i i i * i * k k * * k k 919 Vehicle Ketamine 10 Ro 25-6981 10 Ketamine 10 + Ro 25-6981 10 session 1 session 2 SD CD CDR IDS IDSR IDS2 IDSR2 EDS EDSR session 1 session 2 session 1 session 2 SD CD CDR IDS IDSR IDS2 IDSR2 EDS EDSR Psychopharmacology (2011) 214:911–921 Fig. 5 a–c Effects of Ro 25- 6981 on ketamine-induced defi- cits in the attentional set-shifting task in mice. Ro 25-6981 (10 mg/kg) and ketamine (10 mg/kg) were administered 30 and 50 min before both sessions, respectively (N=8 mice per treatment). Data are pre- sented as the mean ± SEM. Symbols: *P<0.05 vs. vehicle, iP<0.05 vs. IDS2 phase, kP<0.05 vs. ketamine 10 mg/kg group; Newman–Keuls post hoc test A 30 B 25 n iro20 e t irc 15 o lts 10 a irT 5 0 30 i]n25 [m20 n iro15 e t i rc 10 o te 5 m iT 0 C 12 10 iron 8 e itrc 6 o trs 4 o rrE 2 0 SD CD CDR IDS IDSR IDS2 IDSR2 EDS EDSR measured by the Brief Psychiatric Rating Scale, disappeared within 2 h after infusion (Berman et al. 2000; Zarate et al. 2006). Therefore, the current protocol appears to be a promising pharmacological tool for modeling mouse cogni- tive inflexibility. Its predictive validity is based on the inhibitory effects of sertindole (Fig. 3), which also reduced the impairing effects of PCP-like compounds in the rat ASST in former studies (Rodefer et al. 2008; Broberg et al. 2009; Goetghebeur and Dias 2009; Nikiforuk et al. 2010) and alleviated the cognitive impairments associated with schizo- phrenia (Gallhofer et al. 2007) and ketamine administration in healthy volunteers (Vollenweider et al. 1999). The major finding of this set of experiments concerns the pro-cognitive effects of the NMDA NR2B subunit-selective antagonist Ro 25-6981 in the mouse ASST. These effects were shown by the reversal of the ketamine-induced cognitive deficit (Fig. 5) and by cognitive improvement in mice treated with Ro 25-6981 only (Fig. 4). The pro-cognitive effects of the NR2B-selective antagonist are in sharp contrast to the PCP-like antagonists, and to our knowledge, this is the first demonstration of an NMDA antagonist-induced pro- cognitive action in the ASST. The effects of NR2B-selective antagonists on cognitive functions are complicated. The Ro 63-1908 does not affect performance in the Morris water maze and delayed matching to position task (DMTP) performance, though in 5-CSRT Ro 63-1908 produces an increase in premature responses, and in differential rein- forcement of low-rate 24 s (DRL24) task, it reduces the inter- response time, suggesting an impairment of response inhibition (Higgins et al. 2003). Although traxoprodil does not affect spatial learning (Guscott et al. 2003), Ro 25-6981 disrupts spatial reversal learning and enhances perseveration in the Morris water maze (Duffy et al. 2008). Consistent with the latter report, NMDA 2B subunit over-expression results in better performance in learning and memory tasks, like novel object recognition, the Morris water maze, and the t-maze, in mice (Tang et al. 1999; Cao et al. 2007) and rats (Wang et al. 2009). Nonetheless, in tasks specifically assessing cognitive flexibility, like the 5-CSRT, both traxoprodil and Ro 25- 6981 (3–30 mg/kg) increase premature responding and response speed with no error trade-off similar to Ro 63- 1908. At a short inter-trial interval, Ro 63-1908 reliably improved performance, both in terms of response speed and