Skip to main content
SpringerLink
Log in

The role of 5-HT in the impairment of thermoregulation observed in rats administered MDMA (‘ecstasy’) when housed at high ambient temperature

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Administration to rats of a neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) produces an impairment in thermoregulation which is reflected in a prolonged hyperthermic response to a subsequent dose of MDMA given to rats housed at high ambient temperature.

Objective

We wished to examine whether the impaired thermoregulation was associated with decreased cerebral 5-HT content produced by the prior neurotoxic dose of MDMA.

Methods

Rats were injected with drugs decreasing 5-HT function [the tryptophan hydroxlase inhibitor p-chlorophenylalanine (PCPA), and 5-HT receptor antagonists] and rectal temperature was measured after administering MDMA to rats housed at 30°C.

Results

PCPA pretreatment decreased 5-HT and 5-HIAA concentrations in cortex, hippocampus and striatum by >80% and prolonged the hyperthermia induced in rats housed at 30°C by administering MDMA (5 mg/kg i.p.). A similar prolongation of the hyperthermic response to MDMA was seen when rats were pretreated with methysergide (10 mg/kg i.p.) or the 5-HT1A antagonist WAY100635 (0.5 mg/kg s.c.).

Conclusions

Decreasing 5-HT function in diverse ways enhanced the hyperthermic response to MDMA given to rats housed at high ambient temperature. This suggests that loss of 5-HT acting on 5-HT1A receptors leads to impaired thermoregulation in rats and suggests that the impairment seen in MDMA pretreated rats housed at high ambient temperature is due to a loss in 5-HT function. These data could have implications for recreational users of MDMA, who may have damaged serotoninergic neurons because of prior heavy or frequent use of the drug, when taking further doses of MDMA in hot environments such as dance clubs.

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

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152

    Article  CAS  PubMed  Google Scholar 

  • Beveridge TJR, Mechan AO, Sprakes M, Pei Q, Zetterstrom TSC, Green AR, Elliott JM (2004) Effect of 5-HT depletion on hyperthermia and Arc mRNA induction in rat brain. Psychopharmacology 173:346–352

    Article  Google Scholar 

  • Bill DJ, Knight M, Forder EA, Fletcher A (1991) Direct evidence for an important species difference in the mechanism of 8-OHDPAT-induced hypothermia. Br J Pharmacol 103:1857–1864

    Google Scholar 

  • 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 275:325–333

    Google Scholar 

  • Brown PL, Kiyatkin EA (2004) Brain hyperthermia induced by MDMA (‘ecstasy’): modulation by environmental conditions. Eur J Neurosci 20:51–58

    Article  Google Scholar 

  • Brown C, Osterloh J (1987) Multiple severe complications from recreational ingestion of MDMA (‘Ecstasy’). J Am Med Assoc 258:780–781

    Article  Google Scholar 

  • Chance MRA (1947) Factors influencing the toxicity of sympathomimetic amines to solitary mice. J Pharmacol Exp Ther 89:289–296

    Google Scholar 

  • 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 12:889–900

    Google Scholar 

  • Cronin MJ (1976) p-Chlorophenylalanine hyperthermia in a warm environment: reversal with 5-hydroxytryptophan. Brain Res 112:194–199

    Article  Google Scholar 

  • Dafters RI (1994) Effect of ambient temperature on hyperthermia and hyperkinesis induced by 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”) in rats. Psychopharmacology 114:505–508

    CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Dafters RI, Lynch E (1998) Persistent loss of thermoregulation in the rat induced by 3,4-methylenedioxymethamphetamine (MDMA or ‘Ecstasy’) but not by fenfluramine. Psychopharmacology 138:207–212

    Article  Google Scholar 

  • Deakin JFW, Green AR (1978) The effects of putative 5-hydroxytryptamine antagonists on the behaviour produced by administration of tranylcypromine and l-tryptophan or tranylcypromine and l-Dopa to rats. Br J Pharmacol 64:201–209

    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 166:202–211

    CAS  PubMed  Google Scholar 

  • Forster EA, Cliffe EA, Bill DJ, Dover GN, Jones D, Reilly Y, Fletcher A (1995) A pharmacological profile of the selective silent 5-HT1A receptor antagonist WAY-100635. Eur J Pharmacol 281:81–89

