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The effect of long-term repeated exposure to 3,4-methylenedioxymethamphetamine on cardiovascular and thermoregulatory changes

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Abstract

Rationale

3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) disrupts thermoregulation in rats and can lead to life-threatening hyperthermia in humans. MDMA administration can also lead to long-term neurotoxicity in animals and possibly humans.

Objectives

The purpose of the current study was to extend previous results on the acute effects of MDMA on behavioral thermoregulation to a repeated dosing regime, simulating regular weekend use of ecstasy, on measures of thermoregulation and heart rate (HR).

Materials and methods

Sprague–Dawley rats with telemetry implants were administered 40 μmol/kg MDMA on three consecutive days each week for 1 or 6 weeks before being confined to an elevated ambient temperature (T A) (HOT; 30 ± 1°C) or an area at room temperature (ROOM; 21.5 ± 1.5°C) for 30 min. After the final drug administration, rats were placed in a thermal gradient for 4 h to allow behavioral thermoregulation.

Results

HOT rats showed higher core temperature (T C), HR, and locomotor activity than ROOM rats during confinement to a set T A (P < 0.001). HR responses to MDMA over 6 weeks at both T As progressively decreased with repeated dosing (P < 0.05). T C was significantly higher in both 6-week groups compared to the 1-week groups (P < 0.05) at the end of time in the gradient. Cortical concentrations of dihydroxyphenylacetic acid (DOPAC; P < 0.05) and 5-hydroxyindole acetic acid (5-HIAA; P < 0.001) decreased significantly irrespective of T A, while concentrations of dopamine and 5-HT did not change.

Conclusion

Long-term treatment with MDMA resulted in apparent tolerance to the effects of the drug on HR, dysregulation of T C in thermal gradient, and depletion of cortical DOPAC and 5-HIAA.

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References

  • Attia M (1984) Thermal pleasantness and temperature regulation in man. Neurosci Biobehav Rev 8:335–342

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Bexis S, Phillis BD, Ong J, White JM, Irvine RJ (2004) Baclofen prevents MDMA-induced rise in core body temperature in rats. Drug Alcohol Depend 74:89–96

    Article  PubMed  CAS  Google Scholar 

  • Bhaskaran D, Radha E (1984) Circadian variations in the monoamine levels and monoamine oxidase activity in different regions of the rat brain as a function of age. Exp Gerontol 19:153–170

    Article  PubMed  CAS  Google Scholar 

  • Cabrera-Vera TM, Garcia F, Pinto W, Battaglia G (2000) Neurochemical changes in brain serotonin neurons in immature and adult offspring prenatally exposed to cocaine. Brain Res 870:1–9

    Article  PubMed  CAS  Google Scholar 

  • Callaghan PD, Farrand K, Salem A, Hughes P, Daws LC, Irvine RJ (2006) Repeated administration of the substituted amphetamine p-methoxyamphetamine produces reductions in cortical 5-HT transporter binding but not 5-HT content, unlike 3,4-methylenedioxyamethamphetamine. Eur J Pharmacol 546:74–81

    Article  PubMed  CAS  Google Scholar 

  • Chambers JB, Williams TD, Nakamura A, Henderson RP, Overton JM, Rashotte ME (2000) Cardiovascular and metabolic responses of hypertensive and normotensive rats to one week of cold exposure. Am J Physiol Regul Integr Comp Physiol 279:R1486–R1494

    PubMed  CAS  Google Scholar 

  • Clemens KJ, Van Nieuwenhuyzen PS, Li KM, Cornish JL, Hunt GE, McGregor IS (2004) MDMA (“ecstasy”), methamphetamine and their combination: long-term changes in social interaction and neurochemistry in the rat. Psychopharmacology (Berl) 173:318–325

    Article  CAS  Google Scholar 

  • Clemens KJ, Cornish JL, Hunt GE, McGregor IS (2007) Repeated weekly exposure to MDMA, methamphetamine or their combination: long-term behavioural and neurochemical effects in rats. Drug Alcohol Depend 86:183–190

    Article  PubMed  CAS  Google Scholar 

  • 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 124:479–484

    Article  PubMed  CAS  Google Scholar 

  • Dafters RI (1995) Hyperthermia following MDMA administration in rats: effects of ambient temperature, water consumption, and chronic dosing. Physiol Behav 58:877–882

    Article  PubMed  CAS  Google Scholar 

  • Florez-Duquet M, Peloso E, Satinoff E (2001) Fever and behavioral thermoregulation in young and old rats. Am J Physiol Regul Integr Comp Phys 280:R1457–R1461

    CAS  Google Scholar 

  • Gordon CJ (1987) Relationship between preferred ambient temperature and autonomic thermoregulatory function in rat. Am J Physiol 252:R1130–R1137

