, 198:301 | Cite as

The effects of methamphetamine on core body temperature in the rat—PART 1: chronic treatment and ambient temperature

  • Benita J. Myles
  • Lee Ann Jarrett
  • Susan L. Broom
  • H. Anton Speaker
  • Karen E. Sabol
Original Investigation



Stimulants such as methamphetamine (METH) alter core temperature in a manner that is dependent on ambient temperature and that shows tolerance after chronic use. Our objectives were to (1) determine whether tolerance to METH-induced hyperthermia was a consequence of neurotoxicity to dopamine or serotonin and (2) determine the relationship between ambient temperature and chronic treatment on the METH-induced temperature response.

Materials and methods

Rats were treated with 1.0, 5.0, or 10.0 mg/kg METH at 24°C (experiment 1) or treated with 5.0 mg/kg METH at 20°C, 24°C, or 28°C (experiment 2). Treatment occurred for 12 days, and temperature measurements were made once per minute telemetrically during 7-h sessions in computer-regulated environments.


Peak increases in core temperature occurred at 60 min post-treatment for the 1.0 and 10.0 mg/kg doses, and at 180 min for the 5.0 mg/kg dose. Tolerance-like effects were seen with chronic 5.0 (mixed results) and 10.0 mg/kg METH in the absence of dopamine or serotonin depletions measured 2 weeks after the completion of treatment. After 5.0 mg/kg METH, variations in ambient temperature resulted in an early flexible change in core temperature (phase 1) (hyperthermia at 28° and hypothermia at 20°) and a later inflexible hyperthermia (phase 2).


The results suggest that (1) the peak effect of different doses of METH occurs at different times (24°), (2) the diminished temperature response with chronic METH treatment was not associated with long-term dopamine and serotonin depletions, and (3) a two-phase temperature response to METH may reflect two independent mechanisms.


Drug abuse Methamphetamine Temperature Rat Tolerance 



This paper was supported by Biomedical Research Internship, NIH PHS IR25 GM55379, NIDA 08588, and the University of Mississippi Faculty Research Small Grants Program.


