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Mechanisms and environmental factors that underlying the intensification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced serotonin syndrome in rats

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Abstract

Rationale

Illicit use of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) may cause a mild or severe form of the serotonin syndrome. The syndrome intensity is not just influenced by drug doses but also by environmental factors.

Objectives

Warm environmental temperatures and physical activity are features of raves. The purpose of this study was to assess how these two factors can potentially intensify the syndrome.

Methods

Rats were administered MDMA at doses of 0.3, 1, or 3 mg/kg and examined in the absence or presence of warm temperature and physical activity. The syndrome intensity was estimated by visual scoring for behavioral syndrome and also instrumentally measuring changes in symptoms of the syndrome.

Results

Our results showed that MDMA at 3 mg/kg, but not 0.3 or 1 mg/kg, caused a mild serotonin syndrome in rats. Each environmental factor alone moderately intensified the syndrome. When the two factors were combined, the intensification became more severe than each factor alone highlighting a synergistic effect. This intensification was blocked by the 5-HT2A receptor antagonist M100907, competitive N-methyl-d-aspartic acid (NMDA) receptor antagonist CGS19755, autonomic ganglionic blocker hexamethonium, and the benzodiazepine-GABAA receptor agonist midazolam but not by the 5-HT1A receptor antagonist WAY100635 or nicotinic receptor antagonist methyllycaconitine.

Conclusions

Our data suggest that, in the absence of environmental factors, the MDMA-induced syndrome is mainly mediated through the serotonergic transmission (5-hydroxytryptamine (5HT)-dependent mechanism) and therefore is relatively mild. Warm temperature and physical activity facilitate serotonergic and other neural systems such as glutamatergic and autonomic transmissions, resulting in intensification of the syndrome (non-5HT mechanisms).

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References

  • Anneken JH, Cunningham JI, Collins SA, Yamamoto BK, Gudelsky GA (2013) MDMA increases glutamate release and reduces parvalbumin-positive GABAergic cells in the dorsal hippocampus of the rat: role of cyclooxygenase. J NeuroImmune Pharm 8:58–65

    Article  Google Scholar 

  • Arai R, Karasawa N, Nagatsu T, Nagatsu I (1995) Exogenous L-5-hydroxytryptophan is decarboxylated in neurons of the substantia nigra pars compacta and locus coeruleus of the rat. Brain Res 669:145–149

    Article  CAS  PubMed  Google Scholar 

  • Armenian P, Mamantov TM, Tsutaoka BT, Gerona RR, Silman EF, Wu AH, Olson KR (2013) Multiple MDMA (Ecstasy) overdoses at a rave event: a case series. J Intensive Care Med 28:252–258

    Article  PubMed  Google Scholar 

  • Bahora M, Sterk CE, Elifson KW (2009) Understanding recreational ecstasy use in the United States: a qualitative inquiry. Int J Drug Policy 20:62–69

    Article  PubMed Central  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Baumann MH, Zolkowska D, Kim I, Scheidweiler KB, Rothman RB, Huestis MA (2009) Effects of dose and route of administration on pharmacokinetics of (±)-3,4-methylenedioxymethamphetamine in the rat. Drug Metab Dispos 37:2163–2170

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ben-Abraham R, Szold O, Rudick V, Weinbroum AA (2003) ‘Ecstasy’ intoxication: life-threatening manifestations and resuscitative measures in the intensive care setting. J Emerg Med 10:309–313

    Google Scholar 

  • Berridge CW, Morris MF (2000) Amphetamine-induced activation of forebrain EEG is prevented by noradrenergic beta-receptor blockade in the halothane-anesthetized rat. Psychopharmacology (Berlin) 148:307–313

    Article  CAS  Google Scholar 

  • Bexis S, Docherty JR (2005) Role of α2A-adrenoceptors in the effects of MDMA on body temperature in the mouse. Br J Pharmacol 146:1–6

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Boyer EW, Shannon M (2005) The serotonin syndrome. N Engl J Med 352:1112–1120

    Article  CAS  PubMed  Google Scholar 

  • Concheiro M, Baumann MH, Scheidweiler KB, Rothman RB, Marrone GF, Huestis MA (2014) Nonlinear pharmacokinetics of (±)3,4-methylenedioxymethamphetamine (MDMA) and its pharmacodynamic consequences in the rat. Drug Metab Dispos 42:119–125

