, Volume 97, Issue 2, pp 269–274 | Cite as

Hyperthermia induced by m-CPP in the rat and its modification by antidepressant treatments

  • K. M. Wozniak
  • C. S. Aulakh
  • J. L. Hill
  • D. L. Murphy
Original Investigations


Administration of the serotonin agonist m-chlorophenylpiperazine to rats produced a dose-related hyperthermia. Pretreatment with the serotonin receptor antagonist metergoline totally abolished this response, whereas similar treatment with haloperidol, phenoxybenzamine, naloxone, clonidine, pindolol, propranolol, methiotepin, and ritanserin was ineffective. In studies investigating the modification of the response by antidepressant treatments both acute (3 day) and chronic (22 day) administration of the MAO inhibitor clorgyline, as well as the tricyclics clomipramine and imipramine, attenuated the hyperthermic response to m-CPP. These findings are discussed with regard to the specificity of m-CPP-induced hyperthermia and its subsequent modification by antidepressant treatments, in order to evaluate this model's use as a probe for assessment of the serotonergic system.

Key words

m-CPP Temperature Clorgyline Clomipramine Imipramine Antidepressant 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aloi JA, Insel TR, Mueller EA, Murphy DL (1984) Neuroendocrine and behavioral effects of m-chlorophenylpiperazine administration in rhesus monkeys. Life Sci 34:1325–1331Google Scholar
  2. Aulakh CS, Cohen RM, Hill JL, Murphy DL, Zohar J (1987) Long term imipramine treatment enhances locomotor and food intake suppressant effects of m-chlorophenylpiperazine in rats. Br J Pharmacol 81:747–752Google Scholar
  3. Bagdy G, Szemeredi K, Zukowska-Grojec Z, Hill J, Murphy DL (1987) m-Chlorophenylpiperazine increases blood pressure and heart rate in pithed and conscious rats. Life Sci 41:775–782Google Scholar
  4. Brazenor RW, Augus JA (1982) Actions of serotonin antagonists on dog coronary artery. Eur J Pharmacol 81:569–576Google Scholar
  5. Caccia S, Ballabio M, Samanin R (1981) (−)-m-Chlorophenylpiperazine, a central 5-hydroxytryptamine agonist, is a metabolite of trazodone. J Pharm Pharmacol 33:477–478Google Scholar
  6. Caccia S, Fong MH, Garattinis V, Zanini MG (1982) Plasma concentrations of trazodone and 1-(3-chlorophenyl)piperazine in man after a single oral dose of trazodone. J Pharm Pharmacol 34:605–606Google Scholar
  7. Charney DS, Menkes DB, Heninger GR (1981) Receptor sensitivity and the mechanism of action of antidepressant treatment: implications for the etiology and treatment of depression. Arch Gen Psychiatry 88:1160–1180Google Scholar
  8. Cohen ML, Fuller RW (1983) Antagonism of vascular serotonin receptors by m-chlorophenylpiperazine and m-trifluoromethylphenylpiperazine. Life Sci 32:711–718Google Scholar
  9. Cohen RM, Aulakh CS, Murphy DL (1983) Long-term clorgyline treatment antagonizes the eating and motor function responses to m-chlorophenylpiperazine. Eur J Pharmacol 94:175–179Google Scholar
  10. Colpaert FC, Leysen JE (1981) Characterization of in vivo agonist and antagonist activity of purported 5-hydroxytryptamine antagonists and of R 47 465, and LSD antagonist. In: Abstracts of the Eighth International Congress of Pharmacology, IU-PHAR, Tokyo, Japan, p 595Google Scholar
  11. Conn PJ, Sanders-Bush E (1987) Relative efficacies of piperazines at the phosphoinositide hydrolysis-linked serotonergic (5-HT2 and 5-HT1C) receptors. J Pharmacol Exp Ther 552–557Google Scholar
  12. Fuller RW, Snoddy HD, Mason NR, Owen JE (1981) Disposition and pharmacological effects of m-chlorophenylpiperazine in rats. Neuropharmacology 20:155–162Google Scholar
  13. Fuxe K, Agnati L, Everitt B (1975) Effects of methergoline on central monoamine neurones. Evidence for a selective blockade of central 5-HT receptors. Neurosci Lett 1:283–290Google Scholar
  14. Fuxe K, Ogren SO, Agnati LF, Calza L (1982) Evidence for stabilization of cortical 5-HT neurotransmission by chronic treatment with antidepressant drugs: induction of a high and low affinity component in 3H-5-HT binding sites. Acta Physiol Scand 114:477–480Google Scholar
  15. Fuxe K, Ogren S-O, Agnati LF, Benfenati F, Fredholm B, Andersson K, Zini I, Eneroth P (1983) Chronic antidepressant treatment and central 5-HT synapses. Neuropharmacology 22:389–400Google Scholar
  16. Goodwin GM, Green AR (1985) A behavioural and biochemical study in mice and rats of putative selective agonists and antagonists for 5-HT1 and 5-HT2 receptors. Br J Pharmacol 84:743–753Google Scholar