  1. Ando K, Johanson CE, Seiden LS, Schuster CR (1985) Sensitivity changes to dopaminergic agents in fine motor control of rhesus monkeys after repeated methamphetamine administration. Pharmacol Biochem Behav 22:737–743PubMedCrossRefGoogle Scholar
  2. Axt KJ, Molliver ME (1991) Immunocytochemical evidence for methamphetamine-induced serotonergic axon loss in the rat brain. Synapse 9:302–313PubMedCrossRefGoogle Scholar
  3. Bowyer JF, Tank AW, Newport GD, Slikker W, Ali SF, Holson RR (1992) The influence of environmental temperature on the transient effects of methamphetamine on dopamine levels and dopamine release in rat striatum. J Pharmacol Exp Ther 260:817–824PubMedGoogle Scholar
  4. Bowyer JF, Davies DL, Schmued L, Broening HW, Newport GD, Slikker W, Holson RR (1994) Further studies of the role of hyperthermia in methamphetamine neurotoxicity. J Pharmacol Exp Ther 268:1571–1580PubMedGoogle Scholar
  5. Brecht ML, von Mayrhauser C, Anglin MD (2000) Predictors of relapse after treatment for methamphetamine use. J Psychoactive Drugs 32:211–220PubMedGoogle Scholar
  6. Cass WA, Manning MW, Dugan MT (1998) Effects of neurotoxic doses of methamphetamine on potassium and amphetamine evoked overflow of dopamine in the striatum of awake rats. Neurosci Lett 248:175–178PubMedCrossRefGoogle Scholar
  7. Chang L, Ernst T, Speck O, Patel H, DeSilva M, Leonido-Yee M, Miller EN (2002) Perfusion MRI and computerized cognitive test abnormalities in abstinent methamphetamine users. Psychiatry Res 114:65–79PubMedCrossRefGoogle Scholar
  8. Chang L, Alicata D, Ernst T, Volkow N (2007) Structural and metabolic brain changes in the striatum associated with methamphetamine abuse. Addiction 102(Suppl 1):16–32PubMedCrossRefGoogle Scholar
  9. Comer SD, Hart CL, Ward AS, Haney M, Foltin RW, Fischman MW (2001) Effects of repeated oral methamphetamine administration in humans. Psychopharmacology (Berl) 155:397–404CrossRefGoogle Scholar
  10. Cook CE, Jeffcoat AR, Sadler BM, Hill JM, Voyksner RD, Pugh DE, White WR, Perez-Reyes M (1992) Pharmacokinetics of oral methamphetamine and effects of repeated daily dosing in humans. Drug Metab Dispos 20:856–862PubMedGoogle Scholar
  11. Crawshaw LI (1972) Effects of intracerebral 5-hydroxytryptamine injection on thermoregulation in rat. Physiol Behav 9:133–140PubMedCrossRefGoogle Scholar
  12. Danaceau JP, Deering CE, Day JE, Smeal SJ, Johnson-Davis KL, Fleckenstein AE, Wilkins DG (2007) Persistence of tolerance to methamphetamine-induced monoamine deficits. Eur J Pharmacol 559:46–54PubMedCrossRefGoogle Scholar
  13. Faunt JE, Crocker AD (1987) The effects of selective dopamine receptor agonists and antagonists on body temperature in rats. Eur J Pharmacol 133:243–247PubMedCrossRefGoogle Scholar
  14. Finnegan KT, Ricaurte G, Seiden LS, Schuster CR (1982) Altered sensitivity to d-methylamphetamine, apomorphine, and haloperidol in rhesus monkeys depleted of caudate dopamine by repeated administration of d-methylamphetamine. Psychopharmacology 77:43–52PubMedCrossRefGoogle Scholar
  15. Fukumura M, Cappon GD, Pu C, Broening HW, Vorhees CV (1998) A single dose model of methamphetamine-induced neurotoxicity in rats: effects on neostriatal monoamines and glial fibrillary acidic protein. Brain Res 806:1–7PubMedCrossRefGoogle Scholar
  16. Gordon CJ (1990) Thermal biology of the laboratory rat. Physiol Behav 47:963–991PubMedCrossRefGoogle Scholar
  17. Gordon CJ (1993) Temperature regulation in laboratory rodents. Cambridge University Press, New YorkGoogle Scholar
  18. Gudelsky GA, Koenig JI, Meltzer HY (1985) Altered responses to serotonergic agents in Fawn-Hooded rats. Pharmacol Biochem Behav 22:489–492PubMedCrossRefGoogle Scholar
  19. Gudelsky GA, Koenig JI, Meltzer HY (1986) Thermoregulatory responses to serotonin (5-HT) receptor stimulation in the rat. Evidence for opposing roles of 5-HT2 and 5-HT1A receptors. Neuropharmacology 25:1307–1313PubMedCrossRefGoogle Scholar
  20. Gygi MP, Gygi SP, Johnson M, Wilkins DG, Gibb JW, Hanson GR (1996) Mechanisms for tolerance to methamphetamine effects. Neuropharmacology 35:751–757PubMedCrossRefGoogle Scholar
  21. Hansen MG, Whishaw IQ (1973) The effects of 6-hydroxydopamine, dopamine and dl-norepinephrine on food intake and water consumption, self-stimulation, temperature and electroencephalographic activity in the rat. Psychopharmacologia 29:33–44PubMedCrossRefGoogle Scholar
  22. Ishigami A, Kubo S, Gotohda T, Tokunaga I (2003) The application of immunohistochemical findings in the diagnosis in methamphetamine-related death-two forensic autopsy cases. J Med Invest 50:112–116PubMedGoogle Scholar
  23. Johnson-Davis KL, Truong JG, Fleckenstein AE, Wilkins DG (2004) Alterations in vesicular dopamine uptake contribute to tolerance to the neurotoxic effects of methamphetamine. J Pharmacol Exp Ther 309:578–586PubMedCrossRefGoogle Scholar
  24. Keppel G (1991) Design and analysis: a researcher’s handbook. Prentice Hall, Englewood Cliffs, NJGoogle Scholar
  25. Kitaichi K, Morishita Y, Doi Y, Ueyama J, Matsushima M, Zhao YL, Takagi K, Hasegawa T (2003) Increased plasma concentration and brain penetration of methamphetamine in behaviorally sensitized rats. Eur J Pharmacol 464:39–48PubMedCrossRefGoogle Scholar
  26. Lee TF, Mora F, Myers RD (1985) Dopamine and thermoregulation: an evaluation with special reference to dopaminergic pathways. Neurosci Biobehav Rev 9:589–598PubMedCrossRefGoogle Scholar
  27. Lewander T (1971) A mechanism for the development of tolerance to amphetamine in rats. Psychopharmacologia 21:17–31PubMedCrossRefGoogle Scholar
