seiden L (1998) Small changes in ambient temperature cause large changes in 3,4-methylenodioxymethamphetamine (MDMA)-induced serotonin neurotoxicity and core body temperature in the rat. J Neurosci 18:5086–5094

    PubMed  CAS  Google Scholar 

  144. Green AR, O’Shea E, Saadat KS, Elliott JM, Colado MI (2005) Studies on the effect of MDMA (‘ecstasy’) on the body temperature of rats housed at different ambient room temperatures. Br J Pharmacol 146:306–312

    PubMed  CAS  Google Scholar 

  145. Gordon CJ, Watkinson WP, O'Callaghan JP, Miller DB (1991) Effects of 3,4-methylenedioxymethamphetamine on autonomic thermoregulatory responses of the rat. Pharmacol Biochem Behav 38:339–344

    PubMed  CAS  Google Scholar 

  146. Nash JF Jr., Meltzer HY, Gudelsky GA (1988) Elevation of serum prolactin and corticosterone concentrations in the rat after the administration of 3,4-methylenedioxymethamphetamine. J Pharmacol Exp Ther 245:873–879

    PubMed  CAS  Google Scholar 

  147. Schmidt C, Abbate G, Black C, Taylor V (1990) Selective 5-hydroxytryptamine2 receptor antagonists protect against the neurotoxicity of methylenedioxymethamphetamine in rats. J Pharmacol Exp Ther 255:478–483

    PubMed  CAS  Google Scholar 

  148. Mechan AO, Esteban B, O’Shea E, Elliot JM, Colado MI, Green AR (2002) The pharmacology of the acute hyperthermic response that follows administration of 3,4-methylenedioxymethamphetamine (MDMA “ecstasy”) to rats. Br J Pharmacol 135:170–180

    PubMed  CAS  Google Scholar 

  149. Malberg JE, Sabol KE, Seiden LS (1996) Co-administration of MDMA with drugs that protect against MDMA neurotoxicity produces different effects on body temperature in the rat. J Pharmacol Exp Ther 278:258–267

    PubMed  CAS  Google Scholar 

  150. Mechan AO, O’Shea E, Elliot JM, Colado MI, Green AR (2001) A neurotoxic dose of 3, 4-methylenedioxymethamphetamine (MDMA; ecstasy) to rats results in a long-term defect in thermoregulation. Psychopharmacology 155:413–418

    PubMed  CAS  Google Scholar 

  151. Sanchez V, O'Shea E, Saadat KS, Elliott JM, Colado MI, Green AR (2004) Effect of repeated (“binge”) dosing of MDMA to rats housed at normal and high temperature on neurotoxic damage to cerebral 5-HT and dopamine neurones. J Psychopharmacol 18:412–416

    PubMed  CAS  Google Scholar 

  152. Walker Q, Williams C, Jotwani R, Waller S, Francis R, Kuhn C (2007) Sex differences in the neurochemical and functional effects of MDMA in Sprague–Dawley rats. Psychopharmacology 189:435–445

    PubMed  CAS  Google Scholar 

  153. Goni-Allo B, Ó Mathúna B, Segura M, Puerta E, Lasheras B, de la Torre R, Aguirre N (2008) The relationship between core body temperature and 3,4-methylenedioxymethamphetamine metabolism in rats: implications for neurotoxicity. Psychopharmacology 197:263–278

    PubMed  CAS  Google Scholar 

  154. Shioda K, Nisijima K, Yoshino T, Kuboshima K, Iwamura T, Yui K, Kato S (2008) Risperidone attenuates and reverses hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats. Neurotoxicology 29:1030–1036

    PubMed  CAS  Google Scholar 

  155. Fernandez F, Aguerre S, Mormède P, Chaouloff F (2002) Influences of the corticotropic axis and sympathetic activity on neurochemical consequences of 3,4-methylenedioxymethamphetamine (MDMA) administration in Fischer 344 rats. Eur J Neurosci 16:607–618

    PubMed  Google Scholar 

  156. Sprague JE, Banks ML, Cook VJ, Mills EM (2003) Hypothalamic–pituitary–thyroid axis and sympathetic nervous system involvement in hyperthermia induced by 3,4-methylenedioxymethamphetamine (ecstasy). J Pharmacol Exp Ther 305:159–166

    PubMed  CAS  Google Scholar 

  157. Blessing W, Seaman B (2003) 5-Hidroxitriptamine2a receptors regulate sympathetic nerves constricting the cutaneous vascular bed in rabbits and rats. Neuroscience 117:939–948

    PubMed  CAS  Google Scholar 

  158. Blessing WW, Seaman B, Pedersen NP, Ootsuka Y (2003) Clozapine reverses hyperthermia and sympathetically mediated cutaneous vasoconstriction induced by 3,4-methylenedioxymethamphetamine (ecstasy) in rabbits and rats. J Neurosci 23:6385–6391

    PubMed  CAS  Google Scholar 

  159. Saadat KS, Elliott JM, Colado MI, Green AR (2004) Hyperthermic and neurotoxic effect of 3,4-methylenedioxymethamphetamine (MDMA) in guinea pigs. Psychopharmacology 173:452–453

    PubMed  CAS  Google Scholar 

  160. Fiege M, Wappler F, Weisshorn R, Gerbershagen MU, Menge M, Schulte Esch J (2003) Induction of malignant hyperthermia in susceptible swine by 3,4-methylenedioxymethamphetamine (“ecstasy”). Anesthesiology 99:1132–1136

    PubMed  CAS  Google Scholar 

  161. Crean RD, Davis SA, Von Huben SN, Lay CC, Katner SN, Taffe MA (2006) Effects of (±)3,4-methylenedioxymethamphetamine, (±)3,4-methylenedioxyamphetamine and methamphetamine on temperature and activity in rhesus macaques. Neuroscience 142:515–525

    PubMed  CAS  Google Scholar 

  162. Von Huben SN, Lay CC, Crean RD, Davis SA, Katner SN, Taffe MA (2006) Impact of ambient temperature on hyperthermia induced by (±)3,4-methylenedioxymethamphetamine in rhesus macaques. Neuropsychopharmacology 32:673–681

    Google Scholar 

  163. Taffe MA, Lay CC, Von Huben SN, Davis SA, Crean RD, Katner SN (2006) Hyperthermia induced by 3,4-methylenedioxymethamphetamine in unrestrained rhesus monkeys. Drug Alcohol Depend 82:276–281

    PubMed  CAS  Google Scholar 

  164. Banks ML, Sprague JE, Kisor DF, Czoty PW, Nichols DE, Nader MA (2007) Ambient temperature effects on 3,4-methylenedioxymethamphetamine-induced thermodysregulation and pharmacokinetics in male monkeys. Drug Metab Dispos 35:1840–1845

    PubMed  CAS  Google Scholar 

  165. Miller DB, O’Callaghan JP (1994) Environment-, drug- and stress-induced alterations in body temperature affect the neurotoxicity of substituted amphetamines in the C57BL/6J mouse. J Pharmacol Exp Ther 270:752–760

    PubMed  CAS  Google Scholar 

  166. Sanchez V, Camarero J, Esteban B, Peter MJ, Green AR, Colado MI (2001) The mechanisms involved in the long-lasting neuroprotective effect of fluoxetine against MDMA (“ecstasy”)-induced degeneration of 5-HT nerve endings in rat brain. Br J Pharmacol 134:46–57

    PubMed  CAS  Google Scholar 

  167. Schmidt CJ, Taylor VL (1990) Reversal of the acute effects of 3,4-methylenedioxymethamphetamine by 5-HT uptake inhibitors. Eur J Pharmacol 181:133–136

    PubMed  CAS  Google Scholar 

  168. Sugimoto Y, Okhura M, Inoue K, Yamada J (2001) Involvement of serotonergic and dopaminergic mechanisms in hyperthermia induced by a serotonin-releasing drug, p-chloroamphetamine in mice. Eur J Pharmacol 430:265–268

    PubMed  CAS  Google Scholar 

  169. Ootsuka Y, Nalivaiko E, Blessing WW (2004) Spinal 5-HT2a receptors regulate cutaneous sympathetic vasomotor outflow in rabbits and rats: relevance for cutaneous vasoconstriction elicited by MDMA (3,4-methylenedioxymethamphetamine, “ecstasy”) and its reversal by clozapine. Brain Res 1014:34–44

    PubMed  CAS  Google Scholar 

  170. Sprague JE, Brutcher RE, Mills EM, Caden D, Rusyniak DE (2004) Attenuation of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-induced rhabdomyolysis with α1- plus β3-adrenoreceptor antagonists. Br J Pharmacol 142:667–670

    PubMed  CAS  Google Scholar 

  171. Sprague JE, Moze P, Caden D, Rusyniak DE, Holmes C, Goldstein DS, Mills EM (2005) Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) in an animal model. Crit Care Med 33:1311–1316

    PubMed  CAS  Google Scholar 

  172. Bexis S, Docherty JS (2008) Role of α1-adrenoceptor subtypes in the effects of methylenedioxy methamphetamine (MDMA) on body temperature in the mouse. Br J Pharmacol 153:591–597

    PubMed  CAS  Google Scholar 

  173. Wyeth RP, Mills EM, Ullman A, Kenaston MA, Burwell J, Sprague JE (2009) The hyperthermia mediated by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is sensitive to sex differences. Toxicol Appl Pharmacol 235:33–38

    PubMed  CAS  Google Scholar 

  174. Henry J (1992) Ecstasy and the dance of death. Br Med J 350:5–6

    Google Scholar 

  175. McNamara MG, Kelly JP, Leonard BE (1995) Some behavioural and neurochemical aspects of subacute (6)3,4-methylenedioxymethamphetamine administration in rats. Pharmacol Biochem Behav 52:479–484

    PubMed  CAS  Google Scholar 

  176. De Souza I, Kelly JP, Harkin AJ, Leonard BE (1997) An appraisal of the pharmacological and toxicological effects of a single oral administration of 3,4-methylenedioxymethamphetamine (MDMA) in the rat. Pharmacol Toxicol 80:207–210

    PubMed  Google Scholar 

  177. Shankaran M, Gudelsky GA (1999) A neurotoxic regimen of MDMA suppresses behavioral, thermal and neurochemical responses to subsequent MDMA administration. Psychopharmacology 147:66–72

    PubMed  CAS  Google Scholar 

  178. Spanos LJ, Yamamoto BK (1989) Acute and subchronic effects of methylenodioxymethamphetamine [(±)MDMA] on locomotion and serotonin syndrome behavior in the rat. Pharmacol Biochem Behav 32:835–840

    PubMed  CAS  Google Scholar 

  179. Piper BJ, Fraiman JB, Meyer JS (2005) Repeated MDMA (“ecstasy”) exposure in adolescent male rats alters temperature regulation, spontaneous motor activity, attention, and serotonin transporter binding. Developmental Psychobiology 47:145–157

    PubMed  CAS  Google Scholar 

  180. Morley KC, Arnold JC, McGregor IS (2005) Serotonin (1a) receptor involvement in acute 3,4-methylenedioxymethamphetamine (MDMA) facilitation of social interaction in the rat. Prog Neuropsychopharmacol Biol Psychiatry 29:648–657

    PubMed  CAS  Google Scholar 

  181. Fitzgerald JL, Reid JJ (1994) Sympathomimetic actions of methylenedioxymethamphetamine in rat and rabbit isolated cardiovascular tissues. J Pharm Pharmacol 46:826–832

    PubMed  CAS  Google Scholar 

  182. Jaehne EJ, Salem A, Irvine RJ (2008) The effect of long-term repeated exposure to 3,4-methylenedioxymethamphetamine on cardiovascular and thermoregulatory changes. Psychopharmacology 201:161–170

    PubMed  CAS  Google Scholar 

  183. O’Cain PA, Hletko SB, Ogden BA, Varner KJ (2000) Cardiovascular and sympathetic responses and reflex changes elicited by MDMA. Physiol Behav 70:141–148

    PubMed  Google Scholar 

  184. Badon LA, Hicks A, Lord K, Ogden BA, Meleg-Smith S, Varner KJ (2002) Changes in cardiovascular responsiveness and cardiotoxicity elicited during binge administration of ecstasy. J Pharmacol Exp Ther 302:898–907

    PubMed  CAS  Google Scholar 

  185. Bexis S, Docherty JR (2006) Effects of MDMA, MDA and MDEA on blood pressure, heart rate, locomotor activity and body temperature in the rat involve [alpha]-adrenoceptors. Br J Pharmacol 147:926–934

