Hostname: page-component-78c5997874-t5tsf Total loading time: 0 Render date: 2024-11-10T12:03:22.221Z Has data issue: false hasContentIssue false
  • English
  • Français

Evaluation of acetylcholinesterase activity and behavioural alterations induced by ketamine in an animal model of schizophrenia

Published online by Cambridge University Press:  17 June 2013

Alexandra I. Zugno ,
Maria Paula Matos ,
Leila Canever ,
Daiane B. Fraga ,
Renata D. De Luca ,
Fernando V. Ghedim ,
Pedro F. Deroza ,
Mariana B. de Oliveira ,
Felipe D. Pacheco  and
Samira S. Valvassori
...Show all authors
Alexandra I. Zugno*
Affiliation:
Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
Maria Paula Matos
Affiliation:
Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
Leila Canever
Affiliation:
Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
Daiane B. Fraga
Affiliation:
Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
Renata D. De Luca
Affiliation:
Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
Fernando V. Ghedim
Affiliation:
Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
Pedro F. Deroza
Affiliation:
Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
Mariana B. de Oliveira
Affiliation:
Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
Felipe D. Pacheco
Affiliation:
Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
Samira S. Valvassori
Affiliation:
Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
Ana Maria Volpato
Affiliation:
Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
Josiane Budni
Affiliation:
Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
João Quevedo
Affiliation:
Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), and Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
*
Prof. Alexandra Ioppi Zugno, Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil. Tel: +55 48 3431-2792;Fax: +55 48 3431-2618; E-mail: alz@unesc.net
Get access Rights & Permissions [Opens in a new window]

Abstract

Objective

Cognitive deficits in schizophrenia play a crucial role in its clinical manifestation and seem to be related to changes in the cholinergic system, specifically the action of acetylcholinesterase (AChE). Considering this context, the aim of this study was to evaluate the chronic effects of ketamine in the activity of AChE, as well as in behavioural parameters involving learning and memory.

Methods

The ketamine was administered for 7 days. A duration of 24 h after the last injection, the animals were submitted to behavioural tests. The activity of AChE in prefrontal cortex, hippocampus and striatum was measured at different times after the last injection (1, 3, 6 and 24 h).

Results

The results indicate that ketamine did not affect locomotor activity and stereotypical movements. However, a cognitive deficit was observed in these animals by examining their behaviour in inhibitory avoidance. In addition, an increase in AChE activity was observed in all structures analysed 1, 3 and 6 h after the last injection. Differently, serum activity of AChE was similar between groups.

Conclusion

Chronic administration of ketamine in an animal model of schizophrenia generates increased AChE levels in different brain tissues of rats that lead to cognitive deficits. Therefore, further studies are needed to elucidate the complex mechanisms associated with schizophrenia.

