Subchronic PCP “model” of schizophrenia Based on the clinical observation that phencyclidine (PCP) and other NMDAR antagonists mimic symptoms of schizophrenia in healthy individuals, Jentsch and Roth (1999) developed a procedure involving repeated treatment of monkeys and rodents with PCP to produce cognitive deﬁcits and associated prefrontal neurochemical abnormalities. is also very ﬂexible and can be easily adapted to test for other forms of cognition and executive function other than discrimination and reversal, such as extinction (Hefner et al., 2008), spatial paired-associate learning (associating an object with a spatial location) (Talpos et al., 2009) and pattern separation (discrimination of perceptu- ally similar stimuli) (Clelland et al., 2009). In our formulation of the task (Izquierdo et al., 2006; Brigman et al., 2008) (Figure 3), mice are ﬁrst trained to initiate the appearance of the stimuli on-screen by a head entry into a magazine where food pellets are delivered (Figure 3A). There is then some training to shape the mouse to touch the screen to obtain reward before discrimination learning begins (Figure 3B). Discrimination is typically between two (i.e., pairwise) distinct visual stimuli, with responses on one stimulus rewarded with food and responses on the other producing a timeout period during which additional responses can- not be made (Figure 3C). After reaching a pre- determined criterion of discrimination (e.g., >85% correct choices), the stimulus-reward contingencies are reversed and the subject must inhibit perseverative responses to the previously rewarded stimulus and learn to respond to the alternate, previously unrewarded, stimulus (Figure 3D). The capacity for this system to concurrently assess discrimination as well as reversal learn- ing provides an excellent internal control, not only for learning and behavioral performance generally, but also because discrimination is impaired in some cases of schizophrenia. For example, discrimination and reversal learning Cognitive ﬂexibility in mice were signiﬁcantly impaired in chronic hospi- talized schizophrenic patients with frontal lobe damage (Pantelis et al., 1999). Interestingly, more stabilized patients were found to be more speciﬁcally impaired on reversal and EDS shifts (Elliott et al., 1995; Waltz and Gold, 2007) and some ﬁrst-episode schizophrenics exhibited even more restricted, EDS-only, impairment (Hutton et al., 1998; Joyce et al., 2002; Braw et al., 2008). These ﬁndings raise the interesting possibility that the proﬁle of discrimination/reversal/set- shifting impairment may be graded in a manner corresponding to the chronicity of schizophre- nia (Joyce et al., 2002). On the other hand, there are clinical data showing clear deﬁcits in both reversal and set-shifting in ﬁrst-episode schizo- phrenics, and especially in those patients with prominent thought disorganization symptoms (Barnett et al., 2005; Murray et al., 2008; Leeson et al., 2009). One interpretation of these ﬁnd- ings is that the breadth and pattern of deﬁcits in discrimination/reversal/set-shifting may be more of a marker for speciﬁc subtypes of the disease rather than of disease severity (Leeson et al., 2009). The touchscreen procedure could prove to be valuable for delineating discrimina- tion and reversal impairments in mouse models, and thereby shed light on the pathophysiology underlying their dissociation in different sub- populations of schizophrenic patients. EFFECTS OF SUBCHRONIC PCP TREATMENT ON DISCRIMINATION AND REVERSAL There is compelling evidence implicating the glutamate system in the pathophysiology of schizophrenia (Coyle, 2006). As part of a larger Figure 3 |Touchscreen-based operant system for assaying discrimination and reversal learning in mice. Training and testing entails four stages. (A) To ﬁrst teach the mouse to associate rewards with visual stimuli on the touchscreen, food pellets and stimuli are presented concomitantly. (B) Next, the mouse must respond to stimuli on the screen to obtain a reward (and also initiate new trials via a head-entry into the magazine). (C) During discrimination learning, two novel stimuli are presented on the screen, and the mouse must respond to one stimulus (to obtain reward) and not the other (to avoid non-reward and a timeout phase during which no new trials can be initiated). (D) In the ﬁnal stage, the stimulus-reward contingency is reversed, and the mouse must now respond to the previously unrewarded stimulus to obtain reward. Note: the left/right position of rewarded stimuli varies pseudorandomly across trials, and the type of rewarded stimulus is counterbalanced across mice. Frontiers in Neuroscience May 2010 | Volume 4 | Issue 1 | 23