Skip to main content

Advertisement

SpringerLink
Log in

The role of the sympathetic nervous system and uncoupling proteins in the thermogenesis induced by 3,4-methylenedioxymethamphetamine

  • Guest Editor Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Body temperature regulation involves a homeostatic balance between heat production and dissipation. Sympathetic agents such as 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) can disrupt this balance and as a result produce an often life-threatening hyperthermia. The hyperthermia induced by MDMA appears to result from the activation of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-thyroid/adrenal axis. Norepinephrine release mediated by MDMA creates a double-edged sword of heat generation through activation of uncoupling protein (UCP3) along with α1- and β3-adrenoreceptors and loss of heat dissipation through SNS-mediated vasoconstriction. This review examines cellular mechanisms involved in MDMA-induced thermogenesis from UCP activation to vasoconstriction and how these mechanisms are related to other thermogenic conditions and potential treatment modalities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AR :

α1-Adrenoreceptor

BAT :

Brown adipose tissue

DNP :

Dinitrophenol

HPA :

Hypothalamic-pituitary-adrenal

HPT :

Hypothalamic-pituitary-thyroid

MDMA :

3,4-Methylenedioxymethamphetamine

MH :

Malignant hyperthermia

NMS :

Neuroleptic malignant syndrome

ROS :

Reactive oxidant species

SNS :

Sympathetic nervous system

UCP :

Uncoupling protein

References

  1. Farley C J (2000) Rave new world. Time 5:70–72

    Google Scholar 

  2. Green AR, Cross AJ, Goodwin GM (1995) Review of the pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”). Psychopharmacology (Berl) 119:247–260

    Google Scholar 

  3. 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 55:463–508

    Article  CAS  PubMed  Google Scholar 

  4. Brown C, Osterloh J (1987) Multiple severe complications from recreational ingestion of MDMA (‘ecstasy’). JAMA 258:780–781

    Article  CAS  PubMed  Google Scholar 

  5. Dowling GP, McDonough ET, Bost RO (1987) ‘Eve’ and ‘ecstasy’. A report of five deaths associated with the use of MDEA and MDMA. JAMA 257:1615–1617

    Article  CAS  PubMed  Google Scholar 

  6. Chadwick IS, Curry PD, Linsley A, Freemont AJ, Doran B (1991) Ecstasy, 3-4 methylenedioxymethamphetamine (MDMA), a fatality associated with coagulopathy and hyperthermia. J R Soc Med 84:371

    CAS  PubMed  Google Scholar 

  7. Campkin NT, Davies UM (1992) Another death from ecstacy. J R Soc Med 85:61

    CAS  Google Scholar 

  8. Henry JA (1992) Ecstasy and the dance of death. BMJ 305 5–6

    Google Scholar 

  9. Henry JA, Jeffreys KJ, Dawling S (1992) Toxicity and deaths from 3,4-methylenedioxymethamphetamine. Lancet 340 384–387

    Google Scholar 

  10. Barrett PJ, Taylor GT (1993) Ecstasy’ ingestion: a case report of severe complications. J R Soc Med 86:233–234

    CAS  PubMed  Google Scholar 

  11. Colado MI, Williams JL, Green AR (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

    CAS  PubMed  Google Scholar 

  12. Coore JR (1996) A fatal trip with ecstasy: a case of 3,4-methylenedioxymethamphetamine/3,4-methylenedioxyamphetamine toxicity. J R Soc Med 89:51P–52P

    CAS  PubMed  Google Scholar 

  13. Dar KJ, McBrien ME (1996) MDMA induced hyperthermia: report of a fatality and review of current therapy. Intensive Care Med 22:995–996

    Article  CAS  PubMed  Google Scholar 

  14. Demirkiran M, Jankovic J, Dean JM (1996) Ecstasy intoxication: an overlap between serotonin syndrome and neuroleptic malignant syndrome. Clin Neuropharmacol 19:157–164

    CAS  PubMed  Google Scholar 

  15. Dowsett R P (1996) Deaths attributed to “ecstasy” overdose. Med J Aust 164:700

    CAS  Google Scholar 

  16. Cooper AJ, Egleston CV (1997) Accidental ingestion of ecstasy by a toddler: unusual cause for convulsion in a febrile child. Emerg Med J 14:183–184

    CAS  Google Scholar 

  17. Gillman PK (1997) Ecstasy, serotonin syndrome and the treatment of hyperpyrexia. Med J Aust 167:109:111

    Google Scholar 

  18. Gowing LR, Henry-Edwards SM, Irvine RJ, Ali RL (2002) The health effects of ecstasy: a literature review. Drug Alcohol Rev 21:53–63

    Article  PubMed  Google Scholar 

  19. Charkoudian N (2003) Skin blood flow in adult human thermoregulation: how it works, when it does not, and why. Mayo Clin Proc 78:603–612

