Effects of quetiapine and sertindole on subchronic ketamine-induced deficits in attentional set-shifting in rats

RATIONALE: Prefrontal cortical dysfunctions, including an impaired ability to shift perceptual attentional set, are core features of schizophrenia. Nevertheless, the effectiveness of second-generation antipsychotic drugs in treating specific prefrontal dysfunctions remains equivocal. OBJECTIVES: To model schizophrenia-like cognitive inflexibility in rats, we evaluated the effects of repeated administration of ketamine, the noncompetitive antagonist of the N-methyl-d-aspartate receptor, after a washout period of 14 days in the attentional set-shifting task (ASST). Next, we investigated whether the atypical antipsychotics quetiapine and sertindole would alleviate the ketamine-induced set-shifting impairment. METHODS: Ketamine (30 mg/kg) was administered intraperitoneally to rats once daily for 5 or 10 consecutive days to assess its efficacy in producing cognitive impairment. The ASST was performed 14 days following the final drug administration. Quetiapine (0.63, 1.25 or 2.5 mg/kg) or sertindole (2.5 mg/kg) was administered per os 120 min before testing. RESULTS: The results of the present study demonstrate that ketamine treatment for 10 but not 5 days significantly and specifically impaired rats’ performance in the extra-dimensional shift (EDs) stage of the ASST. This cognitive inflexibility was reversed by acute administration of sertindole or quetiapine. Quetiapine also promoted set-shifting in cognitively unimpaired control animals. CONCLUSION: The data presented here show that subchronic administration of ketamine induces cognitive inflexibility after a washout period. This cognitive deficit likely reflects clinically relevant aspects of cognitive dysfunction encountered in schizophrenic patients. The beneficial effects of quetiapine on set-shifting may have therapeutic implications for the treatment of schizophrenia and other disorders associated with frontal-dependent cognitive impairments.