    PubMed  CAS  Google Scholar 

  186. Lin HQ, Burden PM, Christie MJ, Johnston GAR (1999) The anxiogenic-like and anxiolytic-like effects of MDMA on mice in the elevated plus-maze: a comparison with amphetamine. Pharmacol Biochem Behav 62:403–408

    PubMed  CAS  Google Scholar 

  187. Navarro JF, Maldonado E (2002) Acute and subchronic effects of MDMA (“ecstasy”) on anxiety in male mice tested in the elevated plus-maze. Prog Neuropsychopharmacol Biol Psychiatry 26:1151–1154

    PubMed  CAS  Google Scholar 

  188. Sumnall HR, O'Shea E, Marsden CA, Cole JC (2004) The effects of MDMA pretreatment on the behavioural effects of other drugs of abuse in the rat elevated plus-maze test. Pharmacol Biochem Behav 77:805–814

    PubMed  CAS  Google Scholar 

  189. Ho Y-J, Pawlak CR, Guo L, Schwarting RKW (2004) Acute and long-term consequences of single MDMA administration in relation to individual anxiety levels in the rat. Behav Brain Res 149:135–144

    PubMed  CAS  Google Scholar 

  190. Bull EJ, Hutson PH, Fone KCF (2004) Decreased social behaviour following 3,4-methylenedioxymethamphetamine (MDMA) is accompanied by changes in 5-HT2a receptor responsivity. Neuropharmacology 46:202–210

    PubMed  CAS  Google Scholar 

  191. Fone KC, Beckett SR, Topham IA, Swettenham J, Ball M, Maddocks L (2002) Long-term changes in social interaction and reward following repeated MDMA administration to adolescent rats without accompanying serotonergic neurotoxicity. Psychopharmacology 159:437–444

    PubMed  CAS  Google Scholar 

  192. Poland RE (1990) Diminished corticotropin and enhanced prolactin responses to 8-hydroxy-2(di-n-propylamino)tetralin in methylenedioxymethamphetamine pretreated rats. Neuropharmacology 29:1099–1101

    PubMed  CAS  Google Scholar 

  193. Baumann MH, Clark RD, Franken FH, Rutter JJ, Rothman RB (2008) Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges. Neuroscience 152:773–784

    PubMed  CAS  Google Scholar 

  194. Connor TJ (2004) Methylenedioxymethamphetamine (MDMA, ‘ecstasy’): a stressor on the immune system. Immunology 111:357–367

    PubMed  CAS  Google Scholar 

  195. Connor TJ, McNamara MG, Finn D, Currid A, O’Malley M, Redmond AM, Kelly JP, Leonard BE (1998) Acute 3,4-methylenedioxymethamphetamine (MDMA) administration produces a rapid and sustained suppression of immune function in the rat. Immunopharmacology 38:253–260

    PubMed  CAS  Google Scholar 

  196. Connor TJ, Kelly JP, McGee M, Leonard BE (2000) Methylenedioxymethamphetamine (MDMA; ecstasy) suppresses IL-1[beta] and TNF-[alpha] secretion following an in vivo lipopolysaccharide challenge. Life Sci 67:1601–1612

    PubMed  CAS  Google Scholar 

  197. Nelson DA, Nirmaier JL, Singh SJ, Tolbert MD, Bost KL (2008) Ecstasy (3,4-methylenedioxymethamphetamine) limits murine gammaherpesvirus-68 induced monokine expression. Brain Behav Immun 22:912–922

    PubMed  CAS  Google Scholar 

  198. Schenk S, Gittings D, Johnstone M, Daniela E (2003) Development, maintenance and temporal pattern of self-administration maintained by ecstasy (MDMA) in rats. Psychopharmacology 169:21–27

    PubMed  CAS  Google Scholar 

  199. Schenk S, Hely L, Lake B, Daniela E, Gittings D, Mash DC (2007) MDMA self-administration in rats: acquisition, progressive ratio responding and serotonin transporter binding. Eur J Neurosci 26:3229–3236

    PubMed  Google Scholar 

  200. Wakonigg G, Sturm K, Saria A, Zernig G (2003) Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) serves as a robust positive reinforcer in a rat runway procedure. Pharmacology 69:180–182

    PubMed  CAS  Google Scholar 

  201. Trigo JM, Renoir T, Lanfumey L, Hamon M, Lesch K-P, Robledo P, Maldonado R (2007) 3,4-Methylenedioxymethamphetamine self-administration is abolished in serotonin transporter knockout mice. Biol Psychiatry 62:669–679

    PubMed  CAS  Google Scholar 

  202. Touriño C, Ledent C, Maldonado R, Valverde O (2008) CB1 cannabinoid receptor modulates 3,4-methylenedioxymethamphetamine acute responses and reinforcement. Biol Psychiatry 63:1030–1038

    PubMed  Google Scholar 

  203. Lile JA, Ross JT, Nader MA (2005) A comparison of the reinforcing efficacy of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) with cocaine in rhesus monkeys. Drug Alcohol Depend 78:135–140

    PubMed  CAS  Google Scholar 

  204. Fantegrossi WE, Ullrich T, Rice KC, Woods JH, Winger G (2002) 3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) and its stereoisomers as reinforcers in rhesus monkeys: serotonergic involvement. Psychopharmacology 161:356–364

    PubMed  CAS  Google Scholar 

  205. Fantegrossi WE, Woolverton WL, Kilbourn M, Sherman P, Yuan J, Hatzidimitriou G, Ricaurte GA, Woods JH, Winger G (2004) Behavioral and neurochemical consequences of long-term intravenous self-administration of MDMA and its enantiomers by rhesus monkeys. Neuropsychopharmacology 29:1270–1281

    PubMed  CAS  Google Scholar 

  206. Steketee JD (2003) Neurotransmitter systems of the medial prefrontal cortex: potential role in sensitization to psychostimulants. Brain Res Brain Res Rev 41:203–228

    PubMed  CAS  Google Scholar 

  207. Vanderschuren LJMJ, Schmidt ED, De Vries TJ, Van Moorsel CAP, Tilders FJH, Schoffelmeer ANM (1999) A single exposure to amphetamine is sufficient to induce long-term behavioral, neuroendocrine, and neurochemical sensitization in rats. J Neurosci 19:9579–9586

    PubMed  CAS  Google Scholar 

  208. Ramos M, Goni-Allo B, Aguirre N (2005) Administration of SCH 23390 into the medial prefrontal cortex blocks the expression of MDMA-induced behavioral sensitization in rats: an effect mediated by 5-HT2c receptor stimulation and not by D1 receptor blockade. Neuropsychopharmacology 30:2180–2191

    PubMed  CAS  Google Scholar 

  209. Kalivas PW, Duffy P, White SR (1998) MDMA elicits behavioral and neurochemical sensitization in rats. Neuropsychopharmacology 18:469–479

    PubMed  CAS  Google Scholar 

  210. Colussi-Mas J, Schenk S (2008) Acute and sensitized response to 3,4-methylenedioxymethamphetamine in rats: different behavioral profiles reflected in different patterns of Fos expression. Eur J Neurosci 28:1895–1910

    PubMed  Google Scholar 

  211. Hall AP, Henry JA (2006) Acute toxic effects of ‘ecstasy’ (MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaesth 96:678–685

    PubMed  CAS  Google Scholar 

  212. Vollenweider FX, Gamma A, Liechti ME, Huber T (1998) Psychological and cardiovascular effects and short-term sequelae of MDMA (“ecstasy”) in MDMA-naive healthy volunteers. Neuropsychopharmacology 19:241–251

    PubMed  CAS  Google Scholar 

  213. Cohen RS, Cocores J (1997) Neuropsychiatric manifestations following the use of 3,4-methylenedioxymethamphetamine (MDMA: “ecstasy”). Prog Neuropsychopharmacol Biol Psychiatry 21:727–734

    PubMed  CAS  Google Scholar 

  214. Liechti ME, Saur MR, Gamma A, Hell D, Vollenweider FX (2000) Psychological and physiological effects of MDMA (“ecstasy”) after pre-treatment with the 5-HT2 antagonist ketanserin in healthy humans. Neuropsychopharmacology 23:396–404

    PubMed  CAS  Google Scholar 

  215. Kolbrich EA, Goodwin RS, Gorelick DA, Hayes RJ, Stein EA, Huestis MA (2008) Physiological and subjective responses to controlled oral 3,4-methylenedioxymethamphetamine administration. J Clin Psychopharmacol 28:432–440

    PubMed  CAS  Google Scholar 

  216. Tancer M, Johanson C-E (2007) The effects of fluoxetine on the subjective and physiological effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology 189:565–573

    PubMed  CAS  Google Scholar 

  217. Farré M, Abanades S, Roset PN, Peiro AM, Torrens M, O’Mathuna B, Segura M, de la Torre R (2007) Pharmacological interaction between 3,4-methylenedioxymethamphetamine (ecstasy) and paroxetine: pharmacological effects and pharmacokinetics. J Pharmacol Exp Ther 323:954–962

    PubMed  Google Scholar 

  218. Tancer M, Johanson CE (2003) Reinforcing, subjective, and physiological effects of MDMA in humans: a comparison with d-amphetamine and mCPP. Drug Alcohol Depend 72:33–44

    PubMed  CAS  Google Scholar 

  219. Freedman RR, Johanson CE, Tancer ME (2005) Thermoregulatory effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology 183:248–256

    PubMed  CAS  Google Scholar 

  220. Liechti ME, Vollenweider FX (2000) The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of 3,4-methylenedioxymethamphetamine (‘ecstasy’) in healthy volunteers. J Psychopharmacol 14:269–274

    PubMed  CAS  Google Scholar 

  221. Irvine RJ, Keane M, Felgate P, McCann UD, Callaghan PD, White JM (2005) Plasma drug concentrations and physiological measures in “dance party” participants. Neuropsychopharmacology 31:424–430

    Google Scholar 

  222. Kunitz O, Ince A, Kuhlen R, Rossaint R (2003) Hyperpyrexia and rhabdomyolysis after ecstasy (MDMA) intoxication. Anaesthesist 52:511–515

    PubMed  CAS  Google Scholar 

  223. Mallick A, Bodenham AR (1997) MDMA induced hyperthermia: a survivor with an initial body temperature of 42.9 degrees C. J Accid Emerg Med 14:336–338

    PubMed  CAS  Google Scholar 

  224. Connolly E, O'Callaghan G (1999) MDMA toxicity presenting with severe hyperpyrexia: a case report. Crit Care Resusc 1:368–370

    PubMed  CAS  Google Scholar 

  225. Henry JA, Fallon JK, Kicman AT, Hutt AJ, Cowan DA, Forsling M (1998) Low-dose MDMA (“ecstasy”) induces vasopressin secretion. Lancet 351:1784

    PubMed  CAS  Google Scholar 

  226. Wolff K, Tsapakis EM, Winstock AR, Hartley D, Holt D, Forsling ML, Aitchison KJ (2006) Vasopressin and oxytocin secretion in response to the consumption of ecstasy in a clubbing population. J Psychopharmacol 20:400–410

    PubMed  CAS  Google Scholar 

  227. Gerra G, Zaimovic A, Franchini D, Palladino M, Guicastro G, Reali N, Maestri D, Caccavari R, Delsignore R, Brambilla F (1998) Neuroendocrine responses of healthy volunteers to “techno-music”: relationships with personality traits and emotional state. Int J Psychophysiol 28:99–111

    PubMed  CAS  Google Scholar 

  228. Pacifici R, Zuccaro P, Farré M, Pichini S, Di Carlo S, Roset PN, Ortuño J, Pujadas M, Bacosi A, Menoyo E, Segura J, de la Torre R (2001) Effects of repeated doses of MDMA (“ecstasy”) on cell-mediated immune response in humans. Life Sci 69:2931–2941

    PubMed  CAS  Google Scholar 

  229. Klitzman RL, Pope HG Jr., Hudson JI (2000) MDMA (“ecstasy”) abuse and high-risk sexual behaviors among 169 gay and bisexual men. Am J Psychiatry 157:1162–1164

    PubMed  CAS  Google Scholar 

  230. Davison D, Parrott AC (1997) Ecstasy (MDMA) in recreational users: self-reported psychological and physiological effects. Hum Psychopharmacol 12:221–226