    PubMed  Google Scholar 

  20. Screaton GR, Singer M, Cairns HS, Thrasher A, Sarner M, Cohen SL (1992) Hyperpyrexia and rhabdomyolysis after MDMA (“ecstasy”) abuse. Lancet 339 677–678

    Google Scholar 

  21. Fahal IH, Sallomi DF, Yaqoob M, Bell GM (1992) Acute renal failure after ecstasy. BMJ 305:29

    CAS  Google Scholar 

  22. Mueller PD, Korey WS (1998) Death by “ecstasy”: the serotonin syndrome? Ann Emerg Med 32:377–380

    CAS  PubMed  Google Scholar 

  23. Schwartz RH, Miller NS (1997) MDMA (ecstasy) and the rave: a review. Pediatrics 100:705–788

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Simpson DL, Rumack BH (1981) Methylenedioxyamphetamine. Clinical description of overdose, death, and review of pharmacology. Arch Intern Med 141:1507–1509

    Article  CAS  PubMed  Google Scholar 

  26. Nimmo SM, Kennedy BW, Tullett WM, Blyth AS, Dougall JR (1993) Drug-induced hyperthermia. Anaesthesia 48:892–895

    CAS  PubMed  Google Scholar 

  27. Tainter ML, Stockton AB et al (1935) Dinitrophenol in the treatment of obesity. JAMA 105:332–337

    Google Scholar 

  28. Geiger JC (1933) A death from alpha-dinitrophenol poisoning. JAMA 101:1333

    Google Scholar 

  29. Poole FE, Haining RB (1934) Sudden death from dinitrophenol poisoning. JAMA 102:1141–1146

    CAS  Google Scholar 

  30. Tainter ML, Wood DA (1934) A case of fatal dinitrophenol poisoning. JAMA 102:1147–1149

    Google Scholar 

  31. Memon JA (1958) Tropical hazards associated with the use of pentachlorophenol. BMJ 11:1156–1158

    Google Scholar 

  32. Leftwich RB, Floro JF, Neal RA, Wood AJ (1982) Dinitrophenol poisoning: a diagnosis to consider in undiagnosed fever. South Med J 75:182–184

    CAS  PubMed  Google Scholar 

  33. Proudfoot AT (2003) Pentachlorophenol poisoning. Toxicol Rev 22:3–11

    CAS  PubMed  Google Scholar 

  34. Wood S, Rom WN, White GL Jr, Logan DC (1983) Pentachlorophenol poisoning. J Occup Med 25:527–530

    CAS  PubMed  Google Scholar 

  35. Gray RE, Gilliland RD, Smith EE, Lockard VG, Hume AS (1985) Pentachlorophenol intoxication: report of a fatal case, with comments on the clinical course and pathologic anatomy. Arch Environ Health 40:161–164

    CAS  PubMed  Google Scholar 

  36. Parascandola J (1974) Dinitrophenol and bioenergetics: an historical perspective. Mol Cell Biochem 5 (1–2):69–77

    Google Scholar 

  37. Wallace KB, Starkov AA (2000) Mitochondrial targets of drug toxicity. Annu Rev Pharmacol Toxicol 40:353–388

    Article  CAS  PubMed  Google Scholar 

  38. Watson JD, Ferguson C, Hinds CJ, Skinner R, Coakley JH (1993) Exertional heat stroke induced by amphetamine analogues. Does dantrolene have a place? Anaesthesia 48:1057–1060

    CAS  PubMed  Google Scholar 

  39. Mason MF, Wallace SM, Foerster E, Drummond W (1965) Pentachlorophenol poisoning: report of two cases. J Forensic Sci 10:136–147

    CAS  PubMed  Google Scholar 

  40. Denborough MA, Hopkinson KC (1997) Dantrolene and “ecstasy.” Med J Aust 166:165–166

    Google Scholar 

  41. 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

    Article  CAS  PubMed  Google Scholar 

  42. Schmidt CJ, Abbate GM, Black CK, Taylor VL (1990) Selective 5-hydroxytryptamine2 receptor antagonists protect against the neurotoxicity of methyldioxymethamphetamine in rats. J Pharmacol Exp Ther 255:478–483

    CAS  PubMed  Google Scholar 

  43. Stephenson CP, Hunt GE, Topple AN, McGregor IS (1999) The distribution of 3,4-methylenedioxymethamphetamine “ecstasy”-induced c-fos expression in rat brain. Neuroscience 92:1011–1023

    Google Scholar 

  44. Rothwell NJ (1994) CNS regulation of thermogenesis. Crit Rev Neurobiol 8:1–10

    CAS  PubMed  Google Scholar 

  45. Cox B, Lee TF (1980) Further evidence for a physiological role for hypothalamic dopamine in the thermoregulation in the rat. J Physiol (Lond) 300:1–17

