Psychopharmacology (2011) 214:911–921 Vehicle Ro 25-6981 3 mg/kg Ro 25-6981 10 mg/kg 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 918 Fig. 4 a–c Effects of Ro 25- 6981 on attentional set-shifting task performance in mice. Ro 25-6981 (3 or 10 mg/kg) was administered 30 min before both sessions (N=8 mice per treat- ment). Data are presented as the mean ± SEM. Symbols: *P<0.05 vs. vehicle, iP<0.05 vs. IDS2 phase, #P<0.05 vs. Ro 25-6981 at 3 mg/kg; Newman– Keuls post hoc test A 30 B 30 25 ion20 r e itr 15 c o ts10 l a irT 5 0 ] 25 n i [m20 n iro15 e t irc10 o te 5 m iT 0 10 n iro 8 e t irc 6 o trs 4 o rrE 2 0 C 12 SD CD CDR IDS IDSR IDS2 IDSR2 EDS EDSR administration. We confirmed that the atypical antipsychotic sertindole alleviated ketamine-induced cognitive deficits. In addition, the present data suggest that the NR2B subunit- selective NMDA antagonist Ro 25-6981 not only facilitated ASST performance during the EDS phase but also reversed ketamine-induced cognitive inflexibility. Only two published modifications of the primary ASST procedure for rats (Birrell and Brown 2000) have success- fully demonstrated significant EDS phase impairment in mice (Garner et al. 2006; Papaleo et al. 2008). Because mice were unable to complete the test in 1 day under our experimental conditions, we divided the procedure into two sessions and included additional phases (IDS2 and IDSR2). As pointed out by Garner et al. (2006), like reversal phases (CDR and IDSR), these additional phases serve to strengthen the cognitive set formation. This outcome was manifested by a general improvement in performance during the phases ranging from CD to IDSR2 followed by a poorer EDS phase performance, which is regarded as the primary measure of set-shifting. Under these conditions, we demonstrated reliable set-shifting in mice because, in all replications (Figs. 1, 2, 3, 4, and 5), the subjects required significantly more trials to reach the criterion during the EDS phase than during the IDS2 phase of the task. A drawback of the 2-day protocol is that the investigated compound has to be administered twice, but the relatively short duration of the test session could be considered as a potential advantage for the investigation of compounds characterized by a short half-life. The present work confirms the results of Nikiforuk et al. (2010) demonstrating that, in the rat ASST, ketamine produces specific deficits in cognitive flexibility after a single dose given 50 min before the test and extends these findings to the mouse species. Although these studies cannot be compared directly, the observed effect was dose dependent; the higher dose of ketamine (20 mg/kg) more severely impaired the task performance compared to the lower dose (10 mg/kg). It was also time dependent; the ED shift deficit was demonstrated at 50 min, but not 3 or 24 h, following drug administration. The latter observation somewhat contrasts with the findings of Egerton et al. (2005), demonstrating that a single dose of PCP tested 24 h after administration produced an ED shift impairment. However, different NMDA receptor antagonists were used, and the studies were performed in a different species. Notably, in clinical experiments, WCST impairment is observed 40 min after ketamine infusion (Krystal et al. 2000), and ketamine-induced psychotomimetic effects, as # i i i * # i i i *