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Effects of Anesthetic Ketamine on Anxiety-Like Behaviour in Rats

  • Nikolaos PitsikasEmail author
  • Georgia Georgiadou
  • Foteini Delis
  • Katerina Antoniou
Original Paper
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Abstract

There is scarce information regarding the effects of anesthetic doses of the non-competitive N-methyl-d-aspartate receptor antagonist ketamine on anxiety. The current study evaluated the acute effects of intraperitoneally (i.p.) administered anesthetic ketamine (100 mg/kg) i.p. on anxiety in rats. For this purpose, the light/dark and the open field tests were utilized. The effects of anesthetic ketamine on motility were also examined using a motility cage. In the light/dark test, anesthetic ketamine, administered 24 h before testing reduced the number of transitions between the light and dark compartments and the time spent in the light compartment in the rats compared with their control cohorts. In addition, ketamine was found to exert a depressive effect on rats’ motility. In the open field test, animals treated with anesthetic ketamine 24 h before testing spent essentially no time in the central area of the apparatus, decreased horizontal ambulatory activity, and preserved to a certain extent their exploratory behaviour compared to their control counterparts. The results suggest that, in spite of its hypokinetic effect, a single anesthetic ketamine administration apparently induces an anxiety-like state, while largely preserving exploratory behaviour in the rat. These effects were time-dependent they since they were extinguished when testing was carried out 48 h after anesthetic ketamine administration.

Keywords

Anesthetic ketamine Anxiety Rat 

Notes

Compliance with Ethical Standards

Conflict of interest

The authors declare no potential conflicts of interest with respect to authorship and/or publication of this article.

Research Involving Animal Rights

All applicable international and national guidelines for the care and use of animals were followed.