    CAS  Google Scholar 

  231. McCann UD, Slate SO, Ricaurte GA (1996) Adverse reactions with 3,4-methylenedioxymethamphetamine (MDMA; “ecstasy”). Drug Saf 15:107–115

    PubMed  CAS  Google Scholar 

  232. Liechti ME, Kunz I, Kupferschmidt H (2005) Acute medical problems due to ecstasy use. Case-series of emergency department visits. Swiss Med Wkly 135:652–627

    PubMed  Google Scholar 

  233. Milroy CM, Clark JC, Forrest AR (1996) Pathology of deaths associated with “ecstasy” and “Eve” misuse. J Clin Pathol 49:149–153

    PubMed  CAS  Google Scholar 

  234. Logan SC, Stickle B, O’Keefe N, Hewitson H (1993) Survival following “ecstasy” ingestion with a peak temperature of 42°C. Anaesthesia 48:1017–1018

    PubMed  CAS  Google Scholar 

  235. Garcia-Repetto R, Moreno E, Soriano T, Jurado C, Gimenez MP, Menendez M (2003) Tissue concentrations of MDMA and its metabolite MDA in three fatal cases of overdose. Forensic Sci Int 135:110–114

    PubMed  CAS  Google Scholar 

  236. SAMHDA. (2002) Emergency department trends from the drug abuse warning network, final estimates 1994–2001. In DAWN Series D-21 (02-3635, D. P. N. S., Ed.), Substance Abuse and Mental Health Services Administration Office of Applied Studies, Rockville, MD

  237. Gore SM (1999) Fatal uncertainty: death rate from use of ecstasy or heroin. Lancet 354:1265–1266

    PubMed  CAS  Google Scholar 

  238. Schmidt C, Wu L, Lovenberg W (1986) Methylenedioxymethamphetamine: a potentially neurotoxic amphetamine analogue. Eur J Pharmacol 124:175–178

    PubMed  CAS  Google Scholar 

  239. Schmidt CJ (1987) Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. J Pharmacol Exp Ther 240:1–7

    PubMed  CAS  Google Scholar 

  240. Commins DL, Vosmer G, Virus RM, Woolverton WL, Schuster CR, Seiden LS (1987) Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain. J Pharmacol Exp Ther 241:338–345

    PubMed  CAS  Google Scholar 

  241. Stone DM, Johnson M, Hanson GR, Gibb JW (1987) A comparison of the neurotoxic potential of methylenedioxyamphetamine (MDA) and its N-methylated and N-ethylated derivatives. Eur J Pharmacol 134:245–248

    PubMed  CAS  Google Scholar 

  242. Battaglia G, Yeh SY, O’Hearn E, Molliver ME, Kuhar MJ, De Souza EB (1987) 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 242:911–916

    PubMed  CAS  Google Scholar 

  243. Stone DM, Hanson GR, Gibb JW (1987) Differences in the central serotonergic effects of methylenedioxymethamphetamine (MDMA) in mice and rats. Neuropharmacology 26:1657–1661

    PubMed  CAS  Google Scholar 

  244. Ricaurte GA, Bryan G, Strauss L, Seiden LS, Schuster CR (1985) Hallucinogenic amphetamine selectively destroys brain serotonin nerve terminals. Science 229:986–988

    PubMed  CAS  Google Scholar 

  245. Warren M, Larner S, Kobeissy F, Brezing C, Jeung J, Hayes R, Gold M, Wang K (2007) Calpain and caspase proteolytic markers co-localize with rat cortical neurons after exposure to methamphetamine and MDMA. Acta Neuropathologica 114:277–286

    PubMed  CAS  Google Scholar 

  246. Xie T, Tong L, McLane MW, Hatzidimitriou G, Yuan J, McCann U, Ricaurte GA (2006) Loss of serotonin transporter protein after MDMA and other ring-substituted amphetamines. Neuropsychopharmacology 31:2639–2651

    PubMed  CAS  Google Scholar 

  247. Yeh S (1999) N-tert-butyl-alpha-phenylnitrone protects against 3,4-methylenedioxymethamphetamine-induced depletion of serotonin in rats. Synapse 31:169–177

    PubMed  CAS  Google Scholar 

  248. Sprague JE, Nichols DE (1995) Inhibition of MAO-B protects against MDMA-induced neurotoxicity in the striatum. Psychopharmacology 118:357–359

    PubMed  CAS  Google Scholar 

  249. Shankaran M, Yamamoto BK, Gudelsky GA (1999) Involvement of the SERT in the formation of hydroxyl radicals induced by 3,4-methylenedioxymethamphetamine. Eur J Pharmacol 385:103–110

    PubMed  CAS  Google Scholar 

  250. Schmued L (2003) Demonstration and localization of neuronal degeneration in the rat forebrain following a single exposure to MDMA. Brain Res 974:127–133

    PubMed  CAS  Google Scholar 

  251. O’Hearn E, Battaglia G, De Souza EB, Kuhar MJ, Molliver ME (1988) Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity. J Neurosci 8:2788–2803

    PubMed  Google Scholar 

  252. Molliver ME, Berger UV, Mamounas LA, Molliver DC, O’Hearn E, Wilson MA (1990) Neurotoxicity of MDMA and related compounds: anatomic studies. Ann N Y Acad Sci 600:649–664

    PubMed  CAS  Google Scholar 

  253. Fischer C, Hatzidimitriou G, Wlos J, Katz J, Ricaurte G (1995) Reorganization of ascending 5-HT axon projections in animals previously exposed to the recreational drug (±)3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). J Neurosci 15:5476–5485

    PubMed  CAS  Google Scholar 

  254. Colado MI, Murray TK, Green AR (1993) 5-HT loss in rat brain following 3,4 methylenedioxymethamphetamine (MDMA), p-chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine. Br J Pharmacol 108:583–589

    PubMed  CAS  Google Scholar 

  255. Armstrong BD, Noguchi KK (2004) The neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine on serotonin, dopamine, and GABA-ergic terminals: an in-vitro autoradiographic study in rats. Neurotoxicology 25:905–914

    PubMed  CAS  Google Scholar 

  256. Aguirre N, Barrionuevo M, Lasheras B, Del Rio J (1998) The role of dopaminergic systems in the perinatal sensitivity to 3,4-methylenedioxymethamphetamine-induced neurotoxicity in rats. J Pharmacol Exp Ther 286:1159–1165

    PubMed  CAS  Google Scholar 

  257. O'Shea E, Orio L, Escobedo I, Sanchez V, Camarero J, Green AR, Colado MI (2006) MDMA-induced neurotoxicity: long-term effects on 5-HT biosynthesis and the influence of ambient temperature. Br J Pharmacol 148:778–785

    PubMed  Google Scholar 

  258. Izco M, Orio L, O’Shea E, Colado M (2007) Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain. Psychopharmacology 189:459–470

    PubMed  CAS  Google Scholar 

  259. McNamara R, Kerans A, O’Neill B, Harkin A (2006) Caffeine promotes hyperthermia and serotonergic loss following co-administration of the substituted amphetamines, MDMA (“ecstasy”) and MDA (“love”). Neuropharmacology 50:69–80

    PubMed  CAS  Google Scholar 

  260. Hewitt K, Green A (1994) Chlormethiazole, dizocilpine and haloperidol prevent the degeneration of serotonergic nerve terminals induced by administration of MDMA (“ecstasy”) to rats. Neuropharmacology 33:1589–1595

    PubMed  CAS  Google Scholar 

  261. Murray TK, Williams JL, Misra A, Colado MI, Green AR (1997) The spin trap reagent PBN attenuates degeneration of 5-HT neurones in rat brain induced by p-chloroamphetamine but not fenfluramine. Neuropharmacology 35:1615–1620

    Google Scholar 

  262. Chipana C, Camarasa J, Pubill D, Escubedo E (2008) Memantine prevents MDMA-induced neurotoxicity. Neurotoxicology 29:179–183

    PubMed  CAS  Google Scholar 

  263. O'Shea E, Granados R, Esteban B, Colado MI, Green AR (1998) The relationship between the degree of neurodegeneration of rat brain 5-HT nerve terminals and the dose and frequency of administration of MDMA (“ecstasy”). Neuropharmacology 37:919–926

    PubMed  Google Scholar 

  264. Hervías I, Lasheras B, Aguirre N (2000) 2-Deoxy-d-glucose prevents and nicotinamide potentiates 3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity. J Neurochem 75:982–990

    PubMed  Google Scholar 

  265. Bull EJ, Hutson PH, Fone KCF (2003) Reduced social interaction following 3,4-methylenedioxymethamphetamine is not associated with enhanced 5-HT2c receptor responsivity. Neuropharmacology 44:439–448

    PubMed  CAS  Google Scholar 

  266. Schmidt CJ, Taylor VL (1987) Depression of rat brain tryptophan hydroxylase activity following the acute administration of methylenedioxymethamphetamine. Biochem Pharmacol 36:4095–4102

    PubMed  CAS  Google Scholar 

  267. Stone DM, Stahl DC, Hanson GR, Gibb JW (1986) The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain. Eur J Pharmacol 128:41–48

    PubMed  CAS  Google Scholar 

  268. Battaglia G, Yeh SY, De Souza EB (1988) MDMA-induced neurotoxicity: parameters of degeneration and recovery of brain serotonin neurons. Pharmacol Biochem Behav 29:269–274

    PubMed  CAS  Google Scholar 

  269. Johnson M, Letter AA, Merchant K, Hanson GR, Gibb JW (1988) Effects of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine isomers on central serotonergic, dopaminergic and nigral neurotensin systems of the rat. J Pharmacol Exp Ther 244:977–982

    PubMed  CAS  Google Scholar 

  270. Capela JP, Lautenschlager M, Dirnagl U, Bastos ML, Carvalho F, Meisel A (2008) 5,7-Dihydroxitryptamine toxicity to serotonergic neurons in serum free raphe cultures. Eur J Pharmacol 588:232–238

    PubMed  CAS  Google Scholar 

  271. Baumgarten HG, Bjorklund A (1976) Neurotoxic indoleamines and monoamine neurons. Annu Rev Pharmacol Toxicol 16:101–111

    PubMed  CAS  Google Scholar 

  272. Colado MI, Green AR (1995) The spin trap reagent a-phenyl-N-tert-butyl nitrone prevents “ecstasy”-induced neurodegeneration of 5-hydroxytryptamine neurons. Eur J Pharmacol 280:343–346

    PubMed  CAS  Google Scholar 

  273. Aguirre N, Ballaz S, Lasheras B, Del Río J (1998) MDMA (“ecstasy”) enhances 5-HT1a receptor density and 8-OH-DPAT-induced hypothermia: blockade by drugs preventing 5-hydroxytryptamine depletion. Eur J Pharmacol 346:181–188

    PubMed  CAS  Google Scholar 

  274. Scanzello CR, Hatzidimitriou G, Martello AL, Katz JL, Ricaurte GA (1993) Serotonergic recovery after (±)3,4-(methylenedioxy) methamphetamine injury: observations in rats. J Pharmacol Exp Ther 264:1484–1491

    PubMed  CAS  Google Scholar 

  275. Sabol KE, Lew R, Richards JB, Vosmer GL, Seiden LS (1996) Methylenedioxymethamphetamine-induced serotonin deficits are followed by partial recovery over a 52-week period. Part I: synaptosomal uptake and tissue concentrations. J Pharmacol Exp Ther 276:846–854

    PubMed  CAS  Google Scholar 

  276. Lew R, Sabol KE, Chou C, Vosmer GL, Richards J, Seiden LS (1996) Methylenedioxymethamphetamine-induced serotonin deficits are followed by partial recovery over a 52-week period. Part II: radioligand binding and autoradiography studies. J Pharmacol Exp Ther 276:855–865

    PubMed  CAS  Google Scholar 

  277. Kovács GG, Andó RD, Ádori C, Kirilly E, Benedek A, Palkovits M, Bagdy G (2007) Single dose of MDMA causes extensive decrement of serotoninergic fibre density without blockage of the fast axonal transport in dark agouti rat brain and spinal cord. Neuropathol Appl Neurobiol 33:193–203

    PubMed  Google Scholar 

  278. Wang X, Baumann MH, Xu H, Morales M, Rothman RB (2005) (±)-3,4-Methylenedioxymethamphetamine administration to rats does not decrease levels of the serotonin transporter protein or alter its distribution between endosomes and the plasma membrane. J Pharmacol Exp Ther 314:1002–1012