    Google Scholar 

  46. Mallick BN, Jha SK, Islam F (2002) Presence of alpha-1 adrenoreceptors on thermosensitive neurons in the medial preoptico-anterior hypothalamic area in rats. Neuropharmacol 42:697–705

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  48. Nash JF, Meltzer HY, Gudelsky GA (1990) Effect of 3,4-methylenedioxymethamphetamine on 3,4-dihydroxyphenylalanine accumulation in the striatum and nucleus accumbens. J Neurochem 54:1062–1067

    CAS  PubMed  Google Scholar 

  49. Mechan AO, Esteban B, O’Shea E, Elliott 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

    CAS  PubMed  Google Scholar 

  50. McDaid J, Docherty JR (2001) Vascular actions of MDMA involve alpha1 and alpha2-adrenoceptors in the anaesthetized rat. Br J Pharmacol 133:429–437

    CAS  PubMed  Google Scholar 

  51. Steele TD, Nichols DE, Yim GKW (1987) Stereochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related amphetamine derivatives on inhibition of uptake of [3H]-monoamines into synaptosomes from different regions of rat brain. Biochem Pharmacol 36:2297–2303

    Article  CAS  PubMed  Google Scholar 

  52. Himms-Hagen J, Cerf J, Desautels M, Zaror-Behrens G (1978) Thermogenic mechanisms and their control. Experientia Suppl 32:119–134

    CAS  PubMed  Google Scholar 

  53. Lin CS, Klingenberg M (1980) Isolation of the uncoupling protein from brown adipose tissue mitochondria. FEBS Lett 113:299–303

    Article  CAS  PubMed  Google Scholar 

  54. Simon HB (1994) Hyperthermia and heatstroke. Hosp Pract (Off Ed) 29:65–68

    Google Scholar 

  55. Ricquier D, Lin C, Klingenberg M (1982) Isolation of the GDP binding protein from brown adipose tissue mitochondria of several animals and amino acid composition study in rat. Biochem Biophys Res Commun 106:582–589

    CAS  PubMed  Google Scholar 

  56. Smith RE, Horwitz BA (1969) Brown fat and thermogenesis. Physiol Rev 49:330–425

    CAS  PubMed  Google Scholar 

  57. Jezek P, Freisleben HJ (1994) Fatty acid binding site of the mitochondrial uncoupling protein. Demonstration of its existence by EPR spectroscopy of 5-DOXYL-stearic acid. FEBS Lett 343:22–26

    Article  CAS  PubMed  Google Scholar 

  58. Lowell BB, Bachman ES (2003) Beta-adrenergic receptors, diet-induced thermogenesis, and obesity. J Biol Chem 278:29385–29388

    Article  CAS  PubMed  Google Scholar 

  59. Zhao J, Cannon B, Nedergaard J (1997) Alpha1-Adrenergic stimulation potentiates the thermogenic action of beta3-adrenoreceptor-generated cAMP in brown fat cells. J Biol Chem 272:32847–32856

    Article  CAS  PubMed  Google Scholar 

  60. Nicholls P, Wenner CE (1972) Release of respiratory control by uncouplers: the question of stoichiometry. Arch Biochem Biophys 151:206–215

    CAS  PubMed  Google Scholar 

  61. Himms-Hagen J (1989) Brown adipose tissue thermogenesis and obesity. Prog Lipid Res 28:67–115

    Article  CAS  PubMed  Google Scholar 

  62. Brand MD, Chien LF, Ainscow EK, Rolfe DF, Porter RK (1994) The causes and functions of mitochondrial proton leak. Biochim Biophys Acta 1187:132–139

    Article  CAS  PubMed  Google Scholar 

  63. Rolfe DF, Brand MD (1996) Contribution of mitochondrial proton leak to skeletal muscle respiration and to standard metabolic rate. Am J Physiol 271:C1380–C1389

    CAS  PubMed  Google Scholar 

  64. Fleury C, Neverova M, Collins S, Raimbault S, Champigny O, Levi-Meyrueis C, Bouillaud F, Seldin MF, Surwit RS, Ricquier D, Warden CH (1997) Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet 15:269–372

    Article  CAS  PubMed  Google Scholar 

  65. Boss O, Samec S, Paoloni-Giacobino A, Rossier C, Dulloo A, Seydoux J, Muzzin P, Giacobino JP (1997) Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett 408:39–42

    Article  CAS  PubMed  Google Scholar 

  66. Vidal-Puig A, Solanes G, Grujic D, Flier JS, Lowell BB (1997) UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem Biophys Res Commun 235:79–82

    Article  CAS  PubMed  Google Scholar 

  67. Boss O, Hagen T, Lowell BB (2000) Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes 49:143–156

    CAS  PubMed  Google Scholar 

  68. Boss O, Samec S, Paoloni-Giacobino A, Rossier C, Dulloo A, Seydoux J, Muzzin P, Giacobino JP (1997) Tissue-dependent upregulation of rat uncoupling protein-2 expression in response to fasting or cold. FEBS Lett 412:111–114