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Curran HV (2000) Is MDMA (‘Ecstasy’) neurotoxic in humans? An overview of evidence and of methodological problems in research. Neuropsychobiology 42:34–41

    Article  CAS  PubMed  Google Scholar 

  • Darbari FP, Melvin JJ, Piatt JH Jr, Adirim TA, Kothare SV (2005) Intrathecal baclofen overdose followed by withdrawal: clinical and EEG features. Pediatr Neurol 33:373–377

    Article  PubMed  Google Scholar 

  • Davies O, Batajoo-Shrestha B, Sosa-Popoteur J, Olibrice M (2014) Full recovery after severe serotonin syndrome, severe rhabdomyolysis, multi-organ failure and disseminated intravascular coagulopathy from MDMA. Heart Lung 43:117–119

    Article  CAS  PubMed  Google Scholar 

  • Doblin R, Greer G, Holland J, Jerome L, Mithoefer MC, Sessa B (2014) A reconsideration and response to Parrott AC (2013) “Human psychobiology of MDMA or ‘Ecstasy’: an overview of 25 years of empirical research”. Adv Hum Psychopharmacol 29:105–108

    Article  Google Scholar 

  • 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 (Berlin) 166:202–211

    CAS  Google Scholar 

  • 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 272:860–867

    CAS  PubMed  Google Scholar 

  • Feduccia AA, Kongovi N, Duvauchelle CL (2011) Heat increases MDMA-enhanced NAcc 5-HT and body temperature, but not MDMA self-administration. Eur Neuropsychopharmacol 20:884–894

    Article  Google Scholar 

  • Fowler SC, Birkestrand BR, Chen R, Moss SJ, Vorontsova E, Wang G, Zarcone TJ (2001) A force-plate actometer for quantitating rodent behaviors: illustrative data on locomotion, rotation, spatial patterning, stereotypies, and tremor. J Neurosci Methods 107:107–124

    Article  CAS  PubMed  Google Scholar 

  • Fuller RW (1994) Uptake inhibitors increase extracellular serotonin concentration measured by brain microdialysis. Life Sci 55:163–167

    Article  CAS  PubMed  Google Scholar 

  • Gilpin NW, Wright MJ Jr, Dickinson G, Vandewater SA, Price JU, Taffe MA (2011) Influences of activity wheel access on the body temperature response to MDMA and methamphetamine. Pharmacol Biochem Behav 99:295–300

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 

  • Green AR, O’Shea E, Colado MI (2004a) A review of the mechanisms involved in the acute MDMA (ecstasy)-induced hyperthermic response. Eur J Pharmacol 500:3–13

    Article  CAS  PubMed  Google Scholar 

  • Green AR, King MV, Shortall SE, Fone KC (2012) Lost in translation: preclinical studies on 3,4-methylenedioxymethamphetamine provide information on mechanisms of action, but do not allow accurate prediction of adverse events in humans. Br J Pharmacol 166:1523–1536

    Article  PubMed Central  CAS  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  CAS  PubMed  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 Central  CAS  PubMed  Google Scholar 

  • Green AR, Sanchez V, O’Shea E, Saadat KS, Elliott JM, Colado MI (2004b) Effect of ambient temperature and a prior neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA) on the hyperthermic response of rats to a single or repeated ('binge' ingestion) low dose of MDMA. Psychopharmacology (Berlin) 173:264–269

    Article  CAS  Google Scholar 

  • Halpern P, Moskovich J, Avrahami B, Bentur Y, Soffer D, Peleg K (2011) Morbidity associated with MDMA (ecstasy) abuse: a survey of emergency department admissions. Hum Exp Toxicol 30:259–266

    Article  PubMed  Google Scholar 

  • Iannone M, Bulotta S, Paolino D, Zito MC, Gratteri S, Costanzo FS, Rotiroti D (2006) Electrocortical effects of MDMA are potentiated by acoustic stimulation in rats. BMC Neurosci 7:13

    Article  PubMed Central  PubMed  Google Scholar 

  • Isbister GK, Buckley NA (2005) The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment. Clin Neuropharmacol 28:205–214