    PubMed  CAS  Google Scholar 

  279. Baumann MH, Wang X, Rothman RB (2007) 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings. Psychopharmacology 189:407–424

    PubMed  CAS  Google Scholar 

  280. Wang X, Baumann MH, Xu H, Rothman RB (2004) 3,4-Methylenedioxymethamphetamine (MDMA) administration to rats decreases brain tissue serotonin but not serotonin transporter protein and glial fibrillary acidic protein. Synapse 53:240–248

    PubMed  CAS  Google Scholar 

  281. Wang X, Baumann MH, Dersch CM, Rothman RB (2007) Restoration of 3,4-methylenedioxymethamphetamine-induced 5-HT depletion by the administration of l-5-hydroxytryptophan. Neuroscience 148:212–220

    PubMed  CAS  Google Scholar 

  282. Meyer JS, Grande M, Johnson K, Ali SF (2004) Neurotoxic effects of MDMA (“ecstasy”) administration to neonatal rats. Int J Dev Neurosci 22:261–271

    PubMed  CAS  Google Scholar 

  283. Tamburini I, Blandini F, Gesi M, Frenzilli G, Nigro M, Giusiani M, Paparelli A, Fornai F (2006) MDMA induces caspase-3 activation in the limbic system but not in striatum. Ann N Y Acad Sci 1074:377–381

    PubMed  CAS  Google Scholar 

  284. Jensen KF, Olin J, Haykal-Coates N, O’Callaghan J, Miller DB, de Olmos JS (1993) Mapping toxicant-induced nervous system damage with a cupric silver stain: a quantitative analysis of neural degeneration induced by 3,4-methylenedioxymethamphetamine. NIDA Res Monogr 136:133–149, discussion 150–154

    PubMed  CAS  Google Scholar 

  285. Hernandez-Rabaza V, Dominguez-Escriba L, Barcia JA, Rosel JF, Romero FJ, Garcia-Verdugo JM, Canales JJ (2006) Binge administration of 3,4-methylenedioxymethamphetamine (“ecstasy”) impairs the survival of neural precursors in adult rat dentate gyrus. Neuropharmacology 51:967–973

    PubMed  CAS  Google Scholar 

  286. Ádori C, Andó RD, Kovács GG, Bagdy G (2006) Damage of serotonergic axons and immunolocalization of Hsp27, Hsp72, and Hsp90 molecular chaperones after a single dose of MDMA administration in dark agouti rat: temporal, spatial, and cellular patterns. J Comp Neurol 497:251–269

    PubMed  Google Scholar 

  287. Stumm G, Schlegel J, Schafer T, Wurz C, Mennel H, Krieg J, Vedder H (1999) Amphetamines induce apoptosis and regulation of bcl-x splice variants in neocortical neurons. FASEB J 13:1065–1072

    PubMed  CAS  Google Scholar 

  288. Jimenez A, Jorda EG, Verdaguer E, Pubill D, Sureda FX, Canudas AM, Escubedo E, Camarasa J, Camins A, Pallas M (2004) Neurotoxicity of amphetamine derivatives is mediated by caspase pathway activation in rat cerebellar granule cells. Toxicol Appl Pharmacol 196:223–234

    PubMed  CAS  Google Scholar 

  289. Capela JP, Ruscher K, Lautenschlager M, Freyer D, Dirnagl U, Gaio AR, Bastos ML, Meisel A, Carvalho F (2006) Ecstasy-induced cell death in cortical neuronal cultures is serotonin 2a-receptor-dependent and potentiated under hyperthermia. Neuroscience 139:1069–1081

    PubMed  CAS  Google Scholar 

  290. Capela JP, Fernandes E, Remiao F, Bastos ML, Meisel A, Carvalho F (2007) Ecstasy induces apoptosis via 5-HT2a-receptor stimulation in cortical neurons. Neurotoxicology 28:868–875

    PubMed  CAS  Google Scholar 

  291. Aguirre N, Barrionuevo M, Ramirez MJ, Del Rio J, Lasheras B (1999) Alpha-lipoic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity. NeuroReport 10:3675–3680

    PubMed  CAS  Google Scholar 

  292. Pubill D, Canudas AM, Pallas M, Camins A, Camarasa J, Escubedo E (2003) Different glial response to methamphetamine and methylenedioxymethamphetamine-induced neurotoxicity. Naunyn Schmiedebergs Arch Pharmacol 367:490–499

    PubMed  CAS  Google Scholar 

  293. O’Callaghan JP, Miller DB (1994) Neurotoxicity profiles of substituted amphetamines in the C57BL/6J mouse. J Pharmacol Exp Ther 270:741–751

    PubMed  Google Scholar 

  294. Orio L, O’Shea E, Sanchez V, Pradillo JM, Escobedo I, Camarero J, Moro MA, Green AR, Colado MI (2004) 3,4-Methylenedioxymethamphetamine increases interleukin-1β levels and activates microglia in rat brain: studies on the relationship with acute hyperthermia and 5-HT depletion. J Neurochem 89:1445–1453

    PubMed  CAS  Google Scholar 

  295. Straiko MMW, Coolen LM, Zemlan FP, Gudelsky GA (2007) The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain. Neuroscience 144:223–231

    PubMed  CAS  Google Scholar 

  296. Bendotti C, Baldessari S, Pende M, Tarizzo G, Miari A, Presti ML, Mennini T, Samanin R (1994) Does GFAP mRNA and mitochondrial benzodiazepine receptor binding detect serotonergic neuronal degeneration in rat? Brain Res Bull 34:389–394

    PubMed  CAS  Google Scholar 

  297. Dugar A, Patanow C, O’Callaghan JP, Lakoski JM (1998) Immunohistochemical localization and quantification of glial fibrillary acidic protein and synaptosomal-associated protein (mol wt 25000) in the ageing hippocampus following administration of 5,7-dihydroxytryptamine. Neuroscience 85:123–133

    PubMed  CAS  Google Scholar 

  298. Rowland NE, Kalehua AN, Li BH, Semple-Rowland SL, Streit WJ (1993) Loss of serotonin uptake sites and immunoreactivity in rat cortex after dexfenfluramine occur without parallel glial cell reaction. Brain Res 624:35–43

    PubMed  CAS  Google Scholar 

  299. Williams MT, Brown CA, Skelton MR, Vinks AA, Vorhees CV (2004) Absorption and clearance of ±3,4-methylenedioxymethamphetamine from the plasma of neonatal rats. Neurotoxicol Teratol 26:849–856

    PubMed  CAS  Google Scholar 

  300. Colado MI, O'Shea E, Granados R, Misra A, Murray TK, Green AR (1997) A study of the neurotoxic effect of MDMA (“ecstasy”) on 5-HT neurones in the brains of mothers and neonates following administration of the drug during pregnancy. Br J Pharmacol 121:827–833

    PubMed  CAS  Google Scholar 

  301. Kelly PAT, Ritchie IM, Quate L, McBean DE, Olverman HJ (2002) Functional consequences of perinatal exposure to 3,4-methylenedioxymethamphetamine in rat brain. Br J Pharmacol 137:963–970

    PubMed  CAS  Google Scholar 

  302. Campbell NG, Koprich JB, Kanaan NM, Lipton JW (2006) Mdma administration to pregnant Sprague–Dawley rats results in its passage to the fetal compartment. Neurotoxicol Teratol 28:459–465

    PubMed  CAS  Google Scholar 

  303. Koprich JB, Chen E-Y, Kanaan NM, Campbell NG, Kordower JH, Lipton JW (2003) Prenatal 3,4-methylenedioxymethamphetamine (ecstasy) alters exploratory behavior, reduces monoamine metabolism, and increases forebrain tyrosine hydroxylase fiber density of juvenile rats. Neurotoxicol Teratol 25:509–517

    PubMed  CAS  Google Scholar 

  304. Galineau L, Belzung C, Kodas E, Bodard S, Guilloteau D, Chalon S (2005) Prenatal 3,4-methylenedioxymethamphetamine (ecstasy) exposure induces long-term alterations in the dopaminergic and serotonergic functions in the rat. Brain Res Dev Brain Res 154:165–176

    PubMed  CAS  Google Scholar 

  305. Koprich JB, Campbell NG, Lipton JW (2003) Neonatal 3,4-methylenedioxymethamphetamine (ecstasy) alters dopamine and serotonin neurochemistry and increases brain-derived neurotrophic factor in the forebrain and brainstem of the rat. Brain Res Dev Brain Res 147:177–182

    PubMed  CAS  Google Scholar 

  306. Broening HW, Morford LL, Inman-Wood SL, Fukumura M, Vorhees CV (2001) 3,4-Methylenedioxymethamphetamine (ecstasy)-induced learning and memory impairments depend on the age of exposure during early development. J Neurosci 21:3228–3235

    PubMed  CAS  Google Scholar 

  307. Crawford CA, Williams MT, Kohutek JL, Choi FY, Yoshida ST, McDougall SA, Vorhees CV (2006) Neonatal 3,4-methylenedioxymethamphetamine (MDMA) exposure alters neuronal protein kinase A activity, serotonin and dopamine content, and [35S]GTPgammaS binding in adult rats. Brain Res 1077:178–186

    PubMed  CAS  Google Scholar 

  308. Williams MT, Schaefer TL, Ehrman LA, Able JA, Gudelsky GA, Sah R, Vorhees CV (2005) 3,4-Methylenedioxymethamphetamine administration on postnatal day 11 in rats increases pituitary–adrenal output and reduces striatal and hippocampal serotonin without altering SERT activity. Brain Res 1039:97–107

    PubMed  CAS  Google Scholar 

  309. Meyer JS, Ali SF (2002) Serotonergic neurotoxicity of MDMA (ecstasy) in the developing rat brain. Ann NY Acad Sci 965:373–380

    Article  PubMed  CAS  Google Scholar 

  310. Dafters RI, Emily L (1998) Persistent loss of thermoregulation in the rat induced by 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”) but not by fenfluramine. Psychopharmacology 138:207–212

    PubMed  CAS  Google Scholar 

  311. Piper BJ, Meyer JS (2004) Memory deficit and reduced anxiety in young adult rats given repeated intermittent MDMA treatment during the periadolescent period. Pharmacol Biochem Behav 79:723–731

    PubMed  CAS  Google Scholar 

  312. Marston HM, Reid ME, Lawrence JA, Olverman HJ, Butcher SP (1999) Behavioural analysis of the acute and chronic effects of MDMA treatment in the rat. Psychopharmacology 144:67–76

    PubMed  CAS  Google Scholar 

  313. Sprague JE, Preston AS, Leifheit M, Woodside B (2003) Hippocampal serotonergic damage induced by MDMA (ecstasy): effects on spatial learning. Physiol Behav 79:281–287

    PubMed  CAS  Google Scholar 

  314. Cohen AM, Skelton RM, Schaefer TL, Gudelsky GA, Vorhees C, Williams MT (2005) Learning and memory after neonatal exposure to 3,4-methylenedioxymethamphetamine (ecstasy) in rats: interaction with exposure in adulthood. Synapse 57:148–159

    PubMed  CAS  Google Scholar 

  315. Able JA, Gudelsky GA, Vorhees CV, Williams MT (2006) 3,4-Methylenedioxymethamphetamine in adult rats produces deficits in path integration and spatial reference memory. Biol Psychiatry 59:1219–1226

    PubMed  CAS  Google Scholar 

  316. Slikker WJ, Ali SF, Scallet AC, Frith CH, Newport GD, Bailey JR (1988) Neurochemical and neurohistological alterations in the rat and monkey produced by orally administered methylenedioxymethamphetamine (MDMA). Toxicol Appl Pharmacol 96:448–457

    Google Scholar 

  317. Ricaurte GA, Forno LS, Wilson MA, DeLanney LE, Irwin I, Molliver ME, Langston JW (1988) 3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates. J Am Med Assoc 260:51–55

    CAS  Google Scholar 

  318. Ricaurte GA, Martello AL, Katz JL, Martello MB (1992) Lasting effects of (±)-3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons in nonhuman primates: neurochemical observations. J Pharmacol Exp Ther 261:616–622

    PubMed  CAS  Google Scholar 

  319. Insel TR, Battaglia G, Johannessen JN, Marra S, De Souza EB (1989) 3,4-Methylenedioxymethamphetamine (“ecstasy”) selectively destroys brain serotonin terminals in rhesus monkeys. J Pharmacol Exp Ther 249:713–720