    Article  PubMed  Google Scholar 

  69. Richard D, Rivest R, Huang Q, Bouillaud F, Sanchis D, Champigny O, Ricquier D (1998) Distribution of the uncoupling protein 2 mRNA in the mouse brain. J Comp Neurol 397:549–560

    Article  CAS  PubMed  Google Scholar 

  70. Hanak P, Jezek P (2001) Mitochondrial uncoupling proteins and phylogenesis-UCP4 as the ancestral uncoupling protein. FEBS Lett 495:137–141

    Article  CAS  PubMed  Google Scholar 

  71. Sanchis D, Fleury C, Chomiki N, Goubern M, Huang Q, Neverova M, Gregoire F, Easlick J, Raimbault S, Levi-Meyrueis C, Miroux B, Collins S, Seldin M, Richard D, Warden C, Bouillaud F, Ricquier D (1998) BMCP1, a novel mitochondrial carrier with high expression in the central nervous system of humans and rodents, and respiration uncoupling activity in recombinant yeast. J Biol Chem 273:34611–34615

    Article  CAS  PubMed  Google Scholar 

  72. Reitman ML, He Y, Gong DW (1999) Thyroid hormone and other regulators of uncoupling proteins. Int J Obes Relat Metab Disord 23 [Suppl 6]:S56–S59

  73. Acin A, Rodriguez M, Rique H, Canet E, Boutin JA, Galizzi JP (1999) Cloning and characterization of the 5’ flanking region of the human uncoupling protein 3 (UCP3) gene. Biochem Biophys Res Commun 258:278–283

    Article  CAS  PubMed  Google Scholar 

  74. Echtay KS, Murphy MP, Smith RA, Talbot DA, Brand MD (2002) Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. Studies using targeted antioxidants. J Biol Chem 277:47129–47135

    Article  CAS  PubMed  Google Scholar 

  75. Echtay KS, Esteves TC, Pakay JL, Jekabsons MB, Lambert AJ, Portero-Otin M, Pamplona R, Vidal-Puig AJ, Wang S, Roebuck SJ, Brand MD (2003) A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J 22:4103–4110

    Article  CAS  PubMed  Google Scholar 

  76. Murphy MP, Echtay KS, Blaikie FH, Asin-Cayuela J, Cocheme HM, Green K, Buckingham JA, Taylor ER, Hurrell F, Hughes G, Miwa S, Cooper CE, Svistunenko DA, Smith RA, Brand MD (2003) Superoxide activates uncoupling proteins by generating carbon-centered radicals and initiating lipid peroxidation: studies using a mitochondria-targeted spin trap derived from alpha-phenyl-N-tert-butylnitrone. J Biol Chem 278:48534–48545

    Article  CAS  PubMed  Google Scholar 

  77. Brand MD (1990) The proton leak across the mitochondrial inner membrane. Biochim Biophys Acta 1018:128–133

    Article  CAS  PubMed  Google Scholar 

  78. Himms-Hagen J (1970) Regulation of metabolic processes in brown adipose tissue in relation to nonshivering thermogenesis. Adv Enzyme Regul 8:131–151

    Article  CAS  PubMed  Google Scholar 

  79. Enerback S, Jacobsson A, Simpson EM, Guerra C, Yamashita H, Harper ME, Kozak LP (1997) Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387 90–94

    Google Scholar 

  80. Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning BS, Miroux B, Couplan E, Alves-Guerra MC, Goubern M, Surwit R, Bouillaud F, Richard D, Collins S, Ricquier D (2000) Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 26:435–439

    Article  CAS  PubMed  Google Scholar 

  81. Gong DW, Monemdjou S, Gavrilova O, Leon LR, Marcus-Samuels B, Chou CJ, Everett C, Kozak LP, Li C, Deng C, Harper ME, Reitman ML (2000) Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3. J Biol Chem 275:16251–16257

    Article  CAS  PubMed  Google Scholar 

  82. St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277:44784–44790

    Article  CAS  PubMed  Google Scholar 

  83. Mattiasson G, Shamloo M, Gido G, Mathi K, Tomasevic G, Yi S, Warden CH, Castilho RF, Melcher T, Gonzalez-Zulueta M, Nikolich K, Wieloch T (2003) Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 9:1062–1068

    Article  CAS  PubMed  Google Scholar 

  84. Stuart JA, Cadenas S, Jekabsons MB, Roussel D, Brand MD (2001) Mitochondrial proton leak and the uncoupling protein 1 homologues. Biochim Biophys Acta 1504:144–158

    Article  CAS  PubMed  Google Scholar 

  85. Mills EM, Xu D, Fergusson MM, Combs CA, Xu Y, Finkel T (2002) Regulation of cellular oncosis by uncoupling protein 2. J Biol Chem 277:27385–27392