    Article  CAS  PubMed  Google Scholar 

  • Izumi T, Iwamoto N, Kitaichi Y, Kato A, Inoue T, Koyama T (2007) Effects of co-administration of antidepressants and monoamine oxidase inhibitors on 5-HT-related behavior in rats. Eur J Pharmacol 565:105–112

    Article  CAS  PubMed  Google Scholar 

  • Jacobs BL, Klemfuss H (1975) Brain stem and spinal cord mediation of a serotonergic behavioral syndrome. Brain Res 100:450–457

    Article  CAS  PubMed  Google Scholar 

  • Jacobs KM, Donoghue JP (1991) Reshaping the cortical motor map by unmasking latent intracortical connections. Science 251:944–947

    Article  CAS  PubMed  Google Scholar 

  • Krishnamoorthy S, Ma Z, Zhang G, Wei J, Auerbach SB, Tao R (2010) Involvement of 5-HT2A receptors in the serotonin (5-HT) syndrome caused by excessive 5-HT efflux in rat brain. Basic Clin Pharmacol Toxicol 107:830–841

    Article  CAS  PubMed  Google Scholar 

  • Kiyatkin EA, Kim AH, Wakabayashi KT, Baumann MH, Shaham Y (2014) Critical role of peripheral vasoconstriction in fatal brain hyperthermia induced by MDMA (Ecstasy) under conditions that mimic human drug use. J Neurosci 34:7754–7762

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lukas SE, Mendelson JH, Woods BT, Mello NK, Teoh SK (1989) Topographic distribution of EEG alpha activity during ethanol-induced intoxication in women. J Stud Alcohol 50:176–185

    Article  CAS  PubMed  Google Scholar 

  • Ma Z, Rudacille M, Prentice HM, Tao R (2013) Characterization of electroencephalographic and biochemical responses at 5-HT promoting drug-induced onset of serotonin syndrome in rats. J Neurochem 125:774–789

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ma Z, Zhang G, Jenney C, Krishnamoorthy S, Tao R (2008) Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats. Eur J Pharmacol 588:198–206

    Article  PubMed Central  CAS  PubMed  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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Nair SG, Gudelsky GA (2006) 3,4-Methylenedioxymethamphetamine enhances the release of acetylcholine in the prefrontal cortex and dorsal hippocampus of the rat. Psychopharmacology (Berlin) 184:182–189

    Article  CAS  Google Scholar 

  • Nelson LS, Erdman AR, Booze LL, Cobaugh DJ, Chyka PA, Woolf AD, Scharman EJ, Wax PM, Manoguerra AS, Christianson G, Caravati EM, Troutman WG (2007) Selective serotonin reuptake inhibitor poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol 45:315–332

    Article  CAS  Google Scholar 

  • Niemarkt HJ, Halbertsma FJ, Andriessen P, Bambang Oetomo S (2008) Amplitude-integrated electroencephalographic changes in a newborn induced by overdose of morphine and corrected with naloxone. Acta Paediatr 97:132–134

    Article  CAS  PubMed  Google Scholar 

  • Nishida N, Huang ZL, Mikuni N, Miura Y, Urade Y, Hashimoto N (2007) Deep brain stimulation of the posterior hypothalamus activates the histaminergic system to exert antiepileptic effect in rat pentylenetetrazol model. Exp Neurol 205:132–144

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Parrott AC (2012a) MDMA and 5-HT neurotoxicity: the empirical evidence for its adverse effects in humans—no need for translation. Br J Pharmacol 166:1518–1520, discussion 1521–1512

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Parrott AC (2012b) MDMA and temperature: a review of the thermal effects of 'Ecstasy' in humans. Drug Alcohol Depend 121:1–9

    Article  CAS  PubMed  Google Scholar 

  • Parrott AC, Gibbs A, Scholey AB, King R, Owens K, Swann P, Ogden E, Stough C (2011) MDMA and methamphetamine: some paradoxical negative and positive mood changes in an acute dose laboratory study. Psychopharmacology (Berlin) 215:527–536

    Article  CAS  Google Scholar 

  • Rang ST, Field J, Irving C (2008) Serotonin toxicity caused by an interaction between fentanyl and paroxetine. Can J Anaesth 55:521–525

    Article  PubMed  Google Scholar 

  • Romanovsky AA, Ivanov AI, Shimansky YP (2002) Selected contribution: ambient temperature for experiments in rats: a new method for determining the zone of thermal neutrality. J Appl Physiol 92:2667–2679