    PubMed  CAS  Google Scholar 

  320. Hatzidimitriou G, McCann UD, Ricaurte GA (1999) Altered serotonin innervation patterns in the forebrain of monkeys treated with (±)3,4-methylenedioxymethamphetamine seven years previously: factors influencing abnormal recovery. J Neurosci 15:5096–5107

    Google Scholar 

  321. Ali SF, Newport GD, Scallet AC, Binienda Z, Ferguson SA, Bailey JR, Paule MG, Slikker JW (1993) Oral administration of 3,4-methylenedioxymethamphetamine (MDMA) produces selective serotonergic depletion in the nonhuman primate. Neurotoxicol Teratol 15:91–96

    PubMed  CAS  Google Scholar 

  322. Ricaurte GA, DeLanney LE, Irwin I, Langston JW (1988) Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration. Brain Res 446:165–168

    PubMed  CAS  Google Scholar 

  323. Ricaurte GA, Yuan J, McCann UD (2000) (±)3,4-Methylenedioxymethamphetamine (“ecstasy”)-induced serotonin neurotoxicity: studies in animals. Neuropsychobiology 42:5–10

    PubMed  CAS  Google Scholar 

  324. Mechan A, Yuan J, Hatzidimitriou G, Irvine RJ, McCann UD, Ricaurte GA (2005) Pharmacokinetic profile of single and repeated oral doses of MDMA in squirrel monkeys: relationship to lasting effects on brain serotonin neurons. Neuropsychopharmacology 31:339–350

    Google Scholar 

  325. Fantegrossi WE, Ciullo JR, Wakabayashi KT, De La Garza Ii R, Traynor JR, Woods JH (2008) A comparison of the physiological, behavioral, neurochemical and microglial effects of methamphetamine and 3,4-methylenedioxymethamphetamine in the mouse. Neuroscience 151:533–543

    PubMed  CAS  Google Scholar 

  326. Fornai F, Giorgi FS, Gesi M, Chen K, Alessri MG, Shih JC (2001) Biochemical effects of the monoamine neurotoxins DSP-4 and MDMA in specific brain regions of MAO-B-deficient mice. Synapse 39:213–221

    PubMed  CAS  Google Scholar 

  327. Taraska T, Finnegan KT (1997) Nitric oxide and the neurotoxic effects of methamphetamine and 3,4-methylenedioxymethamphetamine. J Pharmacol Exp Ther 280:941–947

    PubMed  CAS  Google Scholar 

  328. Izco M, Marchant I, Escobedo I, Peraile I, Delgado M, Higuera-Matas A, Olias O, Ambrosio E, O’Shea E, Colado MI (2007) Mice with decreased cerebral dopamine function following a neurotoxic dose of MDMA (3,4-methylenedioxymethamphetamine, “ecstasy”) exhibit increased ethanol consumption and preference. J Pharmacol Exp Ther 322:1003–1012

    PubMed  CAS  Google Scholar 

  329. Itzhak Y, Ali SF, Achat CN, Anderson KL (2003) Relevance of MDMA (“ecstasy”)-induced neurotoxicity to long-lasting psychomotor stimulation in mice. Psychopharmacology 166:241–248

    PubMed  CAS  Google Scholar 

  330. Fornai F, Lenzi P, Frenzilli G, Gesi M, Ferrucci M, Lazzeri G, Biagioni F, Nigro M, Falleni A, Giusiani M, Pellegrini A, Blandini F, Ruggieri S, Paparelli A (2004) DNA damage and ubiquitinated neuronal inclusions in the substantia nigra and striatum of mice following MDMA (ecstasy). Psychopharmacology 173:353–363

    PubMed  CAS  Google Scholar 

  331. Thomas DM, Dowgiert J, Geddes TJ, Francescutti-Verbeem D, Liu X, Kuhn DM (2004) Microglial activation is a pharmacologically specific marker for the neurotoxic amphetamines. Neurosci Lett 367:349–354

    PubMed  CAS  Google Scholar 

  332. Fornai F, Gesi M, Lenzi P, Ferrucci M, Pellegrini A, Ruggieri S, Casini A, Paparelli A (2002) Striatal postsynaptic ultrastructural alterations following methylenedioxymethamphetamine administration. Ann N Y Acad Sci 965:381–398

    Article  PubMed  CAS  Google Scholar 

  333. Fornai F, Lazzeri G, Lenzi P, Gesi M, Ferrucci M, Soldani P, Pellegrini A, Capobianco L, Blasi A, Ruggieri S, Paparelli A (2003) Amphetamines induce ubiquitin-positive inclusions within striatal cells. Neurol Sci 24:182–183

    PubMed  CAS  Google Scholar 

  334. Fornai F, Gesi M, Lenzi P, Ferrucci M, Lazzeri G, Pizzanelli C, Pellegrini A, Battaglia G, Ruggieri S, Paparelli A (2004) Effects of repeated low doses of MDMA on EEG activity and fluoro-jade B histochemistry. Ann NY Acad Sci 1025:181–188

    PubMed  CAS  Google Scholar 

  335. Frenzilli G, Ferrucci M, Giorgi FS, Blandini F, Nigro M, Ruggieri S, Murri L, Paparelli A, Fornai F (2007) DNA fragmentation and oxidative stress in the hippocampal formation: a bridge between 3,4-methylenedioxymethamphetamine (ecstasy) intake and long-lasting behavioral alterations. Behav Pharmacol 18:471–481

    PubMed  CAS  Google Scholar 

  336. Trigo J, Cabrero-Castel A, Berrendero F, Maldonado R, Robledo P (2008) MDMA modifies active avoidance learning and recall in mice. Psychopharmacology 197:391–400

    PubMed  CAS  Google Scholar 

  337. Busceti CL, Biagioni F, Riozzi B, Battaglia G, Storto M, Cinque C, Molinaro G, Gradini R, Caricasole A, Canudas AM, Bruno V, Nicoletti F, Fornai F (2008) Enhanced tau phosphorylation in the hippocampus of mice treated with 3,4-methylenedioxymethamphetamine (“ecstasy”). J. Neurosci. 28:3234–3245

    PubMed  CAS  Google Scholar 

  338. Renoir T, Païzanis E, Yacoubi ME, Saurini F, Hanoun N, Melfort M, Lesch KP, Hamon M, Lanfumey L (2008) Differential long-term effects of MDMA on the serotoninergic system and hippocampal cell proliferation in 5-HTt knock-out vs. wild-type mice. Int J Neuropsychopharmacol 11:1149–1162

    PubMed  CAS  Google Scholar 

  339. Easton N, Marsden CA (2006) Ecstasy: are animal data consistent between species and can they translate to humans. J Psychopharmacol 20:194–210

    PubMed  CAS  Google Scholar 

  340. Kish SJ, Furukawa Y, Ang L, Vorce SP, Kalasinsky KS (2000) Striatal serotonin is depleted in brain of a human MDMA (ecstasy) user. Neurology 55:294–296

    PubMed  CAS  Google Scholar 

  341. McCann U, Mertl M, Eligulashvili V, Ricaurte G (1999) Cognitive performance in 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) users: a controlled study. Psychopharmacology 143:417–425

    PubMed  CAS  Google Scholar 

  342. McCann UD, Ridenour A, Shaham Y, Ricaurte GA (1994) Serotonin neurotoxicity after (+/−)3,4-methylenedioxymethamphetamine (MDMA; “ecstasy”): a controlled study in humans. Neuropsychopharmacology 10:129–138

    PubMed  CAS  Google Scholar 

  343. Bolla KI, McCann UD, Ricaurte GA (1998) Memory impairment in abstinent MDMA (“ecstasy”) users. Neurology 51:1532–1537

    PubMed  CAS  Google Scholar 

  344. Cowan RL, Lyoo IK, Sung SM, Ahn KH, Kim MJ, Hwang J, Haga E, Vimal RLP, Lukas SE, Renshaw PF (2003) Reduced cortical gray matter density in human MDMA (ecstasy) users: a voxel-based morphometry study. Drug Alcohol Depend 72:225–235

    PubMed  CAS  Google Scholar 

  345. McCann UD, Szabo Z, Scheffel U, Dannals RF, Ricaurte GA (1998) Positron emission tomographic evidence of toxic effect of MDMA (“ecstasy”) on brain serotonin neurones in human beings. Lancet 352:1433–1437

    PubMed  CAS  Google Scholar 

  346. McCann UD, Szabo Z, Seckin E, Rosenblatt P, Mathews WB, Ravert HT, Dannals RF, Ricaurte GA (2005) Quantitative pet studies of the serotonin transporter in MDMA users and controls using [11C]McN5652 and [11C]DASB. Neuropsychopharmacology 30:1741–1750

    PubMed  CAS  Google Scholar 

  347. McCann UD, Szabo Z, Vranesic M, Palermo M, Mathews WB, Ravert HT, Dannals RF, Ricaurte GA (2008) Positron emission tomographic studies of brain dopamine and serotonin transporters in abstinent (±)3,4-methylenedioxymethamphetamine (“ecstasy”) users: Relationship to cognitive performance. Psychopharmacology 3:439–450

    Google Scholar 

  348. Buchert R, Thomasius R, Nebeling B, Petersen K, Obrocki J, Jenicke L, Wilke F, Wartberg L, Zapletalova P, Clausen M (2003) Long-term effects of “ecstasy” use on serotonin transporters of the brain investigated by PET. J Nucl Med 44:375–384

    PubMed  CAS  Google Scholar 

  349. Buchert R, Thomasius R, Wilke F, Petersen K, Nebeling B, Obrocki J, Schulze O, Schmidt U, Clausen M (2004) A voxel-based pet investigation of the long-term effects of “ecstasy” consumption on brain serotonin transporters. Am J Psychiatry 161:1181–1189

    PubMed  Google Scholar 

  350. Thomasius R, Zapletalova P, Petersen K, Buchert R, Andresen B, Wartberg L, Nebeling B, Schmoldt A (2006) Mood, cognition and serotonin transporter availability in current and former ecstasy (MDMA) users: the longitudinal perspective. J Psychopharmacol 20:211–225

    PubMed  CAS  Google Scholar 

  351. Reneman L, Booij J, de Bruin K, Reitsma JB, de Wolff FA, Gunning WB, den Heeten GJ, van den Brink W (2001) Effects of dose, sex, and long-term abstention from use on toxic effects of MDMA (ecstasy) on brain serotonin neurons. Lancet 358:1864–1869

    PubMed  CAS  Google Scholar 

  352. Semple DM, Ebmeier KP, Glabus MF, O’Carroll RE, Johnstone EC (1999) Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA (“ecstasy”) users. Br J Psychiatry 175:63–69

    PubMed  CAS  Google Scholar 

  353. Reneman L, Endert E, Bruin KD, Lavalaye J, Feenstra M, Wolff FD, Booij J (2002) The acute and chronic effects of MDMA (“ecstasy”) on cortical 5-HT2a receptors in rat and human brain. Neuropsychopharmacology 26:387–396

    PubMed  CAS  Google Scholar 

  354. Kish SJ (2002) How strong is the evidence that brain serotonin neurons are damaged in human users of ecstasy? Pharmacol Biochem Behav 71:845–855

    PubMed  CAS  Google Scholar 

  355. Reneman L, Booij J, Habraken JB, De Bruin K, Hatzidimitriou G, Den Heeten GJ, Ricaurte GA (2002) Validity of [123I]beta-CIT SPECT in detecting MDMA-induced serotonergic neurotoxicity. Synapse 46:199–205

    PubMed  CAS  Google Scholar 

  356. Veryheyden SL, Hadfield J, Calin T, Curran HV (2002) Sub-acute effects of MDMA (±3,4-methylenedioxymethamphetamine “ecstasy”) on mood: evidence of gender differences. Psychopharmacology 161:23–31

    Google Scholar 

  357. Rodgers J (2000) Cognitive performance amongst recreational users of “ecstasy”. Psychopharmacology 151:19–24

    PubMed  CAS  Google Scholar 

  358. Creighton FJ, Black DL, Hyde CE (1991) “Ecstasy” psychosis and flashbacks. Br J Psychiatry 159:713–715

    PubMed  CAS  Google Scholar 

  359. McGuire P (2000) Long-term psychiatric and cognitive effects of MDMA use. Toxicol Lett 112:153–156

    PubMed  Google Scholar 

  360. Gouzoulis-Mayfrank E, Thimm B, Rezk M, Hensen G, Daumann J (2003) Memory impairment suggests hippocampal dysfunction in abstinent ecstasy users. Prog Neuropsychopharmacol Biol Psychiatry 27:819–827

