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The Effects of NMDA Receptor Antagonists on Attentional Set-Shifting Task Performance in Mice

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The Effects of NMDA Receptor Antagonists on Attentional Set-Shifting Task Performance in Mice Psychopharmacology (2011) 214:911–921 DOI 10.1007/s00213-010-2102-6 ORIGINAL INVESTIGATION The effects of NMDA receptor antagonists on attentional set-shifting task performance in mice Tomasz Kos & Agnieszka Nikiforuk & Dominik Rafa & Piotr Popik Received: 29 April 2010 /Accepted: 11 November 2010 /Published online: 16 December 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com. Abstract a facilitation of cognitive flexibility. Finally, as revealed by the Rationale and objectives Cognitive deficits, including an number of trials and time to criterion measures, Ro 25-6981 impaired ability to shift perceptual attentional set, belong to (10 mg/kg) administration to ketamine (10 mg/kg)-pretreated the core features of schizophrenia, are associated with mice inhibited ketamine-induced cognitive inflexibility. prefrontal cortical dysfunctions, and may involve glutamate Conclusion The present study provides an improved and NMDA receptors. Although phencyclidine disturbs cogni- reliable mouse ASST protocol and confirms and extends tive flexibility, little is known about the effects of ketamine previous findings demonstrating that NR2B subunit- and other NMDA antagonists that differ in receptor subunit selective antagonists improve cognitive processes. selectivity, particularly in the mouse species. Methods At different times following the administration of Keywords Ketamine . NMDA receptor antagonist . ketamine, the NMDA NR2B-subtype specific antagonist NR2B-selective antagonist . Mouse . Cognition . Ro 25-6981, or the atypical antipsychotic sertindole, male Schizophrenia . Animal model C57Bl/6J mice were investigated in a modified version of attentional set-shifting task (ASST). Results Specific extra-dimensional shift (EDS) deficit was Introduction observed in all control mice. As revealed by the increased number of trials, time and errors to reach criterion, Schizophrenia is characterized by well-known “positive” ketamine at 10 or 20 mg/kg given 50 min prior to sessions, and “negative” symptoms and by less recognized cognitive but not at 10 mg/kg given 3 or 24 h prior to sessions, further deficits in executive functions, working memory, and worsened the EDS performance. Sertindole (2.5 mg/kg) attention (Bowie and Harvey 2006). These cognitive prevented ketamine-induced cognitive inflexibility, although deficits are present at the onset of illness, persist without it did not affect ASST performance when given alone. In remission throughout most of patients’ lives, and may contrast to ketamine, Ro 25-6981 at 10 but not 3 mg/kg, precede the development of “positive” symptoms (Brewer reduced the number of trials and errors to criterion, suggesting et al. 2006). Flexibility in response to a change in attentional set toward stimuli is controlled by the prefrontal cortex (PFC) and is commonly assessed in patients using T. Kos : A. Nikiforuk : D. Rafa : P. Popik (*) the Wisconsin Card Sorting Test (WCST; Grant and Berg Behavioral Neuroscience, Institute of Pharmacology, 1948; Elliott et al. 1998). A poor WCST performance is Polish Academy of Sciences, observed not only in schizophrenics but also in patients 12 Smętna Street, 31-343, Kraków, Poland with frontal lobe damage (Pantelis et al. 1999). e-mail: [email protected] The impairments in executive functions observed in WCST in humans can be investigated using a rodent P. Popik version of the attentional set-shifting task (ASST) devel- Faculty of Public Health, Collegium Medicum, Jagiellonian University, oped by Birrell and Brown (2000). The ASST requires Kraków, Poland animals to initially learn a rule and form “an attentional set” 912 Psychopharmacology (2011) 214:911–921 within the same stimulus dimension, by discriminating to investigate whether sertindole could reverse ketamine- between, e.g., the odors associated with food reward. induced deficits in the mouse version of the ASST. During the extra-dimensional (ED) shift, the crucial and NMDA receptors are heteromers composed of an obliga- most difficult part of the test, the subjects have to rapidly tory NR1 (mouse zeta 1) subunit and of at least one type of the switch their attention to a new and previously irrelevant NR2 (NR2A–NR2D; mouse epsilon 1–4) subunits (Laube et stimulus dimension and to discriminate between, e.g., the al. 1998; Schorge and Colquhoun 2003). The type of NR2 media covering the food reward. Although an increasing subunit constituting the NMDA receptor affects its physio- number of laboratories have successfully used the ASST in logical and pharmacological properties (Monaghan and rats, most of the attempts to adapt this procedure for use in Larsen 