References

  1. 1.
    Javitt DC, Zukin RS (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308CrossRefGoogle Scholar
  2. 2.
    Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist ketamine, in humans. Psychotomimetic, perceptual, cognitive and neuroendocrine responses. Archiv Gen Psychiatry 51:199–214CrossRefGoogle Scholar
  3. 3.
    Yamakura T, Chavez-Noriega LE, Harris RA (2009) Subunit-dependent inhibition of human neuronal nicotinic acetylcholine receptors and other ligand-gated ion channels by dissociative anesthetics ketamine and dizocilpine. Anesthesiology 92:1144–1153CrossRefGoogle Scholar
  4. 4.
    Corssen G, Domino EF (1966) Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg 45:29–40CrossRefGoogle Scholar
  5. 5.
    Okon T (2007) Ketamine: an introduction for the pain and palliative medicine physician. Pain Phys 10:493–500Google Scholar
  6. 6.
    Akillioglou K, Babar Melik E, Melik E, Boga A (2012) Effects of ketamine on exploratory behaviour in BALB/C and C57BL/6 mice. Pharmacol Biochem Behav 100:513–517CrossRefGoogle Scholar
  7. 7.
    Babar E, Ozgunen T, Melik E, Polat S, Akman H (2001) Effects of ketamine on different types of anxiety/fear and related memory in rats with lesions of the median raphe nucleus. Eur J Pharmacol 431:315–320CrossRefGoogle Scholar
  8. 8.
    Engin E, Treit D, Dickson CT (2009) Anxiolytic- and antidepressant-like properties of ketamine in behavioural and electrophysiological animal models. Neuroscience 161:359–369CrossRefGoogle Scholar
  9. 9.
    de Sousa FC, do Carmo de Oliveira Cito M, da Silva MI, Moura BA, de Aquino Neto MR, Feitosa ML, de Castro Chavez R, Macedo DS, de Vasconcelos SM, de Franca Fonteles MM, de Sousa FC (2010) Behavioraal alterations and pro-oxidant effect of a single ketamine administration in mice. Brain Res Bul 83:9–15CrossRefGoogle Scholar
  10. 10.
    Silvestre JS, Nadal R, Pallares M, Ferre N (1997) Acute effects of ketamine in a holeboard, the elevated plus-maze, and the social interaction test in Wistar rats. Depress Anxiety 5:29–33CrossRefGoogle Scholar
  11. 11.
    Becker A, Peters B, Schroeder H, Mann T, Huether G, Grecksch G (2003) Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27:687–700CrossRefGoogle Scholar
  12. 12.
    Trevlopoulou A, Touzlatzi N, Pitsikas N (2016) The nitric oxide donor sodium nitroprusside attenuates recognition memory deficits and social withdrawal produced by the NMDA receptor antagonist ketamine and induces anxiolytic-like behaviour in rats. Psychopharmacology 233:1045–1054CrossRefGoogle Scholar
  13. 13.
    Magalhaes A, Valentim A, Venancio C, Pereira M, Melo P, Summavielle T, Antunes L (2017) Ketamine alone or combined with midazolam or dexmedetomidine does not affect anxiety-like behaviours and memory in adult Wistar rats. Lab Anim 51:147–159CrossRefGoogle Scholar
  14. 14.
    Crawley JN, Goodwin FK (1980) Preliminary report of a simple animal behaviour for the anxiolytic effect of benzodiazepines. Pharmacol Biochem Behav 13:167–170CrossRefGoogle Scholar
  15. 15.
    Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviours: a review. Eur J Pharmacol 463:3–33CrossRefGoogle Scholar
  16. 16.
    Crawley JN (1985) Exploratory behavior models of anxiety in mice. Neurosci Biobehav Rev 9:37–44CrossRefGoogle Scholar
  17. 17.
    Grivas V, Markou A, Pitsikas N (2013) The metabotropic glutamate 2/3 receptor agonist LY379268 induces anxiety-like behavior at the highest dose tested in two rat models of anxiety. Eur J Pharmacol 715:105–110CrossRefGoogle Scholar
  18. 18.
    Antoniou K, Papathanasiou G, Panagis G, Nomikos GG, Hyphantis T, Papadopoulou-Daifoti Z (2004) Individual responses to novelty predict qualitative differences in d-amphetamine-induced open field but not reward-related behaviors in rats. Neuroscience 23:613–623CrossRefGoogle Scholar
  19. 19.
    Delis F, Polissidis A, Poulia N, Justinova Z, Nomikos GG, Goldberg SR, Antoniou K (2017) Attenuation of cocaine-induced conditioned place preference and motor activity via cannabinoid CB2 receptor agonism and CB1 receptor antagonism in rats. Int J Neuropsychopharmacol 20:269–278Google Scholar
  20. 20.
    Polissidis A, Galanopoulos A, Naxakis G, Papahatjis D, Papadopoulou-Daifoti Z, Antoniou K (2013) The cannabinoid CB1 receptor biphasically modulates motor activity and regulates dopamine and glutamate release region dependently. Int J Neuropsychopharmacol 6:1–11Google Scholar
  21. 21.
    Thiel CM, Muller CP, Huston JP, Schwarting RK (1999) High versus low reactivity to a novel environment: behavioural, pharmacological and neurochemical assessments. Neuroscience 93:243–251CrossRefGoogle Scholar
  22. 22.
    Pitsikas N, Boultadakis A (2009) Pre-training administration of anesthetic ketamine differentially affects rats’ spatial and non-spatial recognition memory. Neuropharmacology 57:1–7CrossRefGoogle Scholar
  23. 23.
    Kirk RE. (1968) Experimental design: procedures for the behavioral science. Brooks/Cole, Belmont, CAGoogle Scholar
  24. 24.
    Bourin M, Hascoet M (2003) The mouse light/dark box test. Eur J Pharmacol 463:55–65CrossRefGoogle Scholar
  25. 25.
    Belzung C, Misslin R, Vogel E, Dodd RH, Chapouthier G (1987) Anxiogenic effects of methyl-β-carboline-carboxylate in a light/dark choice situation. Pharmacol Biochem Behav 28:29–33CrossRefGoogle Scholar
  26. 26.
    Hetzler BE, Wautlet BS (1986) Ketamine-induced locomotion in rats in an open field. Pharmacol Biochem Behav 22:653–655CrossRefGoogle Scholar
  27. 27.
    Mihara T, Kikuchi T, Kamiya Y, Koga M, Uchimoto K, Kurahashi K, Goto T (2012) Day or night administration of ketamine and pentobarbital differentially affect circadian rhythms of pineal melatonin secretion and locomotor activity in rats. Anesth Analg 115:805–813CrossRefGoogle Scholar
  28. 28.
    Ribeiro PO, Rodrigues PC, Valentim AM, Antunes LM (2013) A single intraperitoneal injection of ketamine does not affect spatial working, reference memory or neurodegeneration in adult mice. Eur J Anesthesiol 30:618–626CrossRefGoogle Scholar
  29. 29.
    Irifune M, Shimizu T, Nomoto M (1992) Ketamine-induced anesthesia involves the N-methyl-d-aspartate receptor-channel complex in mice. Brain Res 596:1–9CrossRefGoogle Scholar
  30. 30.
    Irifune M, Sato T, Kamata Y, Nishikawa T, Dohi T, Kawahara M (2000) Evidence for GABA(A) receptor agonistic properties of ketamine: convulsive and anesthetic behavioral models in mice. Anesth Analg 91:230–236Google Scholar
  31. 31.
    Hovatta I, Tennart RS, Helton R, Marr RA, Singer O, Redwine JM, Ellison JA, Schad EE, Verma IM, Lockhart DJ, Barlow C (2005) Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice. Nature 438:662–666CrossRefGoogle Scholar
  32. 32.
    Moller C, Bing O, Heilig M (1994) c-fos expression in the amygdala: in vivo antisense modulation and role in anxiety. Cell Mol Neurobiol 14:415–423CrossRefGoogle Scholar
  33. 33.
    Venancio C, Felix L, Almeida V, Coutinho J, Antunes L, Peixoto F, Summavielle T (2015) Acute ketamine impairs mitochondrial function and promotes superoxide dismutase activity in the rat brain. Anesth Analg 120:320–328CrossRefGoogle Scholar
  34. 34.
    Nakao S, Nagata A, Miyamoto E, Masugawa M, Murayama T, Shingu K (2003) Inhibitory effect of profolol on ketamine-induced c-Fos expression in the rat posterior cingulate and retrospenial cortices is mediated by GABAA receptor activation. Acta Anesthesiol Scand 47:284–290CrossRefGoogle Scholar
  35. 35.
    Bouwknecht JA, Paylor R (2008) Pitfalls in the interpretation of genetic and pharmacological effects of anxiety-like behaviour in rodents. Behav Pharmacol 19:385–402CrossRefGoogle Scholar
  36. 36.
    Ressler KJ, Mayberg HS (2007) Targeting abnormal brain circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat Neurosci 10:116–1124CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Nikolaos Pitsikas
    • 1
    Email author
  • Georgia Georgiadou
    • 1
  • Foteini Delis
    • 2
  • Katerina Antoniou
    • 2
  1. 1.Department of Pharmacology, School of Medicine, Faculty of Health SciencesUniversity of ThessalyLarissaGreece
  2. 2.Department of Pharmacology, Faculty of Medicine, School of Health SciencesUniversity of IoanninaIoanninaGreece

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