    PubMed  CAS  Google Scholar 

  361. Fox HC, McLean A, Turner JJ, Parrott AC, Rogers R, Sahakian BJ (2002) Neuropsychological evidence of a relatively selective profile of temporal dysfunction in drug-free MDMA (‘ecstasy’) polydrug users. Psychopharmacology 162:203–214

    PubMed  CAS  Google Scholar 

  362. Moeller FG, Steinberg JL, Dougherty DM, Narayana PA, Kramer LA, Renshaw PF (2004) Functional MRI study of working memory in MDMA users. Psychopharmacology 177:185–194

    PubMed  CAS  Google Scholar 

  363. Morgan M, McFie L, Fleetwood L, Robinson J (2002) Ecstasy (MDMA): are the psychological problems associated with its use reversed by prolonged abstinence. Psychopharmacology 159:294–303

    PubMed  CAS  Google Scholar 

  364. Quednow BB, Jessen F, Kuhn K-U, Maier W, Daum I, Wagner M (2006) Memory deficits in abstinent MDMA (ecstasy) users: neuropsychological evidence of frontal dysfunction. J Psychopharmacol 20:373–384

    PubMed  Google Scholar 

  365. Jacobsen LK, Mencl WE, Pugh KR, Skudlarski P, Krystal JH (2004) Preliminary evidence of hippocampal dysfunction in adolescent MDMA (“ecstasy”) users: possible relationship to neurotoxic effects. Psychopharmacology 173:383–390

    PubMed  CAS  Google Scholar 

  366. Daumann J, Fischermann T, Heekeren K, Henke K, Thron A, Gouzoulis-Mayfrank E (2005) Memory-related hippocampal dysfunction in poly-drug ecstasy (3,4-methylenedioxymethamphetamine) users. Psychopharmacology 180:607–611

    PubMed  CAS  Google Scholar 

  367. Schilt T, de Win MML, Koeter M, Jager G, Korf DJ, van den Brink W, Schmand B (2007) Cognition in novice ecstasy users with minimal exposure to other drugs: a prospective cohort study. Arch Gen Psychiatry 64:728–736

    PubMed  Google Scholar 

  368. Morgan MJ, Impallomeni LC, Pirona A, Rogers RD (2006) Elevated impulsivity and impaired decision-making in abstinent ecstasy (MDMA) users compared to polydrug and drug-naïve controls. Neuropsychopharmacology 31:1562–1573

    PubMed  CAS  Google Scholar 

  369. Butler GKL, Montgomery AMJ (2004) Impulsivity, risk taking and recreational “ecstasy” (MDMA) use. Drug Alcohol Depend 76:55–62

    PubMed  CAS  Google Scholar 

  370. Daumann J, Fischermann T, Heekeren K, Thron A, Gouzoulis-Mayfrank E (2004) Neural mechanisms of working memory in ecstasy (MDMA) users who continue or discontinue ecstasy and amphetamine use: evidence from an 18-month longitudinal functional magnetic resonance imaging study. Biol Psychiatry 56:349–355

    PubMed  CAS  Google Scholar 

  371. Reneman L, Booij J, Schmand B, Brink WVD, Gunning B (2000) Memory disturbances in “ecstasy” users are correlated with an altered brain serotonin neurotransmission. Psychopharmacology 148:322–324

    PubMed  CAS  Google Scholar 

  372. Lesch KP, Gutknecht L (2005) Pharmacogenetics of the serotonin transporter. Prog Neuropsychopharmacol Biol Psychiatry 29:1062–1073

    PubMed  CAS  Google Scholar 

  373. Roiser JP, Rogers RD, Cook LJ, Sahakian BJ (2006) The effect of polymorphism at the serotonin transporter gene on decision-making, memory and executive function in ecstasy users and controls. Psychopharmacology 188:213–227

    PubMed  CAS  Google Scholar 

  374. Roiser JP, Cook LJ, Cooper JD, Rubinsztein DC, Sahakian BJ (2005) Association of a functional polymorphism in the serotonin transporter gene with abnormal emotional processing in ecstasy users. Am J Psychiatry 162:609–612

    PubMed  Google Scholar 

  375. de Win MML, Schilt T, Reneman L, Vervaeke H, Jager G, Dijkink S, Booij J, van den Brink W (2006) Ecstasy use and self-reported depression, impulsivity, and sensation seeking: a prospective cohort study. J Psychopharmacol 20:226–235

    PubMed  Google Scholar 

  376. Jager G, de Win M, Vervaeke H, Schilt T, Kahn R, van den Brink W, van Ree J, Ramsey N (2007) Incidental use of ecstasy: no evidence for harmful effects on cognitive brain function in a prospective fMRI study. Psychopharmacology 193:403–414

    PubMed  CAS  Google Scholar 

  377. Dafters RI, Hoshi R, Talbot AC (2004) Contribution of cannabis and MDMA (“ecstasy”) to cognitive changes in long-term polydrug users. Psychopharmacology 173:405–410

    PubMed  CAS  Google Scholar 

  378. Gamma A, Buck A, Berthold T, Vollenweider FX (2001) No difference in brain activation during cognitive performance between ecstasy (3,4-methylenedioxymethamphetamine) users and control subjects: a [H2(15)O]-positron emission tomography study. J Clin Psychopharmacol 21:66–71

    PubMed  CAS  Google Scholar 

  379. O'Shea E, Escobedo I, Orio L, Sanchez V, Navarro M, Green AR, Colado MI (2005) Elevation of ambient room temperature has differential effects on MDMA-induced 5-HT and dopamine release in striatum and nucleus accumbens of rats. Neuropsychopharmacology 30:1312–1323

    PubMed  Google Scholar 

  380. Farfel GM, Seiden LS (1995) Role of hypothermia in the mechanism of protection against serotonergic toxicity. Experiments using 3,4-methylenedioxymethamphetamine, dizocilpine, CGS 19755 and NBQX. J Pharmacol Exp Ther 272:860–867

    PubMed  CAS  Google Scholar 

  381. Colado MI, Granados R, O’Shea E, Esteban B, Green AR (1998) Role of hyperthermia in the protective action of chlomethiazole against MDMA (“ecstasy”)-induced neurodegeneration, comparison with the novel NMDA channel blocker AR-R15896AR. Br J Pharmacol 124:479–484

    PubMed  CAS  Google Scholar 

  382. Farfel GM, Vosmer GL, Seiden LS (1992) The antagonist MK-801 protects against serotonin depletions induced by methamphetamine 3,4-methylenedioxymethamphetamine and p-chloroamphetamine. Brain Res 595:121–127

    PubMed  CAS  Google Scholar 

  383. Johnson M, Bush LG, Hanson GR, Gibb JW (1993) Effects of ritanserin on the 3,4-methylenedioxymethamphetamine-induced decrease in striatal serotonin concentration and on the increase in striatal neurotensin and dynorphin A concentrations. Biochem Pharmacol 46:770–772

    PubMed  CAS  Google Scholar 

  384. Stone DM, Johnson M, Hanson GR, Gibb JW (1988) Role of endogenous dopamine in the central serotonergic deficits induced by 3,4-methylenedioxymethamphetamine. J Pharmacol Exp Ther 247:79–87

    PubMed  CAS  Google Scholar 

  385. Colado MI, O'Shea E, Granados R, Murray TK, Green AR (1997) In vivo evidence for free radical involvement in the degeneration of rat brain 5-HT following administration of MDMA (“ecstasy”) and p-chloroamphetamine but not the degeneration following fenfluramine. Br J Pharmacol 121:889–900

    PubMed  CAS  Google Scholar 

  386. Colado MI, O'Shea E, Esteban B, Granados R, Green AR (1999) In vivo evidence against clomethiazole being neuroprotective against MDMA (“ecstasy”)-induced degeneration of rat brain 5-HT nerve terminals by a free radical scavenging mechanism. Neuropharmacology 38:307–314

    PubMed  CAS  Google Scholar 

  387. Gordon CJ, Fogelson L (1994) Metabolic and thermoregulatory responses of the rat maintained in acrylic or wire-screen cages: implications for pharmacological studies. Physiol Behav 56:73–79

    PubMed  CAS  Google Scholar 

  388. Nagatsu T (2004) Progress in monoamine oxidase (MAO) research in relation to genetic engineering. Neurotoxicology 25:11–20

    PubMed  CAS  Google Scholar 

  389. Alves E, Summavielle T, Alves CJ, Gomes-da-Silva J, Barata JC, Fernandes E, de Lourdes Bastos M, Tavares MA, Carvalho F (2007) Monoamine oxidase-B mediates ecstasy-induced neurotoxic effects to adolescent rat brain mitochondria. J. Neurosci. 27:10203–10210

    PubMed  CAS  Google Scholar 

  390. Sprague JE, Everman SL, Nichols DE (1998) An integrated hypothesis for the serotonergic axonal loss induced by 3,4-methylenedioxymethamphetamine. Neurotoxicology 19:427–441

    PubMed  CAS  Google Scholar 

  391. Sprague JE, Nichols DE (1995) The monoamine oxidase-B inhibitor l-deprenyl protects against 3,4-methylenedioxymethamphetamine-induced lipid peroxidation and long-term serotonergic deficits. J Pharmacol Exp Ther 273:667–673

    PubMed  CAS  Google Scholar 

  392. Marchitti SA, Deitrich RA, Vasiliou V (2007) Neurotoxicity and metabolism of the catecholamine-derived 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde: the role of aldehyde dehydrogenase. Pharmacol Rev 59:125–150

    PubMed  CAS  Google Scholar 

  393. Falk EM, Cook VJ, Nichols DE, Sprague JE (2002) An antisense oligonucleotide targeted at MAO-B attenuates rat striatal serotonergic neurotoxicity induced by MDMA. Pharmacol Biochem Behav 72:617–622

    PubMed  CAS  Google Scholar 

  394. Suliman HB, Carraway MS, Velsor LW, Day BJ, Ghio AJ, Piantadosi CA (2002) Rapid mtDNA deletion by oxidants in rat liver mitochondria after hemin exposure. Free Radic Biol Med 32:246–256

    PubMed  CAS  Google Scholar 

  395. Suliman HB, Carraway MS, Piantadosi CA (2003) Postlipopolysaccharide oxidative damage of mitochondrial DNA. Am J Respir Crit Care Med 167:570–579

    PubMed  Google Scholar 

  396. Alves E, Summavielle T, Alves CJ, Gomes-da-Silva J, Barata JC, Fernandes E, Bastos ML, Tavares MA, Carvalho F (2009) Ecstasy-induced oxidative stress to adolescent rat brain mitochondria in vivo: Influence of monoamine oxidase type A. Addict Biol. 14:185–193

    PubMed  CAS  Google Scholar 

  397. Fowler CJ, Tipton KF (1982) Deamination of 5-hydroxytryptamine by both forms of monoamine oxidase in the rat brain. J Neurochem 38:733–736

    PubMed  CAS  Google Scholar 

  398. Amato JL, Bankson MG, Yamamoto BK (2006) Prior exposure to chronic stress and MDMA potentiates mesoaccumbens dopamine release mediated by the 5-HT1b receptor. Neuropsychopharmacology 32:946–954

    PubMed  Google Scholar 

  399. Schmidt CJ, Black CK, Taylor VL (1990) Antagonism of the neurotoxicity due to a single administration of methylenedioxymethamphetamine. Eur J Pharmacol 181:59–70

    PubMed  CAS  Google Scholar 

  400. Shankaran M, Yamamoto BK, Gudelsky GA (1999) Mazindol attenuates the 3,4-methylenedioxymethamphetamine-induced formation of hydroxyl radicals and long-term depletion of serotonin in the striatum. J Neurochem 72:2516–2522

    PubMed  CAS  Google Scholar 

  401. Kanthasamy A, Sprague JE, Shotwell JR, Nichols DE (2002) Unilateral infusion of a dopamine transporter antisense into the substantia nigra protects against MDMA-induced serotonergic deficits in the ipsilateral striatum. Neuroscience 114:917–924

    PubMed  CAS  Google Scholar 

  402. Stone DM, Johnson M, Hanson GR, Gibb JW (1989) Acute inactivation of tryptophan hydroxylase by amphetamine analogs involves the oxidation of sulfhydryl sites. Eur J Pharmacol 7:93–97

