, Volume 116, Issue 1, pp 40–44 | Cite as

The disruptive effects of ketamine on passive avoidance learning in mice: involvement of dopaminergic mechanism

  • Yoshitaka Uchihashi
  • Hisashi Kuribara
  • Yukitaka Isa
  • Toshihiro Morita
  • Tetsuo Sato
Original Investigations


The involvement of dopaminergic mechanisms in ketamine-induced disruption of one trial step-through passive avoidance performance was assessed through the coadministration with the dopamine D1 antagonist SCH 23390, the dopamine D2 antagonist YM-091512 and the dopamine autoreceptor agonist at low doses, apomorphine, in mice. Pretraining (10 min before) administration of ketamine (0; saline, 2.5, 5 and 10 mg/kg SC) dose-dependently reduced the latency in the retention trial conducted 24 h after the training. However, ketamine did not affect the retention latency when administered immediately after the training or prior to retention. YM-09151-2 (0.01 and 0.03 mg/kg SC) and apomorphine (0.01 and 0.03 mg/kg SC), but not SCH 23390 (0.01 and 0.03 mg/kg SC), ameliorated the impaired reduction by ketamine (10 mg/kg) in a dose-dependent manner. These results suggest that ketamine obstructs the acquisition of the passive avoidance task, and that this effect is induced by stimulation of dopamine D2 receptors through dopamine release from the presynaptic terminals.

Key words

Ketamine Passive avoidance Memory Dopaminergic systems SCH 23390 YM-09151-2 Apomorphine Mouse 


