Patients with schizophrenia often manifest deficits in behavioral flexibility. Non-competitive NMDA receptor antagonists such as MK-801 induce schizophrenia-like symptoms in rodents, including cognitive functions. Despite work exploring flexibility has been done employing behavioral paradigms with simple stimuli, much less is known about what kinds of flexibility are affected in an MK-801 model of schizophrenia-like behavior in the spatial domain. We used a rotating arena-based apparatus (Carousel) requiring rats to avoid an unmarked sector defined in either the reference frame of the rotating arena (arena frame task, AF) or the stationary room (room frame task, RF). We investigated behavioral flexibility in four conditions involving different cognitive loads. Each condition encompassed an initial (five sessions) and a test phase (five sessions) in which some aspects of the task were changed to test flexibility and in which rats were given saline, 0.05 mg/kg or 0.1 mg/kg MK-801 thirty minutes prior to a session. In the first condition, rats acquired avoidance in RF with clockwise rotation of the arena while in the test phase the arena rotated counterclockwise. In the second condition, rats initially acquired avoidance in RF with the sector on the north and then it was reversed to south (spatial reversal). In the third and fourth conditions, rats initially performed an AF (RF, respectively) task, followed by an RF (AF, respectively) task, testing the ability of cognitive set-shifting. We found no effect of MK-801 either on simple motor adjustment after reversal of arena rotation or on spatial reversal within the RF. In contrast, administration of MK-801 at a dose of 0.1 mg/kg interfered with set-shifting in both conditions. Furthermore, we observed MK-801 0.1 mg/kg elevated locomotion in all cases. These data suggest that blockade of NMDA receptors by acute system administration of MK-801 preferentially affects set-shifting in the cognitive domain rather than reversal.

Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic ; Laboratory of Neurobehavioral Studies National Institute of Mental Health Klecany Prague Czech Republic

Front Behav Neurosci. 2015 Dec 16;9:348. doi: 10.3389/fnbeh.2015.00348. PubMed

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Ahlander M., Misane I., Schött P. A., Ogren S. O. (1999). A behavioral analysis of the spatial learning deficit induced by the NMDA receptor antagonist MK-801 (dizocilpine) in the rat. Neuropsychopharmacology 21, 414–426. 10.1016/s0893-133x(98)00116-x PubMed DOI

Amitai N., Markou A. (2010). Disruption of performance in the five-choice serial reaction time task induced by administration of N-methyl-D-aspartate receptor antagonists: relevance to cognitive dysfunction in schizophrenia. Biol. Psychiatry 68, 5–16. 10.1016/j.biopsych.2010.03.004 PubMed DOI PMC

Beninger R. J., Forsyth J. K., Van Adel M., Reynolds J. N., Boegman R. J., Jhamandas K. (2009). Subchronic MK-801 behavioural deficits in rats: partial reversal by the novel nitrate GT 1061. Pharmacol. Biochem. Behav. 91, 495–502. 10.1016/j.pbb.2008.09.003 PubMed DOI

Birrell J. M., Brown V. J. (2000). Medial frontal cortex mediates perceptual attentional set shifting in the rat. J. Neurosci. 20, 4320–4324. PubMed PMC

Bubenikova-Valesova V., Stuchlik A., Svoboda J., Bures J., Vales K. (2008). Risperidone and ritanserin but not haloperidol block effect of dizocilpine on the active allothetic place avoidance task. Proc. Natl. Acad. Sci. U S A 105, 1061–1066. 10.1073/pnas.0711273105 PubMed DOI PMC

Bures J., Fenton A. A., Kaminsky Y., Rossier J., Sacchetti B., Zinyuk L. (1997). Dissociation of exteroceptive and idiothetic orientation cues: effect on hippocampal place cells and place navigation. Philos. Trans. R. Soc. Lond. B Biol. Sci. 352, 1515–1524. 10.1098/rstb.1997.0138 PubMed DOI PMC

Chadman K. K., Watson D. J., Stanton M. E. (2006). NMDA receptor antagonism impairs reversal learning in developing rats. Behav. Neurosci. 120, 1071–1083. 10.1037/0735-7044.120.5.1071 PubMed DOI PMC

Cimadevilla J. M., Fenton A. A., Bures J. (2000). Functional inactivation of dorsal hippocampus impairs active place avoidance in rats. Neurosci. Lett. 285, 53–56. 10.1016/s0304-3940(00)01019-3 PubMed DOI