  17. Goodwin GM, DeSouza RJ, Green AR, Heal DJ (1987) The pharmacology of the behavioural and hypothermic responses of rats to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Psychopharmacology 91:506–511Google Scholar
  18. Gothert M (1982) Modulation of serotonin release into the brain via presynaptic receptors. TIPS 3:437–440Google Scholar
  19. Gudelsky GA, Koenig JI, Meltzer HY (1986) Thermoregulatory responses to serotonin (5-HT) receptor stimulation in the rat. Neuropharmacology 25:1307–1313Google Scholar
  20. Hall H, Ogren SO (1981) Effects of antidepressant drugs on different receptors in the brain. Eur J Pharmacol 70:393–407Google Scholar
  21. Hamon M, Cossery JM, Spampinato V, Gozlan H (1986) Are there selective ligands for 5-HT1A and 5-HT1B receptor binding sites in brain. TIPS 7:336–338Google Scholar
  22. Hjorth S (1985) Hypothermia in the rat induced by the potent serotonergic agent 8-OH-DPAT. J Neural Transm 61:131–135Google Scholar
  23. Hjorth S, Carlsson A (1986) Is pindolol a mixed agonist-antagonist at central serotonin receptors? Eur J Pharmacol 129:131–138Google Scholar
  24. Invernizzi R, Cotecchia S, DeBlasi A, Mennini T, Pataccini R, Samanin R (1981) Effects of m-chlorophenylpiperazine on receptor binding and brain metabolism of monoamines in rats. Neurochem Int 3:239–244Google Scholar
  25. Kalkman HO, Timmermans PSMWM, Van Zwieten PA (1982) Characterization of the antihypertensive properties of ketanserin (R 41 468) in rats. J Pharmacol Exp Ther 222:227–231Google Scholar
  26. Kendall DA, Nahorski SR (1984) Suppression of 5-HT receptor mediated inositol phospholipid breakdown in brain by chronic antidepressant treatment. Br J Pharmacol 82:206PGoogle Scholar
  27. Kendall DA, Duman R, Slopis J, Enna SJ (1982) Influence of adrenocorticotrophin hormone and yohimbine on antidepressant-induced declines in rat brain neurotransmitter receptor binding and function. J Pharmacol Exp Ther 22:566–571Google Scholar
  28. Knoll J (1976) Analysis of the pharmacological aspects of selective monoamine oxidase inhibitors. In: Wolstenholme GEW, Knight J (eds) Monoamine oxidase and its inhibition. Elsevier, Amsterdam, pp 135–161Google Scholar
  29. Kruk ZL (1972) The effect of drugs acting on dopamine receptors on the body temperature of the rat. Life Sci 11:845–850Google Scholar
  30. Leysen J (1984) Problems in in vitro receptor binding studies and identification and role of serotonin receptor sites. Neuropharmacology 23:247–254Google Scholar
  31. Leysen JE, Awouters F, Kennis L, Laduron PM, Vandenberk J, Janssen PA (1981) Receptor binding profile of R41-468 a novel antagonist at 5-HT2 receptors. Life Sci 28:1015–1022Google Scholar
  32. Leysen JE, Gommeren W, Van Gompel P, Wynants J, Janssen PFM, Laduron PM (1985) Receptor-binding properties in vitro and in vivo of ritanserin: a very potent and long acting serotonin-S2 antagonist. Mol Pharmacol 27:600–611Google Scholar
  33. Lucki I, Frazer A (1982) Prevention of the serotonin syndrome in rats by repeated administration of monoamine oxidase inhibitors but not tricyclic antidepressants. Psychopharmacology 77:205–211Google Scholar
  34. Maggi A, U'Prichard DC, Enna SJ (1980) Differential effects of antidepressant treatment on brain monoaminergic receptors. Eur J Pharmacol 61:91–98Google Scholar
  35. Maj J, Lewandowska A (1980) Central serotoninmimetic action of phenylpiperazine. Pol J Pharmacol Pharm 32:495–504Google Scholar
  36. Martin LL, Sanders-Bush E (1982) Comparison of the pharmacological characteristics of 5-HT1 and 5-HT2 binding sites with those of serotonin autoreceptors which modulate serotonin release. Naunyn Schmiedeberg's Arch Pharmacol 321:165–170Google Scholar
  37. Mawson C, Whittington H (1970) Evaluation of the peripheral and central antagonistic activities against 5-hydroxytryptamine of some new agents. Br J Pharmacol 39:223PGoogle Scholar
  38. Meltzer HY, Simonovic M, Gudelsky GA (1983) Effects of pirenperone and ketanserin on rat prolactin secretion in vivo and in vitro. Eur J Pharmacol 92:83–89Google Scholar
  39. Melzacka M, Boksa J, Maj J (1979) 1-(m-Chlorophenyl)piperazine: a metabolite of trazodone isolated from rat urine. J Pharm Pharmacol 31:855–856Google Scholar
  40. Mueller EA, Sunderland T, Murphy DL (1985) Neuroendocrine effects of m-CPP, a serotonin agonist, in humans. J Clin Endocrinol Metab 61:1179–1184Google Scholar