    Google Scholar 

  403. Remião F, Rettori D, Han D, Carvalho F, Bastos ML, Cadenas E (2004) Leucoisoprenochrome-o-semiquinone formation in freshly isolated adult rat cardiomyocytes. Chem Res Toxicol 17:1584–1590

    PubMed  Google Scholar 

  404. Costa VM, Silva R, Ferreira LM, Branco PS, Carvalho F, Bastos ML, Carvalho RA, Carvalho M, Remião F (2007) Oxidation process of adrenaline in freshly isolated rat cardiomyocytes: formation of adrenochrome, quinoproteins and GSH-adduct. Chem Res Toxicol 20:1183–1191

    PubMed  CAS  Google Scholar 

  405. Bindoli A, Rigobello MP, Deeble DJ (1992) Biochemical and toxicological properties of the oxidation products of catecholamines. Free Radic Biol Med 13:391–405

    PubMed  CAS  Google Scholar 

  406. Remião F, Milhazes N, Borges F, Carvalho F, Bastos ML, Lemos-Amado F, Domingues P, Ferrer-Correia A (2003) Synthesis and analysis of aminochromes by HPLC-photodiode array. Adrenochrome evaluation in rat blood. Biomed Chromatogr 17:6–13

    PubMed  Google Scholar 

  407. Spencer JPE, Jenner P, Daniel SE, Lees AJ, Marsden DC, Halliwell B (1998) Conjugates of catecholamines with cysteine and GSH in Parkinson’s disease: possible mechanism of formation involving reactive oxygen species. J Neurochem 71:2112–2122

    Article  PubMed  CAS  Google Scholar 

  408. Spencer JPE, Whiteman M, Jenner P, Halliwel B (2002) Cysteinyl-conjugates of catecholamines induce cell damage, extensive DNA base modification and increases in caspase-3 activity in neurons. J Neurochem 81:122–129

    PubMed  CAS  Google Scholar 

  409. Yamamoto BK, Nash JF, Gudelsky GA (1995) Modulation of methylenedioxymethamphetamine-induced striatal dopamine release by the interaction between serotonin and gamma-aminobutyric acid in the substantia nigra. J Pharmacol Exp Ther 273:1063–1070

    PubMed  CAS  Google Scholar 

  410. Bankson MG, Yamamoto BK (2004) Serotonin-GABA interactions modulate MDMA-induced mesolimbic dopamine release. J Neurochem 91:852–859

    PubMed  CAS  Google Scholar 

  411. Breier JM, Bankson MG, Yamamoto BK (2006) l-Tyrosine contributes to (+)-3,4-methylenedioxymethamphetamine-induced serotonin depletions. J Neurosci 26:290–299

    PubMed  CAS  Google Scholar 

  412. Darvesh AS, Yamamoto BK, Gudelsky GA (2005) Evidence for the involvement of nitric oxide in 3,4-methylenedioxymethamphetamine-induced serotonin depletion in the rat brain. J Pharmacol Exp Ther 312:694–701

    PubMed  CAS  Google Scholar 

  413. Goñi-Allo B, Puerta E, Mathúna BO, Hervias I, Lasheras B, de la Torre R, Aguirre N (2008) On the role of tyrosine and peripheral metabolism in 3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity in rats. Neuropharmacology 54:885–900

    PubMed  Google Scholar 

  414. Shankaran M, Gudelsky GA (1998) Effect of 3,4-methylenedioxymethamphetamine (MDMA) on hippocampal dopamine and serotonin. Pharmacol Biochem Behav 61:361–366

    PubMed  CAS  Google Scholar 

  415. Yuan J, Cord BJ, McCann UD, Callahan BT, Ricaurte GA (2002) Effect of depleting vesicular and cytoplasmic dopamine on methylenedioxymethamphetamine neurotoxicity. J Neurochem 80:960–969

    PubMed  CAS  Google Scholar 

  416. Wrona MZ, Yang Z, McAdams M, O’Connor-Coates S, Dryhurst G (1995) Hydroxyl radical-mediated oxidation of serotonin: potential insights into the neurotoxicity of methamphetamine. Journal of Neurochemistry 64:1390–1400

    Article  PubMed  CAS  Google Scholar 

  417. Wrona MZ, Dryhurst G (1998) Oxidation of serotonin by superoxide radical: implications to neurodegenerative brain disorders. Chem Res Toxicol 11:639–650

    PubMed  CAS  Google Scholar 

  418. Jiang XR, Wrona MZ, Dryhurst G (1999) Tryptamine-4,5-dione, a putative endotoxic metabolite of the superoxide-mediated oxidation of serotonin, is a mitochondrial toxin: possible implications in neurodegenerative brain disorders. Chem Res Toxicol 12:429–436

    PubMed  CAS  Google Scholar 

  419. Rothman RB, Baumann MH (2003) Monoamine transporters and psychostimulant drugs. Eur J Pharmacol 479:23–40

    PubMed  CAS  Google Scholar 

  420. Jiang XR, Dryhurst G (2002) Inhibition of the α-ketoglutarate dehydrogenase and pyruvate dehydrogenase complexes by a putative aberrant metabolite of serotonin, tryptamine-4,5-dione. Chem Res Toxicol 15:1242–1247

    PubMed  CAS  Google Scholar 

  421. Wrona MZ, Dryhurst G (2001) A putative metabolite of serotonin, tryptamine-4,5-dione, is an irreversible inhibitor of tryptophan hydroxylase: possible relevance to the serotonergic neurotoxicity of methamphetamine. Chem Res Toxicol 14:1184–1192

    PubMed  CAS  Google Scholar 

  422. Johnson M, Mitros K, Stone DM, Zobrist R, Hanson GR, Gibb JW (1992) Effect of flunarizine and nimodipine on the decrease in tryptophan hydroxylase activity induced by methamphetamine and 3,4-methylenedioxymethamphetamine. J Pharmacol Exp Ther 261:586–591

    PubMed  CAS  Google Scholar 

  423. Bonkale WL, Austin MC (2008) 3,4-Methylenedioxymethamphetamine induces differential regulation of tryptophan hydroxylase 2 protein and mRNA levels in the rat dorsal raphe nucleus. Neuroscience 155:270–276

    PubMed  CAS  Google Scholar 

  424. Elayan I, Gibb JW, Hanson GR, Lim HK, Foltz RL, Johnson M (1993) Short-term effects of 2,4,5-trihydroxyamphetamine, 2,4,5-trihydroxymethamphetamine and 3,4-dihydroxymethamphetamine on central tryptophan hydroxylase activity. J Pharmacol Exp Ther 265:813–818

    PubMed  CAS  Google Scholar 

  425. Kuhn DM, Arthur RA Jr (1997) Molecular mechanism of the inactivation of tryptophan hydroxylase by nitric oxide: attack on critical sulfhydryls that spare the enzyme iron center. J Neurosci 17:7245–7251

    PubMed  CAS  Google Scholar 

  426. Hemeryck A, Belpaire FM (2002) Selective serotonin reuptake inhibitors and cytochrome p-450 mediated drug–drug interactions: an update. Curr Drug Metab 3:13–37

    PubMed  CAS  Google Scholar 

  427. Upreti VV, Eddington ND (2008) Fluoxetine pretreatment effects pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) in rat. J Pharm Sci 97:1593–1605

    PubMed  CAS  Google Scholar 

  428. Yamamoto Y, Tasaki T, Nakamura A, Iwata H, Kazusaka A, Gonzalez FJ, Fujita S (1998) Molecular basis of the Dark Agouti rat drug oxidation polymorphism: importance of CYP2D1 and CYP2D2. Pharmacogenetics 8:73–82

    PubMed  CAS  Google Scholar 

  429. Kawase A, Fujii A, Negoro M, Akai R, Ishikubo M, Komura H, Iwaki M (2008) Differences in cytochrome p450 and nuclear receptor mRNA levels in liver and small intestines between SD and DA rats. Drug Metab Pharmacokinet 23:196–206

    PubMed  CAS  Google Scholar 

  430. Ramamoorthy S, Giovanetti E, Qian Y, Blakely RD (1998) Phosphorylation and regulation of antidepressant-sensitive serotonin transporters. J Biol Chem 273:2458–2466

    PubMed  CAS  Google Scholar 

  431. Kramer HK, Poblete JC, Azmitia EC (1995) 3,4-Methylenedioxymethamphetamine (“ecstasy”) promotes the translocation of protein kinase C (PKC): requirement of viable serotonin nerve terminals. Brain Res 680:1–8

    PubMed  CAS  Google Scholar 

  432. Kramer HK, Poblete JC, Azmitia EC (1997) Activation of protein kinase C (PKC) by 3,4-methylenedioxymethamphetamine (MDMA) occurs through the stimulation of serotonin receptors and transporter. Neuropsychopharmacology 17:117–129

    PubMed  CAS  Google Scholar 

  433. Kramer HK, Poblete JC, Azmitia EC (1998) Characterization of the translocation of protein kinase C (PKC) by 3,4-methylenedioxymethamphetamine (MDMA/ecstasy) in synaptosomes: evidence for a presynaptic localization involving the serotonin transporter (SERT). Neuropsychopharmacology 19:265–277

    PubMed  CAS  Google Scholar 

  434. Yi J-H, Hazell AS (2006) Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochem Int 48:394–403

    PubMed  CAS  Google Scholar 

  435. Nash JF, Yamamoto BK (1992) Methamphetamine neurotoxicity and striatal glutamate release: comparison to 3, 4-methylenedioxymethamphetamine. Brain Res 581:237–243

    PubMed  CAS  Google Scholar 

  436. White SR, Duffy P, Kalivas PW (1994) Methylenedioxymethamphetamine depresses glutamate-evoked neuronal firing and increases extracellular levels of dopamine and serotonin in the nucleus accumbens in vivo. Neuroscience 62:41–50

    PubMed  CAS  Google Scholar 

  437. Obradovic T, Imel KM, White SR (1996) Methylenedioxymethamphetamine-induced inhibition of neuronal firing in the nucleus accumbens is mediated by both serotonin and dopamine. Neuroscience 74:469–481

    PubMed  CAS  Google Scholar 

  438. Chipana C, Torres I, Camarasa J, Pubill D, Escubedo E (2008) Memantine protects against amphetamine derivatives-induced neurotoxic damage in rodents. Neuropharmacology 54:1254–1263

    PubMed  CAS  Google Scholar 

  439. Kindlundh-Hogberg A, Blomqvist A, Malki R, Schioth H (2008) Extensive neuroadaptive changes in cortical gene-transcript expressions of the glutamate system in response to repeated intermittent MDMA administration in adolescent rats. BMC Neurosci 9:39

    PubMed  Google Scholar 

  440. Pannu R, Singh I (2006) Pharmacological strategies for the regulation of inducible nitric oxide synthase: neurodegenerative versus neuroprotective mechanisms. Neurochem Int 49:170–182

    PubMed  CAS  Google Scholar 

  441. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A 87:1620–1624

    PubMed  CAS  Google Scholar 

  442. Zheng Y, Laverty R (1998) Role of brain nitric oxide in (±)3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity in rats. Brain Res 795:257–263

    PubMed  CAS  Google Scholar 

  443. Globus M, Busto R, Lin B, Schnippering H, Ginsberg M (1995) Detection of free radical activity during transient global ischemia and recirculation: effects of intraischemic brain temperature modulation. J Neurochem 65:1250–1256

    Article  PubMed  CAS  Google Scholar 

  444. Kil H, Zhang J, Piantadosi C (1996) Brain temperature alters hydroxyl radical production during cerebral ischemia/reperfusion in rats. J Cereb Blood Flow Metab 16:100–106

    PubMed  CAS  Google Scholar 

  445. Itzhak Y, Anderson KL, Ali SF (2004) Differential response of nNOS knockout mice to MDMA (“ecstasy”)-and methamphetamine-induced psychomotor sensitization and neurotoxicity. Ann N Y Acad Sci 1025:119–128

    PubMed  CAS  Google Scholar 

  446. Itzhak Y, Gandia C, Huang PL, Ali SF (1998) Resistance of neuronal nitric oxide synthase-deficient mice to methamphetamineinduced dopaminergic neurotoxicity. J Pharmacol Exp Ther 284:1040–1047

    PubMed  CAS  Google Scholar 

  447. Itzhak Y, Ali SF (2006) Role of nitrergic system in behavioral and neurotoxic effects of amphetamine analogs. Pharmacol Ther 109:246–262

    PubMed  CAS  Google Scholar 

  448. Willins D, Deutch A, Roth B (1997) Serotonin 5-HT2a receptors are expressed on pyramidal cells and interneurons in the rat cortex. Synapse 27:79–82

    PubMed  CAS  Google Scholar 

  449. Xu T, Pandey SC (2000) Cellular localization of serotonin2A (5HT2a) receptors in the rat brain. Brain Res Bull 51:499–505

    PubMed  CAS  Google Scholar 

  450. O'Shea E, Sanchez V, Orio L, Escobedo I, Green AR, Colado MI (2005) 3,4-Methylenedioxymethamphetamine increases pro-interleukin-1β production and caspase-1 protease activity in frontal cortex, but not in hypothalamus, of dark agouti rats: role of interleukin-1β in neurotoxicity. Neuroscience 135:1095–1105

    PubMed  Google Scholar 

  451. Arai K, Ikegaya Y, Nakatani Y, Kudo I, Nishiyama N, Matsuki N (2001) Phospholipase A2 mediates ischemic injury in the hippocampus: a regional difference of neuronal vulnerability. Eur J Neurosci 13:2319–2323

    PubMed  CAS  Google Scholar 

  452. Azmitia E (2001) Modern views on an ancient chemical: serotonin effects on cell proliferation, maturation, and apoptosis. Brain Res Bull 56:413–424

    PubMed  CAS  Google Scholar 

  453. Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 21:106–115

    Google Scholar 

  454. Klisch J, Bode-Greuel KM, Horvath E, Klisch C, Els T (2003) Additive neuroprotective effect of ketanserin and ipsapirone on the hippocampal damage after transient forebrain ischemia in the Mongolian gerbil. Neurosci Lett 342:25–28

    PubMed  CAS  Google Scholar 

  455. Abekawa T, Ito K, Nakagawa S, Nakato Y, Koyama T (2008) Olanzapine and risperidone block a high dose of methamphetamine-induced schizophrenia-like behavioral abnormalities and accompanied apoptosis in the medial prefrontal cortex. Schizophr Res 101:84–94

    PubMed  Google Scholar 

  456. Esteban B, O'Shea E, Camarero J, Sanchez V, Green AR, Colado MI (2001) 3,4-Methylenedioxymethamphetamine induces monoamine release, but not toxicity, when administered centrally at a concentration occurring following a peripherally injected neurotoxic dose. Psychopharmacology 154:251–260

    PubMed  CAS  Google Scholar 

  457. Paris JM, Cunningham K (1992) Lack of serotonin neurotoxicity after intraraphe microinjection of (+)-3,4-methylenedioxymethamphetamine (MDMA). Brain Res Bull 28:115–119

    PubMed  CAS  Google Scholar 

  458. Monks TJ, Jones DC, Fengju B, Lau SS (2004) The role of metabolism in 3,4-methylenodioxyamphetamine 3,4-methylenodioxymethamphetamine (ecstasy) toxicity. Ther Drug Monit 26:132–136

    PubMed  CAS  Google Scholar 

  459. Erives GV, Lau SS, Monks TJ (2008) Accumulation of neurotoxic thioether metabolites of 3,4-({±})-methylenedioxymethamphetamine in rat brain. J Pharmacol Exp Ther 324:284–291

    PubMed  CAS  Google Scholar 

  460. Miller RT, Lau SS, Monks TJ (1996) Effects of intracerebroventricular administration of 5-(glutathion-S-yl)-α-methyldopamine on brain dopamine, serotonin, and norepinephrine concentrations in male Sprague–Dawley rats. Chem Res Toxicol 9:457–465

    PubMed  CAS  Google Scholar 

  461. McCann UD, Ricaurte GA (1991) Major metabolites of (±)3,4-methylenedioxyamphetamine (MDA) do not mediate its toxic effects on brain serotonin neurons. Brain Res 545:279–282

    PubMed  CAS  Google Scholar 

  462. Escobedo I, O’Shea E, Orio L, Sanchez V, Segura M, de la Torre R, Farre M, Green AR, Colado MI (2005) A comparative study on the acute and long-term effects of MDMA and 3,4-dihydroxymethamphetamine (HHMA) on brain monoamine levels after i.p. or striatal administration in mice. Br J Pharmacol 144:231–241

    PubMed  CAS  Google Scholar 

  463. Yeh SY, Hsu F-L (1991) The neurochemical and stimulatory effects of putative metabolites of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine in rats. Pharmacol Biochem Behav 39:787–790

    PubMed  CAS  Google Scholar 

  464. Miller RT, Lau SS, Monks TJ (1997) 2,5-Bis-(glutathion-S-yl)-α-methyldopamine, a putative metabolite of (±)-3,4-methylenedioxyamphetamine, decreases brain serotonin concentrations. Eur J Pharmacol 323:173–180

    PubMed  CAS  Google Scholar 

  465. Bai F, Lau SS, Monks TJ (1999) Glutathione and N-acetylcysteine conjugates of α-methyldopamine produce serotonergic neurotoxicity: possible role in methylenedioxyamphetamine-mediated neurotoxicity. Chem Res Toxicol 12:1150–1157

    PubMed  CAS  Google Scholar 

  466. Jones DC, Lau SS, Monks TJ (2004) Thioether metabolites of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine inhibit human serotonin transporter (hSERT) function and simultaneously stimulate dopamine uptake into hSERT-expressing SK-N-MC cells. J Pharmacol Exp Ther 311:298–306

    PubMed  CAS  Google Scholar 

  467. Macedo C, Branco P, Ferreira L, Lobo A, Capela JP, Fernandes E, Bastos MDL, Carvalho F (2007) Synthesis and cyclic voltammetry studies of 3,4-methylenedioxymethamphetamine (MDMA) main human metabolites. J Health Sci 53:31–42

    CAS  Google Scholar 

  468. Kleiner HE, Rivera MI, Pumford NR, Monks TJ, Lau SS (1998) Immunochemical detection of quinol-thioether derived covalent protein adducts. Chem Res Toxicol 11:1283–1290

    PubMed  CAS  Google Scholar 

  469. Miyazaki I, Asanuma M, Diaz-Corrales FJ, Fukuda M, Kitaichi K, Miyoshi K, Ogawa N (2006) Methamphetamine-induced dopaminergic neurotoxicity is regulated by quinone formation-related molecules. FASEB J 20:571–573

    PubMed  CAS  Google Scholar 

  470. Felim A, Urios A, Neudorffer A, Herrera G, Blanco M, Largeron M (2007) Bacterial plate assays and electrochemical methods: an efficient tandem for evaluating the ability of catechol-thioether metabolites of MDMA (“ecstasy”) to induce toxic effects through redox-cycling. Chem Res Toxicol 20:685–693

    PubMed  CAS  Google Scholar 

  471. Remião F, Carvalho M, Carmo H, Carvalho F, Bastos ML (2002) Cu2+-induced isoproterenol oxidation into isoprenochrome in adult rat calcium-tolerant cardiomyocytes. Chem Res Toxicol 15:861–869

    PubMed  Google Scholar 

  472. Patel NJ, Fullone JS, Anders MW (1993) Brain uptake of S-(1,2-dichlorovinyl) glutathione and S-(1,2-dichlorovinyl)-l-cysteine, the glutathione and cysteine S-conjugates of the neurotoxin dichloroacetylene. Brain Res Mol Brain Res 17:53–58

    PubMed  CAS  Google Scholar 

  473. del Amo EM, Urtti A, Yliperttula M (2008) Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2. Eur J Pharm Sci 35:161–174

    PubMed  CAS  Google Scholar 

  474. Li S, Whorton AR (2005) Identification of stereoselective transporters for S-nitroso-l-cysteine: role of LAT1 and LAT2 in biological activity of S-nitrosothiols. J Biol Chem 280:20102–20110

    PubMed  CAS  Google Scholar 

  475. Shen XM, Dryhurst G (1996) Further insights into the influence of l-cysteine on the oxidation chemistry of dopamine: reaction pathways of potential relevance to Parkinson’s disease. Chem Res Toxicol 9:751–763

    PubMed  CAS  Google Scholar 

  476. Wan F-J, Tung C-S, Shiah IS, Lin H-C (2006) Effects of [alpha]-phenyl-N-tert-butyl nitrone and N-acetylcysteine on hydroxyl radical formation and dopamine depletion in the rat striatum produced by d-amphetamine. Eur Neuropsychopharmacol 16:147–153

    PubMed  CAS  Google Scholar 

  477. Hart AM, Terenghi G, Kellerth JO, Wiberg M (2004) Sensory neuroprotection, mitochondrial preservation, and therapeutic potential of N-acetyl-cysteine after nerve injury. Neuroscience 125:91–101

    PubMed  CAS  Google Scholar 

  478. Hussain S, Slikker Jr W, Ali SF (1996) Role of metallothionein and other antioxidants in scavenging superoxide radicals and their possible role in neuroprotection. Neurochem Int 29:145–152

    PubMed  CAS  Google Scholar 

  479. Sekhon B, Sekhon C, Khan M, Patel SJ, Singh I, Singh AK (2003) N-acetyl cysteine protects against injury in a rat model of focal cerebral ischemia. Brain Res 971:1–8

    PubMed  CAS  Google Scholar 

  480. Gudelsky G (1996) Effect of ascorbate and cysteine on the 3,4-methylenedioxymethamphetamine-induced depletion of brain serotonin. J Neural Transm 103:1397–1404

    PubMed  CAS  Google Scholar 

  481. Shankaran M, Yamamoto BK, Gudelsky GA (2001) Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT. Synapse 40:55–64

    PubMed  CAS  Google Scholar 

  482. Alves E, Binienda Z, Carvalho F, Alves CJ, Fernandes E, de Lourdes Bastos M, Tavares MA, Summavielle T (2009) Acetyl-l-carnitine provides effective in vivo neuroprotection over 3,4-methylenedioximethamphetamine-induced mitochondrial neurotoxicity in the adolescent rat brain. Neuroscience 158:514–523

    PubMed  CAS  Google Scholar 

  483. Slot AJ, Wise DD, Deeley RG, Monks TJ, Cole SPC (2008) Modulation of human multidrug resistance protein (MRP) 1 (ABCC1) and MRP2 (ABCC2) transport activities by endogenous and exogenous glutathione-conjugated catechol metabolites. Drug Metab Dispos 36:552–560

    PubMed  CAS  Google Scholar 

  484. Ballatori N, Krance SM, Marchan R, Hammond CL (2009) Plasma membrane glutathione transporters and their roles in cell physiology and pathophysiology. Mol Aspects Med. doi:10.1016/j.mam.2008.08.004

  485. Costa VM, Ferreira LM, Branco PS, Carvalho F, Bastos ML, Carvalho RA, Carvalho M, Remião F (2009) Cross-functioning between the extraneuronal monoamine transporter and multidrug resistance protein 1 in the uptake of adrenaline and export of 5-(glutathion-S-yl)adrenaline in rat cardiomyocytes. Chem Res Toxicol 22:129–135

    PubMed  CAS  Google Scholar 

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Acknowledgments

J.P.C. acknowledges “Fundação para a Ciência e a Tecnologia” (FCT) Portugal for his post-doc grant (ref. SFRH/BPD/30776/2006).

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Authors and Affiliations

  1. REQUIMTE (Rede de Química e Tecnologia), Toxicology Department, Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha 164, 4099-030, Porto, Portugal

    João Paulo Capela, Helena Carmo, Fernando Remião, Maria Lourdes Bastos & Félix Carvalho

  2. Faculty of Health Sciences, University Fernando Pessoa, Rua Carlos da Maia 296, 4200-150, Porto, Portugal

    João Paulo Capela

  3. Department of Experimental Neurology and Center for Stroke Research, Charité-Universitätsmedizin, Charitéplatz 1, 10117, Berlin, Germany

    Andreas Meisel

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  1. João Paulo Capela
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  2. Helena Carmo
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  3. Fernando Remião
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  4. Maria Lourdes Bastos
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  5. Andreas Meisel
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  6. Félix Carvalho
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Correspondence to João Paulo Capela or Félix Carvalho.

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Capela, J.P., Carmo, H., Remião, F. et al. Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview. Mol Neurobiol 39, 210–271 (2009). https://doi.org/10.1007/s12035-009-8064-1

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  • DOI: https://doi.org/10.1007/s12035-009-8064-1

Keywords

  • Ecstasy
  • MDMA
  • Drug abuse
  • Hallucinogen
  • Neurotoxicity
  • Mechanism of neurodegeneration