Cimadevilla J. M., Wesierska M., Fenton A. A., Bures J. (2001). Inactivating one hippocampus impairs avoidance of a stable room-defined place during dissociation of arena cues from room cues by rotation of the arena. Proc. Natl. Acad. Sci. U S A 98, 3531–3536. 10.1073/pnas.051628398 PubMed DOI PMC

de Bruin N. M., van Drimmelen M., Kops M., van Elk J., Wetering M. M., Schwienbacher I. (2013). Effects of risperidone, clozapine and the 5-HT6 antagonist GSK-742457 on PCP-induced deficits in reversal learning in the two-lever operant task in male Sprague Dawley rats. Behav. Brain Res. 244, 15–28. 10.1016/j.bbr.2013.01.035 PubMed DOI

Egerton A., Reid L., McKerchar C. E., Morris B. J., Pratt J. A. (2005). Impairment in perceptual attentional set-shifting following PCP administration: a rodent model of set-shifting deficits in schizophrenia. Psychopharmacology (Berl) 179, 77–84. 10.1007/s00213-004-2109-y PubMed DOI

Fenton A. A., Wesierska M., Kaminsky Y., Bures J. (1998). Both here and there: simultaneous expression of autonomous spatial memories in rats. Proc. Natl. Acad. Sci. U S A 95, 11493–11498. 10.1073/pnas.95.19.11493 PubMed DOI PMC

Floresco S. B., Zhang Y., Enomoto T. (2009). Neural circuits subserving behavioral flexibility and their relevance to schizophrenia. Behav. Brain Res. 204, 396–409. 10.1016/j.bbr.2008.12.001 PubMed DOI

Gastambide F., Cotel M. C., Gilmour G., O’Neill M. J., Robbins T. W., Tricklebank M. D. (2012). Selective remediation of reversal learning deficits in the neurodevelopmental MAM model of schizophrenia by a novel mGlu5 positive allosteric modulator. Neuropsychopharmacology 37, 1057–1066. 10.1038/npp.2011.298 PubMed DOI PMC

Goff D. C., Coyle J. T. (2001). The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am. J. Psychiatry 158, 1367–1377. 10.1176/appi.ajp.158.9.1367 PubMed DOI

Hamilton D. A., Brigman J. L. (2015). Behavioral flexibility in rats and mice: contributions of distinct frontocortical regions. Genes Brain Behav. 14, 4–21. 10.1111/gbb.12191 PubMed DOI PMC

Kelemen E., Fenton A. A. (2010). Dynamic grouping of hippocampal neural activity during cognitive control of two spatial frames. PLoS Biol. 8:e1000403. 10.1371/journal.pbio.1000403 PubMed DOI PMC

Kubík S., Buchtová H., Valeš K., Stuchlík A. (2014). MK-801 impairs cognitive coordination on a rotating Arena (Carousel) and contextual specificity of hippocampal immediate-early gene expression in a rat model of psychosis. Front. Behav. Neurosci. 8:75. 10.3389/fnbeh.2014.00075 PubMed DOI PMC

LaCrosse A. L., Burrows B. T., Angulo R. M., Conrad P. R., Himes S. M., Mathews N., et al. . (2015). mGluR5 positive allosteric modulation and its effects on MK-801 induced set-shifting impairments in a rat operant delayed matching/non-matching-to-sample task. Psychopharmacology (Berl) 232, 251–258. 10.1007/s00213-014-3653-8 PubMed DOI PMC

Lobellová V., Brichtová E., Petrásek T., Valeš K., Stuchlík A. (2014). Higher doses of (+)MK-801 (dizocilpine) induced mortality and procedural but not cognitive deficits in delayed testing in the active place avoidance with reversal on the Carousel. Physiol. Res. [Epub ahead of print]. PubMed

Lobellova V., Entlerova M., Svojanovska B., Hatalova H., Prokopova I., Petrasek T., et al. . (2013). Two learning tasks provide evidence for disrupted behavioural flexibility in an animal model of schizophrenia-like behaviour induced by acute MK-801: a dose-response study. Behav. Brain Res. 246, 55–62. 10.1016/j.bbr.2013.03.006 PubMed DOI

