Effect of alpha7 nicotinic acetylcholine receptor agonists on attentional set-shifting impairment in rats

Attentional set shifting, a measure of executive function, is impaired in schizophrenia patients. Current standard of care has little therapeutic benefit for treating cognitive dysfunction in schizophrenia; therefore, novel drugs and animal models for testing novel therapies are needed. The NMDA receptor antagonist, MK-801, produces deficits in a rat maze-based set-shifting paradigm, an effect which parallels deficits observed on tests of executive function in schizophrenia patients. Alpha7 nicotinic acetylcholine receptor (nAChR) agonists, currently under clinical development by several companies, show promise in treating cognitive symptoms in schizophrenia patients and can improve cognition in various animal models. The objectives of the present study were to determine whether the MK-801 deficit in set shifting could be reproduced in a drug discovery setting and to determine whether cognitive improvement could be detected for the first time in this task with alpha7 nAChR agonists. The data presented here replicate findings that a systemic injection of the NMDA receptor antagonist MK-801 can induce a deficit in set shifting in rats. Furthermore, the deficit could be reversed by the atypical antipsychotic clozapine as well as by several alpha7 nAch receptor agonists (SSR-180711, PNU-282987, GTS-21) with varying in vitro properties. Results indicate that the MK-801 set-shift assay is a useful preclinical tool for measuring prefrontal cortical function in rodents and can be used to identify novel mechanisms for the potential treatment of cognitive deficits in schizophrenia.