Disruption of performance in the five-choice serial reaction time task induced by administration of N-methyl-D-aspartate receptor antagonists: relevance to cognitive dysfunction in schizophrenia

Abstract

Schizophrenia patients suffer from cognitive impairments that are not satisfactorily treated by currently available medications. Cognitive dysfunction in schizophrenia encompasses deficits in several cognitive modalities that can be differentially responsive to different medications and are likely to be mediated by different neurobiological substrates. Translational animal models of cognitive deficits with relevance to schizophrenia are critical for gaining insights into the mechanisms underlying these impairments and developing more effective treatments. The five-choice serial reaction time task (5-CSRTT) is a cognitive task used in rodents that allows simultaneous assessment of several cognitive modalities, including attention, response inhibition, cognitive flexibility, and processing speed. Administration of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists disrupts multiple 5-CSRTT performance measures in a way that mirrors various cognitive deficits exhibited by schizophrenia patients. Some of these disruptions are partially attenuated by antipsychotic medications that exhibit partial effectiveness on cognitive dysfunction in schizophrenia, suggesting that the model has predictive validity. Examination of the effects of pharmacological manipulations on 5-CSRTT performance disruptions induced by NMDA antagonists have implicated a range of brain regions, neurotransmitter systems, and specific receptor subtypes in schizophrenia-like impairment of different cognitive modalities. Thus, disruption of 5-CSRTT performance by NMDA antagonists represents a valuable tool for exploring the neurobiological bases of cognitive dysfunction in schizophrenia.

Figure 1

Schematic of a rat’s performance in the 5-choice serial reaction time task.

Figure 2

Effects of chronic clozapine treatment on 5-CSRTT performance disruption induced by repeated PCP. Accuracy (A) and premature responses (B) are shown as mean±SEM. *P<0.05 vs. vehicle group; †P<0.05 vs. performance after saline injections; ↑ or ↓ indicates a PCP injection. CLZ = clozapine; pump in/out = beginning/end of chronic clozapine treatment via subcutaneous minipumps. Adapted from [71], © Springer-Verlag 2007, with kind permission from Springer Science+Business Media.

Figure 3

Effects of PCP on 5-CSRTT performance of C57BL/6N and DBA/2N mice. Accuracy (A), premature responses, (B) and perseverative responses (C) of C57BL/6N mice are shown as mean±SEM; (D), (E), (F) same parameters in DBA/2N mice. *P<0.05 vs. saline group. SAL = saline. Adapted from [25], © Springer-Verlag 2005, with kind permission from Springer Science+Business Media.