912 within the same stimulus dimension, by discriminating between, e.g., the odors associated with food reward. During the extra-dimensional (ED) shift, the crucial and most difficult part of the test, the subjects have to rapidly switch their attention to a new and previously irrelevant stimulus dimension and to discriminate between, e.g., the media covering the food reward. Although an increasing number of laboratories have successfully used the ASST in rats, most of the attempts to adapt this procedure for use in mice have failed to demonstrate an ED shift deficit (Colacicco et al. 2002; Laurent and Podhorna 2004; Zhuo et al. 2007; Levi et al. 2008). Only one procedure, described by Garner et al. (2006) and replicated with slight modification by Papaleo et al. (2008), has shown a significant extra-dimensional shift (EDS) phase deficit in this species. However, our laboratory was unable to demonstrate an ED shift impairment even with these modifications, and therefore, the first goal of the present study was to establish the conditions allowing for the measurement of reliable set-shifting in mice. Converging lines of evidence indicate the involvement of glutamate NMDA transmission in schizophrenia. A single dose of an NMDA receptor antagonist, such as phencyclidine (PCP) or ketamine, induces symptoms of acute psychosis in healthy volunteers (Luby 1959; Javitt and Zukin 1991). Because these symptoms are indistin- guishable from some symptoms of schizophrenia (Krystal et al. 1994), antagonists of NMDA receptors are routinely used in preclinical research as a pharmacological model of this psychosis (Olney and Farber 1995; Jentsch and Roth 1999). The acute administration of ketamine impairs attentional set-shifting as measured by the WCST in healthy humans (Krystal et al. 2000) and in the rat (Nikiforuk et al. 2010). Therefore, the second goal of the present study was to investigate the ketamine-induced impairment of ASST in mice. Compared to conventional antipsychotics, relatively novel atypical compounds, such as sertindole, display an advantageous profile of pro-cognitive actions in schizo- phrenia. A recent multi-center, randomized, double-blinded clinical trial indicated a beneficial effect of sertindole on executive functions in patients with schizophrenia (Gallhofer et al. 2007); this medication also reduced the debilitating effects of ketamine in the Stroop task in healthy volunteers (Vollenweider et al. 1999). Several preclinical 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) and of an acute dose of ketamine (Nikiforuk et al. 2010) in the rat ASST. An obligatory step in the validation of a given procedure relies on the demonstration of a positive effect of the medication previously found to be effective in similar conditions. The third goal of the present study was Psychopharmacology (2011) 214:911–921 to investigate whether sertindole could reverse ketamine- induced deficits in the mouse version of the ASST. NMDA receptors are heteromers composed of an obliga- tory NR1 (mouse zeta 1) subunit and of at least one type of the NR2 (NR2A–NR2D; mouse epsilon 1–4) subunits (Laube et al. 1998; Schorge and Colquhoun 2003). The type of NR2 subunit constituting the NMDA receptor affects its physio- logical and pharmacological properties (Monaghan and Larsen 1997; Loftis and Janowsky 2003). In addition, the brain distribution of NR2 subunits is not uniform (Monyer et al. 1994; Wenzel et al. 1995); although NR2A messenger RNA (mRNA) is distributed particularly in the cerebral cortex, hippocampus, and cerebellum, the NR2B transcript is selectively present in the forebrain with a high level of expression in the cerebral cortex, hippocampus, septum, caudate–putamen, and olfactory bulb. The NR2C mRNA is expressed predominantly in the cerebellum, and the NR2D transcript is detected in the thalamus, brain stem, and olfactory bulb. The NR2C and NR2D transcripts are found in a subset of hippocampal neurons, which are most likely interneurons (Ozawa et al. 1998). This pattern of distribution suggests that subunit-specific NMDA antagonists may have differential effects under various physiological and pathological conditions (Skolnick et al. 2009). Although ketamine is regarded as an NR2-unspecific antagonist (Dravid et al. 2007), recent data indicate that it mainly affects NR1/2C and NR1/2D NMDA receptors (Kotermanski and Johnson 2009). Due to its antagonistic action at hippocampal NMDA receptors, ketamine may cause cortical disinhibition, which is relevant to some symptoms of schizophrenia, including cognitive inflexibility (Greene 2001; Homayoun and Moghaddam 2007; Lisman et al. 2008). In contrast, the NR2B-selective antagonist, CP-101,606 (trax- oprodil), under certain test conditions, improves cognitive flexibility as assessed by the five-choice serial reaction time task (5-CSRT; Higgins et al. 2005). Therefore, the fourth goal of the present study was to investigate the effects of an NR2B-selective antagonist alone and in combination with ketamine in the ASST procedure. We used the Ro 25-6981 compound [(aR,bS)-a-(4-hydroxyphenyl)-b-methyl-4-(phenyl- methyl)-1-piperidinepropanol hydrochloride] that is character- ized by a >5,000-fold selectivity for NR2C/NR2B over NR2C/NR2A subunits of the NMDA receptor, use- dependent binding properties and neuroprotective effects against glutamate toxicity (Fischer et al. 1997). Materials and methods Ethics The experiments were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals