Psychopharmacology

, Volume 197, Issue 2, pp 263–278 | Cite as

The relationship between core body temperature and 3,4-methylenedioxymethamphetamine metabolism in rats: implications for neurotoxicity

  • Beatriz Goni-Allo
  • Brian Ó Mathúna
  • Mireia Segura
  • Elena Puerta
  • Berta Lasheras
  • Rafael de la Torre
  • Norberto Aguirre
Original Investigation

Abstract

Rationale

A close relationship appears to exist between 3,4-methylenedioxymethamphetamine (MDMA)-induced changes in core body temperature and long-term serotonin (5-HT) loss.

Objective

We investigated whether changes in core body temperature affect MDMA metabolism.

Materials and methods

Male Wistar rats were treated with MDMA at ambient temperatures of 15, 21.5, or 30°C to prevent or exacerbate MDMA-induced hyperthermia. Plasma concentrations of MDMA and its main metabolites were determined for 6 h. Seven days later, animals were killed and brain indole content was measured.

Results

The administration of MDMA at 15°C blocked the hyperthermic response and long-term 5-HT depletion found in rats treated at 21.5°C. At 15°C, plasma concentrations of MDMA were significantly increased, whereas those of three of its main metabolites were reduced when compared to rats treated at 21.5°C. By contrast, hyperthermia and indole deficits were exacerbated in rats treated at 30°C. Noteworthy, plasma concentrations of MDMA metabolites were greatly enhanced in these animals. Instrastriatal perfusion of MDMA (100 μM for 5 h at 21°C) did not potentiate the long-term depletion of 5-HT after systemic MDMA. Furthermore, interfering in MDMA metabolism using the catechol-O-methyltransferase inhibitor entacapone potentiated the neurotoxicity of MDMA, indicating that metabolites that are substrates for this enzyme may contribute to neurotoxicity.

Conclusions

This is the first report showing a direct relationship between core body temperature and MDMA metabolism. This finding has implications on both the temperature dependence of the mechanism of MDMA neurotoxicity and human use, as hyperthermia is often associated with MDMA use in humans.

Keywords

4-Methylenedioxymethamphetamine (MDMA “Ecstasy”) 5-Hydroxytryptamine (5-HT serotonin) Hyperthermia Metabolism Neurotoxicity 

Notes

Acknowledgment

The authors would like to thank “Fundación para la Investigación Médica Aplicada” (FIMA) and Ministerio de Educación y Ciencia for a fellowship to B.G.-A. and E.P., respectively. This work was supported by grants from the Ministerio de Educación y Ciencia (SAF2005-07919-C02–02), Ministerio de Sanidad y Consumo (PNSD), and the Spanish Networks of Excellence (ISCIII, Red de Trastornos Adictivos, and Red CIEN).

References

  1. Aguirre N, Barrionuevo M, Ramírez MJ, Del Río J, Lasheras B (1999) α-Lipoic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity. NeuroReport 10:3675–3680PubMedCrossRefGoogle Scholar
  2. Bai F, Jones DC, Lau SS, Monks TJ (2001) Serotonergic neurotoxicity of 3,4-(+/−)-methylenedioxyamphetamine and 3,4-(+/−)-methylendioxymethamphetamine (ecstasy) is potentiated by inhibition of gamma-glutamyl transpeptidase. Chem Res Toxicol 14:863–870PubMedCrossRefGoogle Scholar
  3. Bai F, Lau SS, Monks TJ (1999) Glutathion and N-acetylcysteine conjugates of α-methyldopamine produce serotonergic neurotoxicity: possible role in methylenedioxyamphetamine-mediated neurotoxicity. Chem Res Toxicol 20:1150–1157CrossRefGoogle Scholar
  4. Bongiovanni R, Yamamoto BK, Simpson C, Jaskiw GE (2003) Pharmacokinetics of systemically administered tyrosine: a comparison of serum, brain tissue, and in vivo microdialysate levels in the rat. J Neurochem 87:310–317PubMedCrossRefGoogle Scholar
  5. Breier JM, Bankson MG, Yamamoto BK (2006) l-tyrosine contributes to (+)-3,4-methylenedioxymethamphetamine-induced serotonin depletions. J Neurosci 26:290–299PubMedCrossRefGoogle Scholar
  6. Broening HW, Bowyer JF, Slikker W Jr (1995) Age-dependent sensitivity of rats to the long-term effects of the serotonergic neurotoxicant (+/−) 3,4-methylenedioxymethamphetamine (MDMA) correlates with the magnitude of the MDMA-induced thermal response. J Pharmacol Exp Ther 275:325–333PubMedGoogle Scholar
  7. Che S, Johnson M, Hanson GR, Gibb JW (1995) Body temperature effect on methylenedioxymethamphetamine-induced acute decrease in tryptophan hydroxylase activity. Eur J Pharmacol 293:447–453PubMedCrossRefGoogle Scholar
  8. Colado MI, Esteban B, O, Shea E, Granados R, Green AR (1999) Studies on the neuroprotective effect of pentobarbitone on MDMA-induced neurodegeneration. Psychopharmacology 142:421–425PubMedCrossRefGoogle Scholar
  9. Colado MI, Granados R, O, Shea E, Esteban B, Green AR (1998) Role of hyperthermia in the protective action of clomethiazole against MDMA (‘ecstasy’)-induced neurodegeneration, comparison with the novel NMDA channel blocker AR-R15896AR. Br J Pharmacol 124:479–484PubMedCrossRefGoogle Scholar
  10. de la Torre R, Farre M (2004) Neurotoxicity of MDMA (ecstasy): the limitations of scaling from animals to humans. Trends Pharmacol Sci 25:505–508PubMedCrossRefGoogle Scholar
  11. de la Torre R, Farre M, Roset PN, Pizarro N, Abanades S, Segura M, Segura J, Cami J (2004) Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther Drug Monit 26:137–144PubMedCrossRefGoogle Scholar
  12. Easton N, Marsden CA (2006) Ecstasy: are animal data consistent between species and can they translate to humans? J Psychopharmacol 20:194–210PubMedCrossRefGoogle Scholar
  13. Esteban E, O, Shea E, Camarero J, Sanchez V, Green RA, 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 154:251–260PubMedCrossRefGoogle Scholar
  14. Farfel GM, Seiden LS (1995) Role of hypothermia in the mechanism of protection against serotonergic toxicity. I. Experiments using 3,4-methylenedioxymethamphetamine, dizocilpine, CGS 19755 and NBQX. J Pharmacol Exp Ther 272:860–867PubMedGoogle Scholar
  15. Forsberg MM, Huotari M, Savolainen J, Männistö PT (2005) The role of physicochemical properties of entacapone and tolcapone on their efficacy during local intrastriatal administration. Eur J Pharm Sci 24:503–511PubMedCrossRefGoogle Scholar
  16. Goni-Allo B, Ramos M, Hervias I, Lasheras B, Aguirre N (2006) Studies on striatal neurotoxicity caused by the 3,4-methylenedioxymethamphetamine/malonate combination: implications for serotonin/dopamine interactions. J Psychopharmacol 20:245–256PubMedCrossRefGoogle Scholar
  17. Goni-Allo B, Puerta E, Hervias I, Di Palma R, Ramos M, Lasheras B, Aguirre N (2007) Studies on the mechanisms underlying amiloride enhancement of 3,4-methylenedioxymethamphetamine-induced serotonin depletion in rats. Eur J Pharmacol 562:198–207PubMedCrossRefGoogle Scholar
  18. Green AR, Mechan AO, Elliott JM, O, Shea E, Colado MI (2003) The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev 55:463–508PubMedCrossRefGoogle Scholar
  19. Green AR, O’shea E, Colado MI (2004) A review of the mechanisms involved in the acute MDMA (ecstasy)-induced hyperthermic response. Eur J Pharmacol 500:3–13PubMedCrossRefGoogle Scholar
  20. Greene SL, Dargan PI, O, connor N, Jones AL, Kerins M (2003) Multiple toxicity from 3,4-methylenedioxymethamphetamine (“ecstasy”). Am J Emerg Med 21:121–124PubMedCrossRefGoogle Scholar
  21. Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59:1609–1623Google Scholar
  22. Hem A, Smith AJ, Solberg P (1998) Saphenous vein puncture for blood sampling of the mouse, rat, hamster, gerbil, guinea pig, ferret and mink. Lab Anim 32:364–368PubMedCrossRefGoogle Scholar
  23. Hervias I, Lasheras B, Aguirre N (2000) 2-Deoxy-d-glugose prevents and nicotinamide potentiates 3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity. J Neurochem 75:982–990PubMedCrossRefGoogle Scholar
  24. Hiramatsu M, Kumagai Y, Unger SE, Cho AK (1990) Metabolism of methylenedioxymethamphetamine: formation of dihydroxymethamphetamine and quinone identified as its glutathione adduct. J Pharmacol Exp Ther 254:521–528PubMedGoogle Scholar
  25. Johnson EA, O, Callaghan JP, Miller DB (2004) Brain concentrations of d-MDMA are increased after stress. Psychopharmacology 173:278–286PubMedCrossRefGoogle Scholar
  26. Jones DC, Duvauchelle C, Olsen CM, Lau SS, de la Torre R, Monks TJ (2005) Serotonergic neurotoxic metabolites of ecstasy identified in rat brain. J Pharmacol Exp Ther 313:422–431PubMedCrossRefGoogle Scholar
  27. 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 311:298–306PubMedCrossRefGoogle Scholar
  28. Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, Soares-da-Silva P (2002) Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase. J Med Chem 45:685–695PubMedCrossRefGoogle Scholar
  29. Lim HK, Foltz RL (1988) In vivo and in vitro metabolism of 3,4-(methylenedioxy)-methamphetamine in the rat: identification of metabolites using an ion trap detector. Chem Res Toxicol 1:370–378PubMedCrossRefGoogle Scholar
  30. 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 278:258–267PubMedGoogle Scholar
  31. Malberg JE, Seiden LS (1998) Small changes in ambient temperature cause large changes in 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin neurotoxicity and core body temperature in the rat. J Neurosci 18:5086–5094PubMedGoogle Scholar
  32. Mannisto PT, Kaakkola S (1999) Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 51:593–628PubMedGoogle Scholar
  33. Miller DB, O’Callaghan JP (2003) Elevated environmental temperature and methamphetamine neurotoxicity. Environ Res 92:48–53PubMedCrossRefGoogle Scholar
  34. Miller RT, Lau SS, Monks TJ (1997) 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine, a putative metabolite of (+/-)-3,4-methylenedioxyamphetamine, decreases brain serotonin concentrations. Eur J Pharmacol 323:173–180PubMedCrossRefGoogle Scholar
  35. Monks TJ, Jones DC, Bai F, Lau SS (2004) The role of metabolism in 3,4-(+)-methylenedioxyamphetamine and 3,4-(+)-methylenedioxymethamphetamine (ecstasy) toxicity. Ther Drug Monit 26:132–136PubMedCrossRefGoogle Scholar
  36. Morley KC, Li KM, Hunt GE, Mallet PE, McGregor IS (2004) Cannabinoids prevent the acute hyperthermia and partially protect against the 5-HT depleting effects of MDMA (“Ecstasy”) in rats. Neuropharmacology 46:954–965PubMedCrossRefGoogle Scholar
  37. Nash JF, Yamamoto BK (1992) Methamphetamine neurotoxicity and striatal glutamate release: comparison to 3,4-methylenedioxymethamphetamine. Brain Res 581:237–243PubMedCrossRefGoogle Scholar
  38. Nixdorf WL, Burrows KB, Gudelsky GA, Yamamoto BK (2001) Enhancement of 3,4-methylenedioxymethamphetamine neurotoxicity by the energy inhibitor malonate. J Neurochem 77:647–654PubMedCrossRefGoogle Scholar
  39. O’Shea E, Easton N, Fry JR, Green AR, Marsden CA (2002) Protection against 3,4-methylenedioxymethamphetamine-induced neurodegeneration produced by glutathione depletion in rats is mediated by attenuation of hyperthermia. J Neurochem 81:686–695PubMedCrossRefGoogle Scholar
  40. 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 148:778–785PubMedCrossRefGoogle Scholar
  41. Parrott AC (2004) MDMA (3,4-Methylenedioxymethamphetamine) or Ecstasy: the neuropsychobiological implications of taking it at dances and raves. Neuropsychobiology 50:329–335PubMedCrossRefGoogle Scholar
  42. Patel N, Kumagai Y, Unger SE, Fukuto JM, Cho AK (1991) Transformation of dopamine and α-methyl-dopamine by NG-108–15 cells: Formation of thiol adducts. Chem Res Toxicol 4:421–426PubMedCrossRefGoogle Scholar
  43. Paxinos G, Watson C (1997) The rat brain in sterotaxic coordinates. Academic, New YorkGoogle Scholar
  44. Pizarro N, Ortuno J, Farre M, Hernandez-Lopez C, Pujadas M, Llebaria A, Joglar J, Roset PN, Mas M, Segura J, Cami J, de la Torre R (2002) Determination of MDMA and its metabolites in blood and urine by gas chromatography-mass spectrometry and analysis of enantiomers by capillary electrophoresis. J Anal Toxicol 26:157–165PubMedGoogle Scholar
  45. Quinton MS, Yamamoto BK (2006) Causes and consequences of methamphetamine and MDMA toxicity. AAPS J 8:337–347CrossRefGoogle Scholar
  46. 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 18:412–416PubMedCrossRefGoogle Scholar
  47. Schmidt CJ, Black CK, Abbate GM, Taylor VL (1990) Methylenedioxymethamphetamine-induced hyperthermia and neurotoxicity are independently mediated by 5-HT2 receptors. Brain Res 529:85–90PubMedCrossRefGoogle Scholar
  48. Segura M, Ortuno J, Farre 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 14:1203–1208PubMedCrossRefGoogle Scholar
  49. 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 40:55–64PubMedCrossRefGoogle Scholar
  50. 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 305:159–166PubMedCrossRefGoogle Scholar
  51. Taraska T, Finnegan KT (1997) Nitric oxide and the neurotoxic effects of methamphetamine and 3,4-methylenedioxymethamphetamine. J Pharmacol Exp Ther 280:941–947PubMedGoogle Scholar
  52. Weir E (2000) Raves: a review of the culture, the drugs and the prevention of harm. CMAJ 162:1843–1848PubMedGoogle Scholar
  53. Yeh SY (1999) N-tert-butyl-alpha-phenylnitrone protects against 3,4-methylenedioxymethamphetamine-induced depletion of serotonin in rats. Synapse 31:169–177Google Scholar
  54. Yuan J, Cord BJ, McCann UD, Callahan BT, Ricaurte GA (2002) Effect of depleting vesicular and cytoplasmic dopamine on methylenedioxymethamphetamine Neurotoxicity. J Neurochem 80:960–969PubMedCrossRefGoogle Scholar
  55. Zheng Y, Laverty R (1998) Role of brain nitic oxide in (+/−)3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity in rats. Brain Res 795:257–263Google Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Beatriz Goni-Allo
    • 1
  • Brian Ó Mathúna
    • 2
    • 3
  • Mireia Segura
    • 2
    • 3
  • Elena Puerta
    • 1
  • Berta Lasheras
    • 1
  • Rafael de la Torre
    • 2
    • 3
  • Norberto Aguirre
    • 1
  1. 1.Department of PharmacologySchool of Medicine, University of NavarraPamplonaSpain
  2. 2.Pharmacology Research UnitInstitut Municipal d’Investigació Mèdica (IMIM)BarcelonaSpain
  3. 3.Universitat Pompeu FabraBarcelonaSpain

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