  41. Mueller EA, Murphy DL, Sunderland T (1986) Further studies of the putative serotonin agonist, m-chlorophenylpiperazine: evidence for a serotonin receptor mediated mechanism of action in humans. Psychopharmacology 89:388–391Google Scholar
  42. Ogren SO, Fuxe K, Agnati LF, Gustafsson JA, Jonsson G, Holm AC (1979) Reevaluation of the indoleamine hypothesis of depression. Evidence for a reduction of functional activity of central 5-HT systems by antidepressant drugs. J Neural Transm 46:85–103Google Scholar
  43. Olpe HR (1981) Differential effect of chlorimipramine and clorgyline on the sensitivity of cortical neurons to serotonin. Eur J Pharmacol 69:375–377Google Scholar
  44. Pawlowski L (1984) Amitriptyline and femoxetine, but not clomipramine or citalopram, antagonize hyperthermia induced by directly acting 5-hydroxytryptamine-like drugs in heat adapted rats. J Pharm Pharmacol 36:197–199Google Scholar
  45. Persson B, Hedner T, Henning M (1982) Cardiovascular effects in the rat of ketanserin, a novel 5-hydroxytryptamine receptor blocking agent. J Pharm Pharmacol 34:442–445Google Scholar
  46. Peroutka SJ, Snyder SH (1980) Long term antidepressant treatment decreases spiroperidol-labelled serotonin receptor binding. Science 210:88–90Google Scholar
  47. Pettibone DJ, Williams M (1984) Serotonin-releasing effects of substituted piperazines in vitro. Biochem Pharmacol 33:1531–1535Google Scholar
  48. Quattrone A, Schettini G, Annunziato L, Di Renzo G (1981) Pharmacological evidence of supersensitivity of central serotonergic receptors involved in the control of prolactin secretion. Eur J Pharmacol 76:9–13Google Scholar
  49. Rowan MJ, Anwyl R (1985) The effect of prolonged treatment with tricyclic antidepressants on the actions of 5-hydroxytryptamine in the hippocampal slice of the rat. Neuropharmacology 24:131–137Google Scholar
  50. Samanin R, Mennini T, Ferraris A, Bendotti C, Borsini F, Garattini S (1979) m-Chlorophenylpiperazine: a central serotonin agonist causing powerful anorexia in rats. Naunyn-Schmiedeberg's Arch Pharmacol 308:159–163Google Scholar
  51. Samanin R, Mennini T, Ferraris A, Bendotti C, Borsini F (1980) Hyper- and hyposensitivity of central serotonin receptors: 3H-serotonin binding and functional studies in the rat. Brain Res 189:449–457Google Scholar
  52. Savage DD, Mendels J, Frazer A (1980) Monoamine oxidase inhibitors and serotonin uptake inhibitors: differential effects on [3H]serotonin binding sites in rat brain. J Pharmacol Exp Ther 212:259–263Google Scholar
  53. Segawa T, Mizuta T, Nomura Y (1979) Modifications of central 5-hydroxytryptamine binding sites in synaptic membranes from rat brain after long-term administration of tricyclic antidepressants. Eur J Pharmacol 58:75–83Google Scholar
  54. Sills MA, Wolfe BB, Frazer A (1984) Determination of selective and non-selective compounds for the 5-HT1A and 5-HT1B receptor subtypes in rat frontal cortex. J Pharmacol Exp Ther 231:480–487Google Scholar
  55. Stolz JF, Marsden CA, Middlemiss DN (1983) Effect of chronic antidepressant treatment and subsequent withdrawal on [3H]-5-hydroxytryptamine and [3H]-spiperone binding in rat frontal cortex and serotonin receptor mediated behaviour. Psychopharmacology 80:150–155Google Scholar
  56. Tang SW, Seeman P (1980) Effect of antidepressant drugs on serotonergic and adrenergic receptors. Naunyn-Schmiedeberg's Arch Pharmacol 311:255–261Google Scholar
  57. Willner P (1985) Antidepressant and serotonergic neurotransmission: an integrative review. Psychopharmacology 85:387–404Google Scholar
  58. Wozniak KM, Aulakh CS, Hill JL, Murphy DL (1988) The effect of 8-OH-DPAT on temperature in the rat and its modification by chronic antidepressant treatments. Pharmacol Biochem Behav 30:451–456Google Scholar
  59. Yang H-Y, Neff NH (1974) The monoamine oxidases of brain: selective inhibition with drugs and the consequence for the metabolism of the biogenic amines. J Pharmacol Exp Ther 189:733–740Google Scholar
  60. Zohar J, Insel TR, Zohar-Kadouch RC, Hill JL, Murphy DL (1988) Serotonergic responsivity in obsessive-compulsive disorder: effects of chronic clomipramine treatment. Arch Gen Psychiatry 45:167–172Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • K. M. Wozniak
    • 1
  • C. S. Aulakh
    • 1
  • J. L. Hill
    • 1
  • D. L. Murphy
    • 1
  1. 1.Laboratory of Clinical ScienceNational Institute of Mental Health, N.I.H. Clinical CenterBethesdaUSA

Personalised recommendations