    Article  CAS  PubMed  Google Scholar 

  • Giacchino JL, Schertel ER, Horowitz JM, Horwitz BA (1983) Effect of p-chlorophenylalanine on thermoregulation in unrestrained rats. Am J Physiol 244:R299–R302

    Google Scholar 

  • Goodwin GM, Green AR (1985) A behavioural and biochemical study in mice and rats of putative selective agonists for 5-HT1 and 5-HT2 receptors. Br J Pharmacol 84:743–753

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

    Article  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 173:264–269

    Article  Google Scholar 

  • Hedlund PB, Kelly L, Mazur C, Lovenberg T, Sutcliffe JG, Bonaventure P (2004) 8-OH-DPAT acts on both 5-HT1A and 5-HT7 receptors to induce hypothermia in rodents. Eur J Pharmacol 487:125–132

    Article  Google Scholar 

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

    Article  Google Scholar 

  • Hjorth S (1985) Hypothermia in the rat induced by the potent serotonergic agent 8-OH-DPAT. J Neural Transm 61:131–135

    Google Scholar 

  • Koe BK, Weissman A (1966) p-Chlorophenylalanine, a specific depletor of brain serotonin. J Pharmacol Exp Ther 154:499–516

    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 

  • McGregor IS, Clemens KJ, Van der Plasse G, Li KM, Hunt GE, Chen F, Lawrence AJ (2003) Increased anxiety 3 months after brief exposure to MDMA (‘Ecstasy’) in rats: association with altered 5-HT transporter and receptor density. Neuropsychopharmacology 28:1472–1484

    Article  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 155:413–418

    Article  Google Scholar 

  • 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 

  • Middlemiss DN, Fozard JR (1983) 8-Hydroxy-2-(di-n-propylamino)tetralin discriminates between subtypes of the 5-HT1 recognition site. Eur J Pharmacol 90:151–153

    Article  Google Scholar 

  • Nash JF, 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

    Google Scholar 

  • Nicholas AC, Seiden LS (2003) Ambient temperature influences core body temperature response in rat lines bred for differences in sensitivity to 8-hydroxy-dipropylaminotetralin. J Pharmacol Exp Ther 305:368–374

    Article  Google Scholar 

  • Nimgaonkar VL, Goodwin GM, Davies CL, Green AR (1985) Down regulation of β-adrenoceptors in rat cortex by repeated administration of desipramine, electroconvulsive shock and clenbuterol requires 5-HT neurones but not 5-HT. Neuropharmacology 24:279–283

    Article  Google Scholar 

  • O’Connell MT, Sarna G, Curzon G (1992) Evidence for postsynaptic mediation in the hypothermic effect of 5-HT1A receptor activation. Br J Pharmacol 106:603–609

    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  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 18:375–379

    Article  Google Scholar 

  • Reid WD, Volicer L, Smooker H, Beaven MA, Brodie BB (1968) Brain amines and temperature regulation. Pharmacology 1:329–344

    Google Scholar 

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

    Google Scholar 

  • Zuideveld KP, Treijtel N, Maas HJ, Gubbens-Stibbe JM, Peletier LA, Van der Graaf PH, Danhof M (2002) A competitive interaction model predicts the effect of WAY-100,635 on the time course of R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin-induced hypothermia. J Pharmacol Exp Ther 300:330–338

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neuropharmacology Research Group, Leicester School of Pharmacy, De Montfort University, The Gateway Leicester, LE1 9BH, UK

    Kathryn S. Saadat, J. Martin Elliott & A. Richard Green

  2. Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, 28040, Spain

    Esther O’Shea & M. Isabel Colado

  3. AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK

    A. Richard Green

Authors
  1. Kathryn S. Saadat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Esther O’Shea
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Isabel Colado
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Martin Elliott
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Richard Green
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Richard Green.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Saadat, K.S., O’Shea, E., Colado, M.I. et al. The role of 5-HT in the impairment of thermoregulation observed in rats administered MDMA (‘ecstasy’) when housed at high ambient temperature. Psychopharmacology 179, 884–890 (2005). https://doi.org/10.1007/s00213-004-2106-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-004-2106-1

Keywords

Search

Navigation