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  87. Cunningham M (1997) Ecstasy-induced rhabdomyolysis and its role in the development of acute renal failure. Intensive Crit Care Nurs 13:216–223

    CAS  PubMed  Google Scholar 

  88. 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

    Article  CAS  PubMed  Google Scholar 

  89. Chan CB, MacDonald PE, Saleh MC, Johns DC, Marban E, Wheeler MB (1999) Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulin secretion from rat islets. Diabetes 48:1482–1486

    CAS  PubMed  Google Scholar 

  90. Chavin KD, Yang S, Lin HZ, Chatham J, Chacko VP, Hoek JB, Walajtys-Rode E, Rashid A, Chen CH, Huang CC, Wu TC, Lane MD, Diehl AM (1999) Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. J Biol Chem 274:5692–5700

    Article  CAS  PubMed  Google Scholar 

  91. Krauss S, Zhang CY, Scorrano L, Dalgaard LT, St-Pierre J, Grey ST, Lowell BB (2003) Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction. J Clin Invest 112:1831–1842

    Article  CAS  PubMed  Google Scholar 

  92. 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

    Article  CAS  PubMed  Google Scholar 

  93. Curtin NA, Clapham JC, Barclay CJ (2002) Excess recovery heat production by isolated muscles from mice overexpressing uncoupling protein-3. J Physiol (Lond) 542:231–235

    Google Scholar 

  94. Brown JM, Yamamoto BK (2003) Effects of amphetamines on mitochondrial function: role of free radicals and oxidative stress. Pharmacol Ther 99:45–53

    Article  CAS  PubMed  Google Scholar 

  95. Rusyniak DE, Tandy SL, Hekmatyar SK, Mills EM, Smith DJ, Bansal N, Sprague JE (2004) The role of mitochondrial uncoupling in 3,4-methylenedioxymethamphetamine mediated skeletal muscle hyperthermia and rhabdomyolysis. J Pharmacol Exp Ther (under review)

  96. Rusyniak DE, Scruggs SL, Kamendulis LM, Sprague JE, Klaunig JE (2004) The effects of ecstasy (MDMA) on rat liver bioenergetics. Acad Emer Med 11:723–729

    Article  Google Scholar 

  97. Zaninovich AA, Rebagliati I, Raices M, Ricci C, Hagmuller K (2003) Mitochondrial respiration in muscle and liver from cold-acclimated hypothyroid rats. J Appl Physiol 95:1584–1590

    CAS  PubMed  Google Scholar 

  98. 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

    Article  CAS  PubMed  Google Scholar 

  99. Stuerenburg HJ, Petersen K, Baumer T, Rosenkranz M, Buhmann C, Thomasius R (2002) Plasma concentrations of 5-HT, 5-HIAA, norepinephrine, epinephrine and dopamine in ecstasy users. Neuroendocrinol Lett 23:259–261

    CAS  PubMed  Google Scholar 

  100. Ribeiro MO, Carvalho SD, Schultz JJ, Chiellini G, Scanlan TS, Bianco AC, Brent GA (2001) Thyroid hormone-sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoform-specific. J Clin Invest 108:97–105

    Article  CAS  PubMed  Google Scholar 

  101. Ye JM, Clark MG, Colquhoun EQ (1995) Constant-pressure perfusion of rat hindlimb shows alpha- and beta-adrenergic stimulation of oxygen consumption. Am J Physiol 269:E960–E968

    CAS  PubMed  Google Scholar 

  102. McDaid J, Docherty JR (2001) Vascular actions of MDMA involve alpha1 and alpha2-adrenoceptors in the anaesthetized rat. Br J Pharmacol 133:429–437

    CAS  PubMed  Google Scholar 

  103. Pedersen NP Blessing WW (2001) Cutaneous vasoconstriction contributes to hyperthermia induced by 3,4-methylenedioxymethamphetamine (ecstasy) in conscious rabbits. J Neurosci 21:8648–8654

    CAS  PubMed  Google Scholar 

  104. Gong DW, He Y, Karas M, Reitman M (1997) Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta3-adrenergic agonists, and leptin. J Biol Chem 272:24129–24132

    Article  CAS  PubMed  Google Scholar 

  105. Nakamura Y, Nagase I, Asano A, Sasaki N, Yoshida T, Umekawa T, Sakane N, Saito M (2001) Beta 3-adrenergic agonist up-regulates uncoupling proteins 2 and 3 in skeletal muscle of the mouse. J Vet Med Sci 63:309–314

    Article  CAS  PubMed  Google Scholar 

  106. Martin WH, Tolley TK, Saffitz JE (1990) Autoradiographic delineation of skeletal muscle alpha 1-adrenergic receptor distribution. Am J Physiol 259:H1402–H1408

    CAS  PubMed  Google Scholar 

  107. Sillence MN, Moore NG, Pegg GG, Lindsay DB (1993) Ligand binding properties of putative beta 3-adrenoceptors compared in brown adipose tissue and in skeletal muscle membranes. Br J Pharmacol 109:1157–1163