Keywords

acetylcholinesteraseketaminememoryschizophrenia
Type
Original Articles
Information
Acta Neuropsychiatrica , Volume 26 , Issue 1 , February 2014 , pp. 43 - 50
Copyright
Copyright © Scandinavian College of Neuropsychopharmacology 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1.Weiden, PJ, Buckley, PF, Grody, M. Understanding and Treating ‘First-Episode’ Schizophrenia. Psychiatr Clin North Am 2007;30:481–510.Google Scholar
2.Kraepelin, E, Robertson, GM, Barclay, RM, eds. Dementia Praecox and Paraphrenia. Huntington, NY: Krieger Publishing Co, 1971:3–4.Google Scholar
3.Healy, D. The creation of psychopharmacology. Cambridge, MA, USA: Harvard University Press, 2002.Google Scholar
4.Thornicroft, G, Tansella, M, Becker, Tet al. The personal impact of schizophrenia in Europe. Schizophr Res 2004;69:125–132.Google Scholar
5.Carlsson, A, Waters, N, Carlsson, ML. Neurotransmitter interactions in schizophrenia-therapeutic implications. Eur Arch Psychiatry Clin Neurosci 1999;249:37–43.Google Scholar
6.Grace, AA. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 1999;41:1–24.Google Scholar
7.Jentsch, JD, Roth, RH. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacoly 1999;20:201–225.Google Scholar
8.Coyle, JT, Tsai, G, Goff, D. Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann NY Acad Sci 2003;1003:318–327.Google Scholar
9.Sawada, K, Barr, AM, Nakamura, MK. Hippocampal complexin proteins and cognitive dysfunction in schizophrenia. Arch Gen Psychiatry 2005;62:263–272.Google Scholar
10.Woolf, NJ, Butcher, LL. Cholinergic systems in the rat brain: III. Projections from the pontomesencephalic tegmentum to the thalamus, tectum, basal ganglia, and basal forebrain. Brain Res Bull 1986;16:603–637.Google Scholar
11.Yakel, JL. Cholinergic receptors: functional role of nicotinic ACh receptors in brain circuits and disease. Pflugers Arch 2013;465:441–450.Google Scholar
12.Hutson, PH, Hogg, JE. Effects of and interactions between antagonists for different sites on the NMDA receptor complex on hippocampal and striatal acetylcholine efflux in vivo. Eur J Pharmacol 1996;295:45–52.Google Scholar
13.Gu, Z, Yakel, JL. Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity. Neuron 2011;71:155–165.Google Scholar
14.De Leon, J, Diaz, FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr Res 2005;76:135–157.Google Scholar
15.Nishimoto, T, Kadoyama, K, Taniguchi, Tet al. Synaptotagmin1 synthesis induced by synaptic plasticity in mouse hippocampus through activation of nicotinic acetylcholine receptors. Neurosci Lett 2011;489:25–29.Google Scholar
16.Soreq, H, Seidman, S. Acetylcholinesterase: new roles for an old actor. Nat Rev Neurosci 2001;4:294–302.Google Scholar
17.Calabria, M, Geroldi, C, Lussignoli, G, Sabbatini, F, Zanetti, O. Efficacy of acetyl-cholinesterase-inhibitor (ACHEI) treatment in alzheimer's disease: a 21-month follow-up ‘real world’ study. Arch Gerontol Geriatr 2009;49:6–11.Google Scholar
18.Bergman, J, Lerner, V. Successful use of donepezil for the treatment of psychotic symptoms in patients with Parkinson's disease. Clin Neuropharmacolog 2002;25:107–110.Google Scholar
19.Ribeiz, SR, Bassitt, DP, Arrais, JA, Avila, R, Steffens, DC, Bottino, CM. Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature. CNS Drugs 2010;24(4):303–317.Google Scholar
20.Becker, A, Peters, B, Shroeder, H, Mann, T, Huether, G, Grecksch, G. Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:687–700.Google Scholar
21.Do, KQ, Cabungcal, JH, Frank, A, Steullet, P, Cuenod, M. Redox dysregulation, neurodevelopment, and schizophrenia. Curr Opin Neurobiol 2009;19:220–230.Google Scholar
22.Becker, A, Grecksch, G. Ketamine-induced changes in rat behavior: a possible animal model of schizophrenia. Test of predictive validity. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:1267–1277.Google Scholar