Morice R. (1990). Cognitive inflexibility and pre-frontal dysfunction in schizophrenia and mania. Br. J. Psychiatry 157, 50–54. 10.1192/bjp.157.1.50 PubMed DOI

Murray G. K., Cheng F., Clark L., Barnett J. H., Blackwell A. D., Fletcher P. C., et al. . (2008). Reinforcement and reversal learning in first-episode psychosis. Schizophr. Bull. 34, 848–855. 10.1093/schbul/sbn078 PubMed DOI PMC

Olney J. W., Farber N. B. (1995). Glutamate receptor dysfunction and schizophrenia. Arch. Gen. Psychiatry 52, 998–1007. 10.1001/archpsyc.1995.03950240016004 PubMed DOI

Orellana G., Slachevsky A. (2013). Executive functioning in schizophrenia. Front. Psychiatry 4:35. 10.3389/fpsyt.2013.00035 PubMed DOI PMC

Pantelis C., Barber F. Z., Barnes T. R., Nelson H. E., Owen A. M., Robbins T. W. (1999). Comparison of set-shifting ability in patients with chronic schizophrenia and frontal lobe damage. Schizophr. Res. 37, 251–270. 10.1016/s0920-9964(98)00156-x PubMed DOI

Rodefer J. S., Saland S. K., Eckrich S. J. (2012). Selective phosphodiesterase inhibitors improve performance on the ED/ID cognitive task in rats. Neuropharmacology 62, 1182–1190. 10.1016/j.neuropharm.2011.08.008 PubMed DOI

Shapiro M. L., Tanila H., Eichenbaum H. (1997). Cues that hippocampal place cells encode: dynamic and hierarchical representation of local and distal stimuli. Hippocampus 7, 624–642. 10.1002/(sici)1098-1063(1997)7:6<624::aid-hipo5>3.3.co;2-t PubMed DOI

Stefani M. R., Moghaddam B. (2005). Systemic and prefrontal cortical NMDA receptor blockade differentially affect discrimination learning and set-shift ability in rats. Behav. Neurosci. 119, 420–428. 10.1037/0735-7044.119.2.420 PubMed DOI

Stefani M. R., Moghaddam B. (2010). Activation of type 5 metabotropic glutamate receptors attenuates deficits in cognitive flexibility induced by NMDA receptor blockade. Eur. J. Pharmacol. 639, 26–32. 10.1016/j.ejphar.2010.01.028 PubMed DOI PMC

Stuchlik A., Rezacova L., Vales K., Bubenikova V., Kubik S. (2004). Application of a novel Active Allothetic Place Avoidance task (AAPA) in testing a pharmacological model of psychosis in rats: comparison with the Morris Water Maze. Neurosci. Lett. 366, 162–166. 10.1016/j.neulet.2004.05.037 PubMed DOI

Vales K., Bubenikova-Valesova V., Klement D., Stuchlik A. (2006). Analysis of sensitivity to MK-801 treatment in a novel active allothetic place avoidance task and in the working memory version of the Morris water maze reveals differences between long-evans and Wistar rats. Neurosci. Res. 55, 383–388. 10.1016/j.neures.2006.04.007 PubMed DOI

van der Meulen J. A., Bilbija L., Joosten R. N., de Bruin J. P., Feenstra M. G. (2003). The NMDA-receptor antagonist MK-801 selectively disrupts reversal learning in rats. Neuroreport 14, 2225–2228. 10.1097/00001756-200312020-00018 PubMed DOI

van der Staay F. J., Rutten K., Erb C., Blokland A. (2011). Effects of the cognition impairer MK-801 on learning and memory in mice and rats. Behav. Brain Res. 220, 215–229. 10.1016/j.bbr.2011.01.052 PubMed DOI

Wesierska M., Dockery C., Fenton A. A. (2005). Beyond memory, navigation and inhibition: behavioral evidence for hippocampus-dependent cognitive coordination in the rat. J. Neurosci. 25, 2413–2419. 10.1523/jneurosci.3962-04.2005 PubMed DOI PMC

Wesierska M., Klinowska H. D., Adamska I., Fresko I., Sadowska J., Albrecht J. (2006). Cognitive flexibility but not cognitive coordination is affected in rats with toxic liver failure. Behav. Brain Res. 171, 70–77. 10.1016/j.bbr.2006.03.019 PubMed DOI

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