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 Rationale and objectives Cognitive deficits, including an impaired ability to shift perceptual attentional set, belong to the core features of schizophrenia, are associated with prefrontal cortical dysfunctions, and may involve glutamate NMDA receptors. Although phencyclidine disturbs cogni- tive flexibility, little is known about the effects of ketamine and other NMDA antagonists that differ in receptor subunit selectivity, particularly in the mouse species. Methods At different times following the administration of ketamine, the NMDA NR2B-subtype specific antagonist Ro 25-6981, or the atypical antipsychotic sertindole, male C57Bl/6J mice were investigated in a modified version of attentional set-shifting task (ASST). Results Specific extra-dimensional shift (EDS) deficit was observed in all control mice. As revealed by the increased number of trials, time and errors to reach criterion, ketamine at 10 or 20 mg/kg given 50 min prior to sessions, but not at 10 mg/kg given 3 or 24 h prior to sessions, further worsened the EDS performance. Sertindole (2.5 mg/kg) prevented ketamine-induced cognitive inflexibility, although it did not affect ASST performance when given alone. In contrast to ketamine, Ro 25-6981 at 10 but not 3 mg/kg, reduced the number of trials and errors to criterion, suggesting T. Kos : A. Nikiforuk : D. Rafa : P. Popik (*) Behavioral Neuroscience, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343, Kraków, Poland e-mail: nfpopik@cyf-kr.edu.pl P. Popik Faculty of Public Health, Collegium Medicum, Jagiellonian University, Kraków, Poland a facilitation of cognitive flexibility. Finally, as revealed by the number of trials and time to criterion measures, Ro 25-6981 (10 mg/kg) administration to ketamine (10 mg/kg)-pretreated mice inhibited ketamine-induced cognitive inflexibility. Conclusion The present study provides an improved and reliable mouse ASST protocol and confirms and extends previous findings demonstrating that NR2B subunit- selective antagonists improve cognitive processes. Keywords Ketamine . NMDA receptor antagonist . NR2B-selective antagonist . Mouse . Cognition . Schizophrenia . Animal model Introduction Schizophrenia is characterized by well-known “positive” and “negative” symptoms and by less recognized cognitive deficits in executive functions, working memory, and attention (Bowie and Harvey 2006). These cognitive deficits are present at the onset of illness, persist without remission throughout most of patients’ lives, and may precede the development of “positive” symptoms (Brewer 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 the Wisconsin Card Sorting Test (WCST; Grant and Berg 1948; Elliott et al. 1998). A poor WCST performance is observed not only in schizophrenics but also in patients with frontal lobe damage (Pantelis et al. 1999). The impairments in executive functions observed in WCST in humans can be investigated using a rodent version of the attentional set-shifting task (ASST) devel- oped by Birrell and Brown (2000). The ASST requires animals to initially learn a rule and form “an attentional set”