    CAS  PubMed  Google Scholar 

  108. Ye JM, Clark MG, Colquhoun EQ (1995) Constant-pressure perfusion of rat hindlimb shows alpha- and beta-adrenergic stimulation of oxygen consumption. Am J Physiol 269:E960–E968

    CAS  PubMed  Google Scholar 

  109. Chamberlain PD, Jennings KH, Paul F, Cordell J, Berry A, Holmes SD, Park J, Chambers J, Sennitt MV, Stock MJ, Cawthorne MA, Young PW, Murphy GJ (1999) The tissue distribution of the human beta3-adrenoceptor studied using a monoclonal antibody: direct evidence of the beta3-adrenoceptor in human adipose tissue, atrium and skeletal muscle. Int J Obes Relat Metab Disord 23:1057–1065

    Article  CAS  PubMed  Google Scholar 

  110. De Matteis R, Arch JR, Petroni ML, Ferrari D, Cinti S, Stock MJ (2002) Immunohistochemical identification of the beta (3)-adrenoceptor in intact human adipocytes and ventricular myocardium: effect of obesity and treatment with ephedrine and caffeine. Int J Obes Relat Metab Disord 26:1442–1450

    Article  PubMed  Google Scholar 

  111. Yoshida T, Umekaw T, Kumamoto K, Sakane N, Kogure A, Kondo M, Wakabayashi Y, Kawada T, Nagase I, Masyuki S (1998) β3-adrenergic agonist induces a functionally active uncoupling protein in fat and slow-twitch muscle fibers. Am J Physiol 274:E469–E475

    CAS  PubMed  Google Scholar 

  112. Nagase I, Yoshida T, Kumamoto K, Umekawa T, Sakane N, Nikami H, Kawada T, Saito M (1996) Expression of uncoupling protein in skeletal muscle and white fat of obese mice treated with thermogenic β3-adrenergic agonist. J Clin Invest 97:2898–2904

    CAS  PubMed  Google Scholar 

  113. Morley JE, Shafer RB, Elson MK, Slag MF, Raleigh MJ, Brammer GL, Yuwiler A, Hershman JM (1980) Amphetamine-induced hyperthyroxinemia. Ann Intern Med 93:707–709

    CAS  PubMed  Google Scholar 

  114. Lanni A, Beneduce L, Lombardi A, Moreno M, Boss O, Muzzin P, Giacobino JP, Goglia F (1999) Expression of uncoupling protein-3 and mitochondrial activity in the transition from hypothyroid to hyperthyroid state in rat skeletal muscle. FEBS Lett 444:250–254

    Article  CAS  PubMed  Google Scholar 

  115. Lanni A, Moreno M, Lombardi A, Goglia F (2003) Thyroid hormone and uncoupling proteins. FEBS Lett 543:5–10

    Article  CAS  PubMed  Google Scholar 

  116. Cunningham O, McElligott AM, Carroll AM, Breen E, Reguenga C, Oliveira ME, Azevedo JE, Porter RK (2003) Selective detection of UCP 3 expression in skeletal muscle: effect of thyroid status and temperature acclimation. Biochim Biophys Acta 1604:170–179

    Article  CAS  PubMed  Google Scholar 

  117. Rubio A, Raasmaja A, Maia AL, Kim KR, Silva JE (1995) Effects of thyroid hormone on norepinephrine signaling in brown adipose tissue. I. Beta 1- and beta 2-adrenergic receptors and cyclic adenosine 3’,5’-monophosphate generation. Endocrinol 136:3267–3276

    Article  CAS  Google Scholar 

  118. Dolfini E, Kobayashi M (1967) Studies with amphetamine in hyper-and hypothyroid rats. Eur J Pharmacol 2:65–66

    Article  CAS  PubMed  Google Scholar 

  119. Halpern BN, Drudi-Baracoo C, Bessirard D (1964) Exahtation of toxicity of sympathomimetic amines by thyroxine. Nature 204:387–388

    CAS  PubMed  Google Scholar 

  120. Sprague JE, Mallett NM, Rusyniak DE, Mills EM (2004) UCP3 and thyroid hormone involvement in methamphetamine-induced hyperthermia. Eur J Pharmacol 68:1339–1343

    Article  CAS  Google Scholar 

  121. Garlid KD, Orosz DE, Modriansky M, Vassanelli S, Jezek P (1996) On the mechanism of fatty acid-induced proton transport by mitochondrial uncoupling protein. J Biol Chem 217:2615–2620

