Brigman et al. research program to elucidate the role of gluta- mate in cognitive and executive functions, we have studied the effects of mutations in various components of the glutamate system on the touchscreen-based method (Brigman et al., 2008; Karlsson et al., 2008; Wiedholz et al., 2008; Karlsson et al., 2009). To compliment and extend these studies, we (Brigman et al., 2009) investi- gated a pharmacological model of glutamatergic dysfunction in schizophrenia – subchronic PCP treatment. PCP and other NMDAR antagonists (e.g., ketamine) mimic positive and negative symp- toms of schizophrenia in otherwise healthy indi- viduals (Javitt and Zukin, 1991; Krystal et al., 1994). Based upon this observation, Jentsch and colleagues subchronically treated monkeys and rats with PCP and found cognitive deﬁcits and associated prefrontal neurochemical abnormali- ties (reviewed in Jentsch and Roth, 1999). The subchronic PCP model has since been quite widely employed as a rodent model for execu- tive dysfunctions in schizophrenia. In order to test the subchronic PCP model in the touchscreen-based assay, Brigman et al. (2009) treated C57BL/6J mice with 5 mg/kg PCP twice daily for 7 days and, after a 7-day withdrawal period, tested for discrimination and (in a separate group of mice) reversal in the touchscreen-based task. This treatment and withdrawal duration was based on previous work by Jentsch et al. (1997a). Results showed no signiﬁcant impairments in drug-treated mice in comparison to vehicle treated controls on either discrimination or reversal, as meas- ured using a range of dependent variables. By contrast, the same treatment regimen that failed to affect discrimination or reversal was sufﬁcient to reduce social behavior – demonstrating that treatment was sufﬁcient to mimic some symp- toms of schizophrenia. While Brigman et al. (2009) was the ﬁrst study of the PCP model in a rodent touch- screen-based procedure, the lack of impair- ment may appear somewhat surprising, given PCP-induced deﬁcits have been found on other measures of reversal in rats and mice (summa- rized in Table 1). However, similar to Brigman et al., negative effects on reversal have also been reported (including in studies in which there are clear PCP-induced deﬁcits in the EDS com- ponent, e.g., Rodefer et al., 2005, 2008; Egerton et al., 2008). Direct comparisons between stud- ies are further complicated by variations in treat- ment regimen and methodology. For example, while Neill and colleagues (Abdul-Monim et al., 2006, 2007) have demonstrated reversal impair- ments in a light-cue based operant task in rats subjected to a PCP treatment and withdrawal procedure comparable to Brigman et al., their task required subjects to completely inhibit responses on some trials to obtain reward, which likely placed greater demands on inhibi- tory control than the task used by Brigman et al. (in which a response was always available). This is likely a salient difference because subchronic PCP treatment impairs inhibitory control in rats and non-human primates (Jentsch et al., 1997b, 2000; Jentsch and Taylor, 2001). Clearly, further work is needed to parse the most critical features of reversal assays that render them sensitive to subchronic PCP treatment. Table 1 | Studies on the effects of acute and chronic PCP treatment on measures of cognitive ﬂexibility. Species Assay (stimulus modality) PCP treatment regimen (dose) Rat Rat Rat Rat Mouse Rat Rat Rat Rat Mouse Rat Rat Monkey Operant reversal (visual) Operant reversal (visual) Operant reversal (visual) Operant reversal (visual) Operant reversal (visual) Spatial reversal (visual) IDS/EDS (tactile/olfactory) IDS/EDS (tactile/olfactory) IDS/EDS (tactile/olfactory) IDS/EDS (tactile/olfactory) IDS/EDS (tactile/olfactory) IDS/EDS (tactile/olfactory) Detour reaching task Acute (1.0–1.5 mg/kg) Acute (1.5–2.0 mg/kg) Chronic, daily (2 mg/kg) × 7 days, +7 days w/d Chronic, daily (2 mg/kg) × 7 days, +7 days w/d Chronic, twice daily (5 mg/kg) × 7 days, +7 days w/d Chronic, twice daily (5 mg/kg) × 7 days, +7 days w/d Acute (2.58 mg/kg) Repeated (10–20 mg/kg) on postnatal days P7, 9, 11 Chronic, daily (2.6 mg/kg) × 5 days, +3 days w/d Chronic, daily (0.63–1.3 mg/kg) × 10 days Chronic, twice daily (5 mg/kg) × 7 days, +10 days w/d Chronic, twice daily (5 mg/kg) × 7 days, +10 days w/d Chronic, twice daily (0.3 mg/kg) × 14 days, +7 days w/d IDS/EDS, intra-dimensional/extra-dimensional set shifting; w/d, withdrawal period prior to testing. 24 | May 2010 | Volume 4 | Issue 1 Reference Abdul-Monim et al. (2003) Idris et al. (2005) Abdul-Monim et al. (2006) Abdul-Monim et al. (2007) Brigman et al. (2009) Jentsch and Taylor (2001) Egerton et al. (2005) Broberg et al. (2008) Egerton et al. (2008) Laurent and Podhorna (2004) Rodefer et al. (2005) Rodefer et al. (2008) Jentsch et al. (1997a) www.frontiersin.org