1997; Loftis and Janowsky 2003). In addition, the mice have failed to demonstrate an ED shift deficit brain distribution of NR2 subunits is not uniform (Monyer et (Colacicco et al. 2002; Laurent and Podhorna 2004; Zhuo al. 1994; Wenzel et al. 1995); although NR2A messenger et al. 2007;Levietal.2008). Only one procedure, RNA (mRNA) is distributed particularly in the cerebral described by Garner et al. (2006) and replicated with slight cortex, hippocampus, and cerebellum, the NR2B transcript is modification by Papaleo et al. (2008), has shown a selectively present in the forebrain with a high level of significant extra-dimensional shift (EDS) phase deficit in expression in the cerebral cortex, hippocampus, septum, this species. However, our laboratory was unable to caudate–putamen, and olfactory bulb. The NR2C mRNA is demonstrate an ED shift impairment even with these expressed predominantly in the cerebellum, and the NR2D modifications, and therefore, the first goal of the present transcript is detected in the thalamus, brain stem, and study was to establish the conditions allowing for the olfactory bulb. The NR2C and NR2D transcripts are found measurement of reliable set-shifting in mice. in a subset of hippocampal neurons, which are most likely Converging lines of evidence indicate the involvement interneurons (Ozawa et al. 1998). of glutamate NMDA transmission in schizophrenia. A This pattern of distribution suggests that subunit-specific single dose of an NMDA receptor antagonist, such as NMDA antagonists may have differential effects under various phencyclidine (PCP) or ketamine, induces symptoms of physiological and pathological conditions (Skolnick et al. acute psychosis in healthy volunteers (Luby 1959; Javitt 2009). Although ketamine is regarded as an NR2-unspecific and Zukin 1991). Because these symptoms are indistin- antagonist (Dravid et al. 2007), recent data indicate that it guishable from some symptoms of schizophrenia (Krystal mainly affects NR1/2C and NR1/2D NMDA receptors et al. 1994), antagonists of NMDA receptors are routinely (Kotermanski and Johnson 2009). Due to its antagonistic used in preclinical research as a pharmacological model of action at hippocampal NMDA receptors, ketamine may cause this psychosis (Olney and Farber 1995; Jentsch and Roth cortical disinhibition, which is relevant to some symptoms of 1999). The acute administration of ketamine impairs schizophrenia, including cognitive inflexibility (Greene 2001; attentional set-shifting as measured by the WCST in healthy Homayoun and Moghaddam 2007;Lismanetal.2008). In humans (Krystal et al. 2000) and in the rat (Nikiforuk et al. contrast, the NR2B-selective antagonist, CP-101,606 (trax- 2010). Therefore, the second goal of the present study was oprodil), under certain test conditions, improves cognitive to investigate the ketamine-induced impairment of ASST in flexibilityasassessedbythefive-choiceserialreactiontime mice. task (5-CSRT; Higgins et al. 2005). Therefore, the fourth goal Compared to conventional antipsychotics, relatively of the present study was to investigate the effects of an novel atypical compounds, such as sertindole, display an NR2B-selective antagonist alone and in combination with advantageous profile of pro-cognitive actions in schizo- ketamine in the ASST procedure. We used the Ro 25-6981 phrenia. A recent multi-center, randomized, double-blinded compound [(aR,bS)-a-(4-hydroxyphenyl)-b-methyl-4-(phenyl- clinical trial indicated a beneficial effect of sertindole on methyl)-1-piperidinepropanol hydrochloride] that is character- executive functions in patients with schizophrenia ized by a >5,000-fold selectivity for NR2C/NR2B over (Gallhofer et al. 2007); this medication also reduced the NR2C/NR2A subunits of the NMDA receptor, use- debilitating effects of ketamine in the Stroop task in healthy dependent binding properties and neuroprotective effects volunteers (Vollenweider et al. 1999). Several preclinical against glutamate toxicity (Fischer et al. 1997). studies have shown that sertindole reduces or reverses the impairing effects of subchronic PCP treatment (Rodefer et al. 2008; Broberg et al. 2009; Goetghebeur and Dias 2009) Materials and methods and of an acute dose of ketamine (Nikiforuk et al. 2010)in the rat ASST. An obligatory step in the validation of a Ethics given procedure relies on the demonstration of a positive effect of the medication previously found to be effective in The experiments were conducted in accordance with the similar conditions. The third goal of the present study was NIH Guide for the Care and Use of Laboratory Animals Psychopharmacology (2011) 214:911–921 913 Table 1 Pairs of different stim- uli used in the mouse version of Dimension Exemplar pairs the ASST Odor Orange Lemon Spicy Cream Arrack Almond Vanilla Rum Medium Fine gravel Crumpled tissue Cardboard Bamboo sticks Beads Aluminum
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