  28. 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 363:107–112PubMedCrossRefGoogle Scholar
  29. Malberg J, 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
  30. 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 135:170–180PubMedCrossRefGoogle Scholar
  31. Myles BM, Sabol KE (2008) The effects of methamphetamine on core body temperature in the rat. Part 2: an escalating regimen. Psychopharmacology DOI 10.1007/s00213-007-1060-0
  32. NRC (1996) Guide for the care and use of laboratory animals. National Academy, Washington, DCGoogle Scholar
  33. Paulus MP, Hozack NE, Zauscher BE, Frank L, Brown GG, Braff DL, Schuckit MA (2002) Behavioral and functional neuroimaging evidence for prefrontal dysfunction in methamphetamine-dependent subjects. Neuropsychopharmacology 26:53–63PubMedCrossRefGoogle Scholar
  34. Perez-Reyes M, White WR, McDonald SA, Hicks RE, Jeffcoat AR, Hill JM, Cook CE (1991) Clinical effects of daily methamphetamine administration. Clin Neuropharmacol 14:352–358PubMedCrossRefGoogle Scholar
  35. Reiber C, Galloway G, Cohen J, Hsu JC, Lord RH (2000) A descriptive analysis of participant characteristics and patterns of substance use in the CSAT methamphetamine treatment project: the first six months. J Psychoactive Drugs 32:183–191PubMedGoogle Scholar
  36. Ricaurte GA, Schuster CR, Seiden LS (1980) Long-term effects of repeated methylamphetamine administration on dopamine and serotonin neurons in the rat brain: a regional study. Brain Res 193:153–160PubMedCrossRefGoogle Scholar
  37. Riddle EL, Kokoshka JM, Wilkins DG, Hanson GR, Fleckenstein AE (2002) Tolerance to the neurotoxic effects of methamphetamine in young rats. Eur J Pharmacol 435:181–185PubMedCrossRefGoogle Scholar
  38. Rusyniak DE, Zaretskaia MV, Zaretsky DV, DiMicco JA (2007) 3,4-Methylenedioxymethamphetamine- and 8-hydroxy-2-di-n-propylamino-tetralin-induced hypothermia: role and location of 5-hydroxytryptamine 1A receptors. J Pharmacol Exp Ther 323:477–487PubMedCrossRefGoogle Scholar
  39. Sabol KE, Richards JB, Yung K (2000) The effects of high-dose methamphetamine in the aging rat: differential reinforcement of low-rate 72-s schedule behavior and neurochemistry. J Pharmacol Exp Ther 294:850–863PubMedGoogle Scholar
  40. Sabol KE, Roach JT, Broom SL, Ferreira C, Preau MM (2001) Long-term effects of a high-dose methamphetamine regimen on subsequent methamphetamine-induced dopamine release in vivo. Brain Res 892:122–129PubMedCrossRefGoogle Scholar
  41. Salmi P, Ahlenius S (1998) Evidence for functional interactions between 5-HT1A and 5-HT2A receptors in rat thermoregulatory mechanisms. Pharmacol Toxicol 82:122–127PubMedCrossRefGoogle Scholar
  42. Salmi P, Jimenez P, Ahlenius S (1993) Evidence for specific involvement of dopamine D1 and D2 receptors in the regulation of body temperature in the rat. Eur J Pharmacol 236:395–400PubMedCrossRefGoogle Scholar
  43. Salo R, Nordahl TE, Possin K, Leamon M, Gibson DR, Galloway GP, Flynn NM, Henik A, Pfefferbaum A, Sullivan EV (2002) Preliminary evidence of reduced cognitive inhibition in methamphetamine-dependent individuals. Psychiatry Res 111:65–74PubMedCrossRefGoogle Scholar
  44. Schmidt CJ (1987) Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. J Pharmacol Exp Ther 240:1–7PubMedGoogle Scholar
  45. Schmidt CJ, Black CK, Taylor VL (1991) l-DOPA potentiation of the serotonergic deficits due to a single administration of 3,4-methylenedioxymethamphetamine, p-chloroamphetamine or methamphetamine to rats. Eur J Pharmacol 203:41–49PubMedCrossRefGoogle Scholar
  46. Simon SL, Domier CP, Sim T, Richardson K, Rawson RA, Ling W (2002a) Cognitive performance of current methamphetamine and cocaine abusers. J Addict Dis 21:61–74PubMedCrossRefGoogle Scholar
  47. Simon SL, Richardson K, Dacey J, Glynn S, Domier CP, Rawson RA, Ling W (2002b) A comparison of patterns of methamphetamine and cocaine use. J Addict Dis 21:35–44PubMedCrossRefGoogle Scholar
  48. 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
  49. Sprague JE, Yang X, Sommers J, Gilman TL, Mills EM (2007) Roles of norepinephrine, free fatty acids, thyroid status, and skeletal muscle uncoupling protein 3 expression in sympathomimetic-induced thermogenesis. J Pharmacol Exp Ther 320:274–280PubMedCrossRefGoogle Scholar
  50. Thompson PM, Hayashi KM, Simon SL, Geaga JA, Hong MS, Sui Y, Lee JY, Toga AW, Ling W, London ED (2004) Structural abnormalities in the brains of human subjects who use methamphetamine. J Neurosci 24:6028–6036PubMedCrossRefGoogle Scholar
  51. Thornhill JA, Hirst M, Gowdey CW (1977) Variability in development of tolerance to repeated injections of low doses of dl-amphetamine in rats. Can J Physiol Pharmacol 55:1170–1178PubMedGoogle Scholar
  52. 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 158:377–382PubMedCrossRefGoogle Scholar
  53. Wagner GC, Ricaurte GA, Seiden LS, Schuster CR, Miller RJ, Westley J (1980) Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine. Brain Res 181:151–160PubMedCrossRefGoogle Scholar
  54. Yehuda S, Wurtman RJ (1972) The effects of d-amphetamine and related drugs on colonic temperatures of rats kept at various ambient temperatures. Life Sci I 11:851–859PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Benita J. Myles
    • 2
  • Lee Ann Jarrett
    • 1
  • Susan L. Broom
    • 1
  • H. Anton Speaker
    • 1
  • Karen E. Sabol
    • 1
    • 2
  1. 1.Department of PsychologyUniversity of MississippiUniversityUSA
  2. 2.Department of PharmacologyUniversity of MississippiUniversityUSA

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