Effect of clozapine on ketamine-induced deficits in attentional set shift task in mice

RATIONALE: Clozapine (CLZ) is an effective treatment for schizophrenia, producing improvements in both negative symptoms and cognitive impairments. Cognitive impairments can be modelled in animals by ketamine (KET) and assessed using the attentional set-shift task (ASST). OBJECTIVE: Our first aim was to determine whether CLZ improves cognitive function and reverses KET-induced cognitive impairments using the ASST. Our second aim was to assess dose dependency of these effects. RESULTS: Our findings demonstrate that acute as well as sub-chronic administration of KET cause cognitive deficits observed as increase in number of trails and errors to reach the criterion in the EDS phase. CLZ 0.3 mg/kg reversed the effects of both acute and sub-chronic KET, with no effects on locomotor activity. However, clozapine’s effect after sub-chronic administration of dose 0.3 mg/kg was not as explicit as in the case of acute treatment. Moreover, administration of 1 mg/kg CLZ to KET-treated mice induced or enhanced deficits in the extra-dimensional shift phase compared to 1 mg/kg CLZ administration to mice not receiving KET. Locomotor activity test showed sedation effects of CLZ 1 mg/kg after acute treatment; therefore, effect of CLZ 1 mg/kg on KET-induced cognitive deficits was not evaluated in the attentional set-shift task (ASST) test. CONCLUSIONS: The present findings support dose-dependent effects of CLZ to reverse KET-induced cognitive deficits. The observed dose dependency may be mediated by activation of different receptors, including monomers and/or heterodimers.