    Google Scholar 

  122. Roberts JR, Hedges JR (1998) Clinical procedures in emergency medicine, 3rd edn. Saunders, Philadelphia

  123. 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

    CAS  PubMed  Google Scholar 

  124. Baldessarini RJ, Frankenburg FR (1991) Clozapine. A novel antipsychotic agent. N Engl J Med 324:746–754

    CAS  PubMed  Google Scholar 

  125. Mechan AO, Esteban B, O’Shea E, Elliott 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

    CAS  PubMed  Google Scholar 

  126. Nash JF, Meltzer HY, Gudelsky GA (1990) Effect of 3,4-methylenedioxymethamphetamine on 3,4-dihydroxyphenylalanine accumulation in the striatum and nucleus accumbens. J Neurochem 54:1062–1067

    CAS  PubMed  Google Scholar 

  127. Blessing WW, Seaman B (2003) 5-Hydroxytryptamine (2A) receptors regulate sympathetic nerves constricting the cutaneous vascular bed in rabbits and rats. Neuroscience 117:939–948

    Google Scholar 

  128. Ginsberg MD, Hertzman M, Schmidt-Nowara WW (1970) Amphetamine intoxication with coagulopathy, hyperthermia, and reversible renal failure. A syndrome resembling heatstroke. Ann Intern Med 73:81–85

    CAS  PubMed  Google Scholar 

  129. Kendrick WC, Hull AR, Knochel JP (1977) Rhabdomyolysis and shock after intravenous amphetamine administration. Ann Intern Med 86:381–387

    CAS  PubMed  Google Scholar 

  130. Roberts JR, Quattrocchi E, Howland MA (1984) Severe hyperthermia secondary to intravenous drug abuse. Am J Emerg Med 2:373

    Article  CAS  PubMed  Google Scholar 

  131. Callaway CW, Clark RF (1994) Hyperthermia in psychostimulant overdose. Ann Emerg Med 24:68–76

    CAS  PubMed  Google Scholar 

  132. Vogel WH, Miller J, DeTurck KH, Routzahn BK Jr (1984) Effects of psychoactive drugs on plasma catecholamines during stress in rats. Neuropharmacology 23:1105–1108

    Article  CAS  PubMed  Google Scholar 

  133. Sofuoglu M, Nelson D, Babb DA, Hatsukami DK (2001) Intravenous cocaine increases plasma epinephrine and norepinephrine in humans. Pharmacol Biochem Behav 68:455–459

    Article  CAS  PubMed  Google Scholar 

  134. Makisumi T, Yoshida K, Watanabe T, Tan N, Murakami N, Morimoto A (1998) Sympatho-adrenal involvement in methamphetamine-induced hyperthermia through skeletal muscle hypermetabolism. Eur J Pharmacol 363:107–112

    Article  CAS  PubMed  Google Scholar 

  135. Chiueh CC, Kopin IJ (1978) Centrally mediated release by cocaine of endogenous epinephrine and norepinephrine from the sympathoadrenal medullary system of unanesthetized rats. J Pharmacol Exp Ther 205:148–154

    CAS  PubMed  Google Scholar 

  136. Swerdlow NR, Koob GF, Cador M, Lorang M, Hauger RL (1993) Pituitary-adrenal axis responses to acute amphetamine in the rat. Pharmacol Biochem Behav 45:629–637

    Article  CAS  PubMed  Google Scholar 

  137. Mueller PD, Korey WS (1998) Death by “ecstasy”: the serotonin syndrome? Ann Emerg Med 32:377–380

    CAS  PubMed  Google Scholar 

  138. Mills KC (1997) Serotonin syndrome. A clinical update. Crit Care Clin 13:763–783

    CAS  PubMed  Google Scholar 

  139. Neuvonen PJ, Pohjola-Sintonen S, Tacke U, Vuori E (1993) Five fatal cases of serotonin syndrome after moclobemide-citalopram or moclobemide-clomipramine overdoses. Lancet 342:1419

    Article  CAS  Google Scholar 

  140. Mason PJ, Morris VA, Balcezak TJ (2000) Serotonin syndrome. Presentation of 2 cases and review of the literature. Medicine (Baltimore) 79:201–209

    Google Scholar 

  141. Nisijima K, Yoshino T, Ishiguro T (2000) Risperidone counteracts lethality in an animal model of the serotonin syndrome. Psychopharmacology (Berl) 150:9–14

    Google Scholar 

  142. Nisijima K, Shioda K, Yoshino T, Takano K, Kato S (2003) Diazepam and chlormethiazole attenuate the development of hyperthermia in an animal model of the serotonin syndrome. Neurochem Int 43:155–164

    Article  CAS  PubMed  Google Scholar 

  143. Nisijima K (2000) Abnormal monoamine metabolism in cerebrospinal fluid in a case of serotonin syndrome. J Clin Psychopharmacol 20:107–108

    Article  CAS  PubMed  Google Scholar 

  144. Nisijima K, Nibuya M, Sugiyama H (2003) Abnormal CSF monoamine metabolism in serotonin syndrome. J Clin Psychopharmacol 23:528–531