23.Krystal, JH, Karper, LP, Seibyl, JP, Freeman, GK, Delaney, R, Bremner, JD. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994;51:199–214.Google Scholar
24.Battisti, JJ, Shreffler, CB, Uretsky, NJ, Wallace, LJ. NMDA antagonists block expression of sensitization of amphetamine- and apomorphine-induced stereotypy. Pharmacol Biochem Behav 2000;67:241–246.Google Scholar
25.De Oliveira, L, Fraga, DB, De Luca, RDet al. Behavioral changes and mitochondrial dysfunction in a rat model of schizophrenia induced by ketamine. Metab Brain Dis 2011;26:69–77.Google Scholar
26.Quevedo, J, Vianna, M, Zanatta, MS, Roesler, R, Izquierdo, I, Jerusalinsky, D. Involvement of mechanisms dependent on NMDA receptors, nitric oxide and protein kinase A in the hippocampus but not in the caudate nucleus in memory. Behav Pharmacol 1997;8:713–717.Google Scholar
27.Roesler, R, Schröder, N, Vianna, MR, Quevedo, J, Bromberg, E, Kapczinski, F. Differential involvement of hippocampal and amygdalar NMDA receptors in contextual and aversive aspects of inhibitory avoidance memory in rats. Brain Res 2003;975:207–213.CrossRefGoogle ScholarPubMed
28.Barros, DM, Ramirez, MR, Izquierdo, I. Modulation of working, short- and long-term memory by nicotinic receptors in the basolateral amygdala in rats. Neurobiol Learn Mem 2005;83:113–118.Google Scholar
29.Izquierdo, I, Medina, JA. Mechanisms for memory types differ. Nature 1998;393:635–636.Google Scholar
30.Bevilaqua, LRM, Rossato, JI, Clarke, JHR, Medina, JH, Izquierdo, I, Cammarota, M. Inhibition of hippocampal jun N-terminal kinase enhances short term memory but blocks long-term memory formation and retrieval of an inhibitory avoidance task. Eur J Neurosci 2003;17:897–902.Google Scholar
31.Lima, MN, Laranja, DC, Bromberg, E, Roesler, R, Schröder, N. Pre- or post-training administration of the NMDA receptor blocker MK-801 impairs object recognition memory in rats. Behav Brain Res 2005;156:139–143.Google Scholar
32.Ennaceur, A, Delacour, J. A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data. Behav Brain Res 1988;31:47–59.Google Scholar
33.Pitsikas, N, Boultadakis, A. Pre-training administration of anesthetic ketamine differentially affects rats’ spatial and non-spatial recognition memory. Neuropharmacology 2009;57:1–7.Google Scholar
34.Ellman, GL, Courtney, KD, Andres, V Jr, Feather-Stone, RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 2006;7:88–95.Google Scholar
35.Lowry, OH, Rosebrough, NJ, Farr, AL, Randall, RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265–267.CrossRefGoogle ScholarPubMed
36.Elvevag, B, Goldberg, TE. Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev Neurobiol 2000;14:1–21.Google Scholar
37.Reichenberg, A. A population-based cohort study of premorbid intellectual, language, and behavioral functioning in patients with schizophrenia, schizoaffective disorder, and nonpsychotic bipolar disorder. Am J Psychiatry 2002;159:2027–2035.Google Scholar
38.Keefe, RS, Fenton, WS. How should DSM-V criteria for schizophrenia include cognitive impairment? Schizophr Bull 2007;33:912–920.Google Scholar
39.Green, MF, Kern, RS, Braff, DL, Mintz, J. Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the ‘right stuff’? Schizophr Bull 2000;26:119–136.Google Scholar
40.Green, MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996;153:321–330.Google Scholar
41.Addington, J, Addington, D, Gasbarre, L. Neurocognitive and social functioning in schizophrenia and other diagnoses. Schizophr Res 2001;48:367–368.Google Scholar
42.Chatterjee, M, Ganguly, S, Srivastava, M, Palit, G. Effect of ‘chronic’ versus ‘acute’ ketamine administration and its ‘withdrawal’ effect on behavioural alterations in mice: implications for experimental psychosis. Behav Brain Res 2011;216:247–254.Google Scholar
