Re-evaluating the PCP challenge as a pre-clinical model of impaired cognitive flexibility in schizophrenia

Abstract

NMDA-R antagonists are a popular translational pharmacological challenge to induce cognitive deficits associated with schizophrenia. Amongst their many cognitive and non-cognitive effects is an ability to impair cognitive flexibility in general, and reversal learning in particular. Here, we test the hypothesis that the NMDA-R antagonist phencyclidine when given acutely selectively effects reversal learning by simultaneously measuring reversal learning and baseline responding, or acquisition and baseline responding, under identical conditions. Animals were trained to simultaneously perform two different visual discriminations in a touch-screen equipped operant box. Accordingly the reward contingencies associated with one pair could be altered, while the second pair acted as an experimental control. As such, the effect of a manipulation on reversal learning, stimuli acquisition, or baseline responding can be more accurately evaluated through the use of a double visual discrimination. A similar approach was also used to investigate the influence of sub-chronic phencyclidine administration on cognitive flexibility. Phencyclidine (1mg/kg) given before testing caused a slowing in acquisition and reversal learning, while having a minimal effect on secondary measures. Sub-chronic phencyclidine administration had no significant effect on any of the measures used within this study. While acute phencyclidine impairs reversal learning, it is clear from these results that other aspects of cognition (learning/relearning) are also impaired, potentially questioning the specificity of acute phencyclidine in conjunction with reversal learning paradigms as a model of impaired cognitive flexibility.