    Article  PubMed  Google Scholar 

  145. Welch JE, Saphier D (1994) Central and peripheral mechanisms in the stimulation of adrenocortical secretion by the 5-hydroxytryptamine2 agonist (+-)-1-(2:5-dimethoxy-4-iodophenyl)-2-aminopropane. J Pharmacol Exp Ther 270:918–928

    CAS  PubMed  Google Scholar 

  146. Kaus SJ, Rockoff MA (1994) Malignant hyperthermia. Pediatr Clin North Am 41:221–237

    CAS  PubMed  Google Scholar 

  147. Haggendal J, Jonsson L, Carlsten J (1990) The role of sympathetic activity in initiating malignant hyperthermia. Acta Anaesthesiol Scand 34:677–682

    CAS  PubMed  Google Scholar 

  148. Williams CH, Dozier SE, Buzello W, Gehrke CW, Wong JK, Gerhardt KO (1985) Plasma levels of norepinephrine and epinephrine during malignant hyperthermia in susceptible pigs. J Chromatogr 344:71–80

    Article  CAS  PubMed  Google Scholar 

  149. Lister D, Hall GM, Lucke JN (1976) Porcine malignant hyperthermia. III. Adrenergic blockade. Br J Anaesth 48:831–838

    CAS  PubMed  Google Scholar 

  150. Gerdes C, Richter A, Annies R, Loscher W (1992) Increase of serotonin in plasma during onset of halothane-induced malignant hyperthermia in pigs. Eur J Pharmacol 220:91–94

    Article  CAS  PubMed  Google Scholar 

  151. Loscher W, Witte U, Fredow G, Ganter M, Bickhardt K (1990) Pharmacodynamic effects of serotonin (5-HT) receptor ligands in pigs: stimulation of 5-HT2 receptors induces malignant hyperthermia. Naunyn Schmiedebergs Arch Pharmacol 341:483–493

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  153. Gerbershagen MU, Wappler F, Fiege M, Kolodzie K, Weisshorn R, Szafarczyk W, Kudlik C, Schulte Am Esch J (2003) Effects of a 5HT (2) receptor agonist on anaesthetized pigs susceptible to malignant hyperthermia. Br J Anaesth 91:281–284

    Article  CAS  PubMed  Google Scholar 

  154. Loscher W, Gerdes C, Richter A (1994) Lack of prophylactic or therapeutic efficacy of 5-HT2A receptor antagonists in halothane-induced porcine malignant hyperthermia. Naunyn Schmiedebergs Arch Pharmacol 350:365–374

    CAS  PubMed  Google Scholar 

  155. Lucke JN, Denny H, Hall GM, Lovell R, Lister D (1978) Porcine malignant hyperthermia. VI. The effects of bilateral adrenalectomy and pretreatment with bretylium on the halothane-induced response. Br J Anaesth 50:241–246

    CAS  PubMed  Google Scholar 

  156. Maccani RM, Wedel DJ, Hofer RE (1996) Norepinephrine does not potentiate porcine malignant hyperthermia. Anesth Analg 82:790–795

    Article  CAS  PubMed  Google Scholar 

  157. Nierenberg D, Disch M, Manheimer E, Patterson J, Ross J, Silvestri G, Summerhill E (1991) Facilitating prompt diagnosis and treatment of the neuroleptic malignant syndrome. Clin Pharmacol Ther 50:580–586

    CAS  PubMed  Google Scholar 

  158. Henderson VW, Wooten GF (1981) Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockade? Neurology 31:132–137

    CAS  PubMed  Google Scholar 

  159. Gurrera RJ (1999) Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry 156:169–180

    CAS  PubMed  Google Scholar 

  160. Feibel JH, Schiffer RB (1981) Sympathoadrenomedullary hyperactivity in the neuroleptic malignant syndrome: a case report. Am J Psychiatry 138:1115–1116

    CAS  PubMed  Google Scholar 

  161. Nisijima K, Ishiguro T (1995) Cerebrospinal fluid levels of monoamine metabolites and gamma-aminobutyric acid in neuroleptic malignant syndrome. J Psychiatr Res 29:233–244

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892-1770, USA

    Edward M. Mills

  2. School of Medicine, Indiana University, Indianapolis, IN 46202, USA

    Daniel E. Rusyniak

  3. Edward Via Virginia College of Osteopathic Medicine and Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, 2265 Kraft Drive, Blacksburg, VA 24060, USA

    Jon E. Sprague

Authors
  1. Edward M. Mills
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel E. Rusyniak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jon E. Sprague
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jon E. Sprague.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mills, E.M., Rusyniak, D.E. & Sprague, J.E. The role of the sympathetic nervous system and uncoupling proteins in the thermogenesis induced by 3,4-methylenedioxymethamphetamine. J Mol Med 82, 787–799 (2004). https://doi.org/10.1007/s00109-004-0591-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-004-0591-7

Keywords

Search

Navigation