    PubMed  CAS  Google Scholar 

  • Gordon CJ (1990) Thermal biology of the laboratory rat. Physiol Behav 47:963–991

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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  PubMed  CAS  Google Scholar 

  • 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 500:3–13

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Irvine RJ, White J, Chan R (1997) The influence of restraint on blood pressure in the rat. J Pharmacol Toxicol Methods 38:157–162

    Article  PubMed  CAS  Google Scholar 

  • Irvine RJ, Keane M, Felgate P, McCann UD, Callaghan PD, White JM (2006) Plasma drug concentrations and physiological measures in ‘dance party’ participants. Neuropsychopharmacology 31:424–430

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Jaehne EJ, Salem A, Irvine RJ (2005) Effects of 3,4-methylenedioxymethamphetamine and related amphetamines on autonomic and behavioral thermoregulation. Pharmacol Biochem Behav 81:485–496

    Article  PubMed  CAS  Google Scholar 

  • Jaehne EJ, Salem A, Irvine RJ (2007) Pharmacological and behavioral determinants of cocaine, methamphetamine, 3,4-methylenedioxymethamphetamine, and para-methoxyamphetamine-induced hyperthermia. Psychopharmacology (Berl) 194:41–52

    Article  CAS  Google Scholar 

  • Lester SJ, Baggott M, Welm S, Schiller NB, Jones RT, Foster E, Mendelson J (2000) Cardiovascular effects of 3,4-methylenedioxymethamphetamine. A double-blind, placebo-controlled trial. Ann Intern Med 133:969–973

    PubMed  CAS  Google Scholar 

  • Lyles J, Cadet JL (2003) Methylenedioxymethamphetamine (MDMA, ecstasy) neurotoxicity: cellular and molecular mechanisms. Brain Res Brain Res Rev 42:155–168

    Article  PubMed  CAS  Google Scholar 

  • 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 18:5086–5094

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • McDougall SJ, Lawrence AJ, Widdop RE (2005) Differential cardiovascular responses to stressors in hypertensive and normotensive rats. Exp Physiol 90:141–150

    Article  PubMed  Google Scholar 

  • Mechan AO, O’Shea E, Elliott 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 (Berl) 155:413–418

    Article  CAS  Google Scholar 

  • Miguez JM, Aldegunde M, Paz-Valinas L, Recio J, Sanchez-Barcelo E (1999) Selective changes in the contents of noradrenaline, dopamine and serotonin in rat brain areas during aging. J Neural Transm 106:1089–1098

    Article  PubMed  CAS  Google Scholar 

  • Morishima MS, Gale CC (1972) Relationship of blood pressure and heart rate to body temperature in baboons. Am J Physiol 223:387–395

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Parrott AC (2002) Recreational ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity. Pharmacol Biochem Behav 71:837–844

    Article  PubMed  CAS  Google Scholar 

  • Parrott AC, Rodgers J, Buchanan T, Ling J, Heffernan T, Scholey AB (2006) Dancing hot on ecstasy: physical activity and thermal comfort ratings are associated with the memory and other psychobiological problems reported by recreational MDMA users. Hum Psychopharmacol 21:285–298

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Sessler DI (1997) Mild perioperative hypothermia. N Engl J Med 336:1730–1737

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • United Nations Office on Drugs and Crime (2003) Ecstasy and amphetamines global survey 2003. United Nations, New York

    Google Scholar 

  • Volkow ND, Chang L, Wang GJ, Fowler JS, Leonido-Yee M, Franceschi D, Sedler MJ, Gatley SJ, Hitzemann R, Ding YS, Logan J, Wong C, Miller EN (2001) Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 158:377–382

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Williamson S, Gossop M, Powis B, Griffiths P, Fountain J, Strang J (1997) Adverse effects of stimulant drugs in a community sample of drug users. Drug Alcohol Depend 44:87–94

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the National Health and Medical Research Council of Australia for their financial support. We would also like to thank Thomas Sullivan of the Discipline of Public Health, University of Adelaide, for performing some of the statistical analysis of results.

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Authors and Affiliations

  1. Discipline of Pharmacology, School of Medical Sciences, Level 5 Medical School North, University of Adelaide, Adelaide, SA, 5005, Australia

    Emily Joy Jaehne, Abdallah Salem & Rodney James Irvine

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  1. Emily Joy Jaehne
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  2. Abdallah Salem
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  3. Rodney James Irvine
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Correspondence to Emily Joy Jaehne.

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Jaehne, E.J., Salem, A. & Irvine, R.J. The effect of long-term repeated exposure to 3,4-methylenedioxymethamphetamine on cardiovascular and thermoregulatory changes. Psychopharmacology 201, 161–170 (2008). https://doi.org/10.1007/s00213-008-1258-9

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