    Article  PubMed  Google Scholar 

  • Rusyniak DE, Sprague JE (2005) Toxin-induced hyperthermic syndromes. Emerg Med Clin North Am 89:1277–1296

    Article  CAS  Google Scholar 

  • Rutter JJ, Auerbach SB (1993) Acute uptake inhibition increases extracellular serotonin in the rat forebrain. J Pharmacol Exp Ther 265:1319–1324

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Shortall SE, Green AR, Swift KM, Fone KC, King MV (2013) Differential effects of cathinone compounds and MDMA on body temperature in the rat, and pharmacological characterization of mephedrone-induced hypothermia. Br J Pharmacol 168:966–977

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Stanley N, Salem A, Irvine RJ (2007) The effects of co-administration of 3,4-methylenedioxymethamphetamine ("ecstasy") or para-methoxyamphetamine and moclobemide at elevated ambient temperatures on striatal 5-HT, body temperature and behavior in rats. Neuroscience 146:321–329

    Article  CAS  PubMed  Google Scholar 

  • Starr MA, Page ME, Waterhouse BD (2008) MDMA (3,4-methylenedioxymethamphetamine)-mediated distortion of somatosensory signal transmission and neurotransmitter efflux in the ventral posterior medial thalamus. J Pharmacol Exp Ther 327:20–31

    Article  CAS  PubMed  Google Scholar 

  • Starr MA, Page ME, Waterhouse BD (2012) Effects of repeated 3,4-methylenedioxymethamphetamine administration on neurotransmitter efflux and sensory-evoked discharge in the ventral posterior medial thalamus. J Pharmacol Exp Ther 340:73–82

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sternbach H (1991) The serotonin syndrome. Am J Psychiatry 148:705–713

    Article  CAS  PubMed  Google Scholar 

  • Tao R, Rudacille M, Zhang G, Ma Z (2014) Changes in intensity of serotonin syndrome caused by adverse interaction between monoamine oxidase inhibitors and serotonin reuptake blockers. Neuropsychopharmacology in press.

  • Turner JJ, Parrott AC (2000) 'Is MDMA a human neurotoxin?': Diverse views from the discussants. Neuropsychobiology 42:42–48

    Article  CAS  PubMed  Google Scholar 

  • Von Huben SN, Lay CC, Crean RD, Davis SA, Katner SN, Taffe MA (2007) Impact of ambient temperature on hyperthermia induced by (±) 3,4-methylenedioxymethamphetamine in rhesus macaques. Neuropsychopharmacology 32:673–681

    Article  Google Scholar 

  • Zhang G, Krishnamoorthy S, Ma Z, Vukovich NP, Huang X, Tao R (2009) Assessment of 5-hydroxytryptamine efflux in rat brain during a mild, moderate and severe serotonin-toxicity syndrome. Eur J Pharmacol 615:66–75

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the NIH grant (R15DA029863), the FAU university program for undergraduate research, and the Ross University School of Veterinary Medicine seed grant. We would like to thank the National Institute on Drug Abuse (Rockville, MD) for providing (±)3,4-methylenedioxymethamphetamine (±MDMA) and M100907 to this work. The authors wish to acknowledge Mary Rudacille for her skillful technical assistance.

Conflict of interest

The authors do not have any conflict of interest to report.

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Authors and Affiliations

  1. Charles E. Schmidt College of Medicine, Florida Atlantic University, 777 Glades Road, Boca Raton, FL, 33431, USA

    Rui Tao, Ibrahim M. Shokry, H. Daniel Adams & Zhiyuan Ma

  2. School of Veterinary Medicine, Ross University, St. Kitts, West Indies

    Ibrahim M. Shokry & John J. Callanan

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  1. Rui Tao
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  2. Ibrahim M. Shokry
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  3. John J. Callanan
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  4. H. Daniel Adams
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  5. Zhiyuan Ma
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Correspondence to Rui Tao.

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Tao, R., Shokry, I.M., Callanan, J.J. et al. Mechanisms and environmental factors that underlying the intensification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced serotonin syndrome in rats. Psychopharmacology 232, 1245–1260 (2015). https://doi.org/10.1007/s00213-014-3759-z

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