43.Vutskits, L, Gascon, E, Potter, G, Tassonyi, E, Kiss, JZ. Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture. Toxicology 2007;234:216–226.Google Scholar
44.Gama, CS, Canever, L, Panizzutti, Bet al. Effects of omega-3 dietary supplement in prevention of positive, negative and cognitive symptoms: a study in adolescent rats with ketamine-induced model of schizophrenia. Schizophr Res 2012;141:162–167.Google Scholar
45.Imre, G, Fokkema, DS, Den Boer, JA, Ter Horst, GJ. Dose-response characteristics of ketamine effect on locomotion, cognitive function and central neuronal activity. Brain Res Bull 2006;14:338–345.Google Scholar
46.Kos, T, Popik, P, Pietraszek, Met al. Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice. Eur Neuropsychopharmacol 2006;16:297–310.Google Scholar
47.Pitsikas, N, Boultadakis, A, Sakellaridis, N. Effects of sub-anesthetic doses of ketamine on rats’ spatial and non-spatial recognition memory. Neuroscience 2008;154:454–460.Google Scholar
48.Gold, PE. Acetylcholine modulation of neural systems involved in learning and memory. Neurobiol Learn Mem 2003;80:194–210.Google Scholar
49.Sarter, M, Nelson, CL, Bruno, JP. Cortical cholinergic transmission and cortical information processing in schizophrenia. Schizophr Bull 2005;31:117–138.Google Scholar
50.Prado, VF, Martins-Silva, C, De Castro, BM, Lima, RF, Barros, DM, Amaral, E. Mice deficient for the vesicular acetylcholine transporter are myasthenic and have deficits in object and social recognition. Neuron 2006;51:601–612.Google Scholar
51.Sarter, M, Paolone, G. Deficits in attentional control: cholinergic mechanisms and circuitry-based treatment approaches. Behav Neurosci 2011;125(6):825–835.Google Scholar
52.Hut, RA, Van der Zee, EA. The cholinergic system, circadian rhythmicity, and time memory. Behav Brain Res 2011;221(2):466–480.Google Scholar
53.Bradford, A. The dopamine and glutamate theories of schizophrenia: a short review. Curr Anesth Crit Care 2009;20:240–241.Google Scholar
54.Colgin, LL, Kubota, D, Lynch, G. Cholinergic plasticity in the hippocampus. Neuroscience 2003;100:2872–2877.Google Scholar
55.Lorrain, DS, Baccei, CS, Bristow, LJ, Anderson, JJ, Varney, MA. Effects of ketamine and N-methyl-d-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience 2003;117:697–706.CrossRefGoogle ScholarPubMed
56.Hallanger, AE, Wainer, BH, Rye, DB. Colocalization of gamma-aminobutyric acid and acetylcholinesterase in rodent cortical neurons. J Neurosci 2006;26:1588–1595.Google Scholar
57.Allen, TGJ, Abogadie, FC, Brown, DA. Simultaneous release of glutamate and acetylcholine from single magnocellular ‘cholinergic’ basal forebrain neurons. J Neurosci 2006;26:1588–1595.Google Scholar
58.Powell, JA, Rieger, F, Holmes, N. Acetylcholinesterase is regulated by action potential generation and not by muscle contractile activity per se in mouse muscle in vitro. Neurosci Lett 1986;68:277–281.Google Scholar
59.McCreadile, RG. On behalf of the Scottish Comorbidity Study Group: use of drugs, alcohol and tobacco by people with schizophrenia: case-control study. J Psychiatry 2002;181:321–325.Google Scholar
60.Lherena, A, De la Rubia, A, Peñas-Lledó, EM. Schizophrenia and tobacco smoking in a Spanish psychiatric hospital. Schizoph Res 2003;60:313–317.Google Scholar
61.Aguilar, MC, Gurpegui, M, Dias, F, de Leon, J. Nicotine dependence and symptoms in schizophrenia: naturalistic study of complex interactions. Br J Psychiatry 2005;186:215–221.Google Scholar
62.Ziedonis, DM, Kosten, TR, Glazer, WM, Frances, RJ. Nicotine dependence and schizophrenia. Hosp Community Psychiatry 1994;45:204–206.Google Scholar
63.Kalman, D, Morissette, SB, George, TP. Co-morbidity of smoking in patients with psychiatric and substance use disorders. Am J Addict 2005;14:106–123.Google Scholar
64.Harvey, CR, Curson, DA, Pantelis, C. Four behavioural syndromes of schizophrenia. Br J Psychiatry 1996;168:562–570.Google Scholar