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  1. Alessandri B, Battig K, Welzl H (1989) Effects of ketamine on tunnel maze and water maze performance in the rat. Behav Neural Biol 52:194–212Google Scholar
  2. Anis NA, Berry SC, Burton NR, Lodge D (1983) The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurons byN-methyl aspartate. Br J Pharmacol 79:565–575Google Scholar
  3. Aronstam RS, Narayanan L, Wenger DA (1982) Ketamine inhibition of ligand binding to cholinergic receptors and ion channels. Eur J Pharmacol 78:367–370Google Scholar
  4. Bracs PU, Gregory P, Jackson DM (1984) Passive avoidance in rats: disruption by dopamine applied to the nucleus accumbens. Psychopharmacology 83:70–75Google Scholar
  5. Di Chiara G, Porceddu ML, Vargiu L, Argiolas A, Gessa GL (1976) Evidence for dopamine receptors mediating sedation in the mouse brain. Nature 264:564–567Google Scholar
  6. Domino EF, Chodoff P, Corssen G (1965) Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther 6:279–291Google Scholar
  7. Fernaddez-Tome MP, Sanchez-Blazquez P, del Rio J (1979) Impairment by apomorphine of one-trial passive avoidance learning in mice: the opposing roles of the dopamine and noradrenaline systems. Psychopharmacology 61:43–47Google Scholar
  8. Gandolfi O, Dall'Olio R, Roncada P, Montanaro N (1990) NMDA antagonists interact with 5-HT-stimulated phosphatidylinositol metabolism and impair passive avoidance retention in the rat. Neurosci Lett 113:304–308Google Scholar
  9. Glisson SN, El-Etr AA, Bloor BC (1976) The effect of ketamine upon norepinephrine and dopamine levels in rabbit brain parts. Naunyn-Schmiedebergs Arch Pharmacol 295:149–152Google Scholar
  10. Hetzler BE, Wautlet BS (1985) Ketamine-induced locomotion in rats in an open-field. Pharmacol Biochem Behav 22:653–655Google Scholar
  11. Ichihara K, Nabeshima T, Kameyama T (1987) Opposite effects induced by low and high doses of apomorphine on single-trial passive avoidance learning in mice. Pharmacol Biochem Behav 30:107–113Google Scholar
  12. Ikemoto Y (1986) Ketamine depression of excitatory and inhibitory cholinergic responses inAplysia neurons. Eur J Pharmacol 132:97–100Google Scholar
  13. Iorio LC, Barnett A, Leitz FH, Houser VP, Korduba CA (1983) SCH 23390, a potential benzazepine antipsychotic with unique interaction on dopaminergic systems. J Pharmacol Exp Ther 226:462–468Google Scholar
  14. Irifune M, Shimizu T, Nomoto M (1991) Ketamine-induced hyperlocomotion associated with alteraction of presynaptic components of dopamine neurons in the nucleus accumbens of mice. Pharmacol Biochem Behav 40:399–407Google Scholar
  15. Jones KW, Schaeffer CL, DeNoble VJ (1988) Systemically administeredN-methyl-d-aspartate interferes with acquisition of a passive avoidance response in rats. Pharmacol Biochem Behav 34:181–185Google Scholar
  16. Jones KW, Bauerle LM, DeNoble VJ (1990) Differential effects of sigma and phencyclidine receptor ligands on learning. Eur J Pharmacol 179:97–102Google Scholar
  17. Koek W, Colpaert FC, Woods JH, Kamenka J-M (1989) The phencyclidine (PCP) analogN-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine shares cocaine-like but not other characteristic behavior effects with PCP, ketamine and MK-801. J Pharmacol Exp Ther 250:1019–1027Google Scholar
  18. Kuribara H, Tadokoro S (1984) Augmentation of sensitivity to ambulation-increasing effect of apomorphine induced by repeated administratin in mice. Jpn J Psychopharmacol 4:181–190Google Scholar
  19. Lalonde R, Joyal CC (1991) Effects of ketamine andl-glutamic acid diethyl ester on concept learning in rats. Pharmacol Biochem Behav 39:829–833Google Scholar
  20. Morris RGM (1990) The role of NMDA receptors in certain kinds of learning and memory. In: Squire LR, Lindenlaub E (eds) The biology of memory. Symposia Medica 23, Stuttgart, New York, pp 299–316Google Scholar
  21. Myslobodsky MS, Ackermann RF, Golovchinsky V, Engel J Jr (1979) Ketamine-induced rotation: interaction with GABA-transaminase inhibitors and picrotoxin. Pharmacol Biochem Behav 11:483–486Google Scholar
  22. Paalzow G, Paalzow L (1983) Opposing effects of apomorphine on pain in rats. Evaluation of the dose-response curve. Eur J Pharmacol 88:27–35Google Scholar
  23. Smith DJ, Azzaro AJ, Turndorf H, Abbott SB (1975) The effect of ketamine HCl on the in vitro metabolism of norepinephrine in rat cerebral cortex tissue. Neuropharmacology 14:473–481Google Scholar
  24. Snell LD, Mueller ZL, Gannon RL, Silverman PB, Johnson KM (1984) A comparison between classes of drugs having phencyclidine-like behavioral properties on dopamine efflux in vitro and dopamine metabolism in vivo. J Pharmacol Exp Ther 231:261–269Google Scholar
  25. Sprints AM (1989) Mechanisms of memory disturbance during stages of memory acquisition and fixation. Neurosci Behav Physiol 19:387–892Google Scholar
  26. Sung YF, Frederickson EL, Hotlzman SG (1973) Effect of intravenous anesthetics on brain monoamines in the rat. Anesthesiology 39:478–487Google Scholar
  27. Terai M, Usuda S, Kuroiwa I, Noshiro O, Maeno H (1983) Selective binding of YM-09151-2, a new potent neuroleptic, to D2-dopamine receptors. Jpn J Pharmacol 33:749–755Google Scholar
  28. Thomson AM, West DC, Lodge D (1985) AnN-methylaspartate receptor-mediated synapse in rat cerebral cortex: a site of action of ketamine? Nature 313:479–481Google Scholar
  29. Uchihashi Y, Kuribara H, Tadokoro S (1992) Assessment of the ambulation-increasing effect of ketamine by coadministration with central-acting drugs in mice. Jpn J Pharmacol 60:25–31Google Scholar
  30. Uchihashi Y, Kuribara H, Morita T, Fujita T (1993) The repeated administration of ketamine induces an enhancement of its stimulant action in mice. Jpn J Pharmacol 61:149–151Google Scholar
  31. Veliskova J, Velisek L, Mares P, Rokyta R (1990) Ketamine suppresses both bicuculline- and picrotoxin-induced generalized tonic-clonic seizures during ontogenesis. Pharmacol Biochem Behav 37:667–674Google Scholar
  32. Verma A, Kulkarni SK (1991) Modulation of MK-801 response by dopaminergic agents in mice. Psychopharmacology 107:432–436Google Scholar
  33. Wesierska M, Macias-Gonzalez R, Bures J (1990) Differential effect of ketamine on the reference and working memory versions of the Morris water maze task. Behav Neurosci 104:74–83Google Scholar
  34. Ylitalo P, Saarnivaara L, Ahtee L (1976) Effect of ketamine anaesthesia on the content of monoamines and their metabolites in the rat brain. Acta Anaesth Scand 20:216–220Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Yoshitaka Uchihashi
    • 1
    • 2
  • Hisashi Kuribara
    • 2
  • Yukitaka Isa
    • 3
  • Toshihiro Morita
    • 3
  • Tetsuo Sato
    • 1
  1. 1.Department of AnesthesiologyNational Defense Medical CollegeTokorozawaJapan
  2. 2.Division for Behaviour Analysis, Behaviour Research InstituteGunma University School of MedicineMaebashiJapan
  3. 3.Department of Anesthesiology and ResuscitologyGunma University School of MedicineMaebashiJapan

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