Differential Effects of Olanzapine and Haloperidol on MK-801-induced Memory Impairment in Mice

Objective: We investigated the differential effects of the antipsychotic drugs olanzapine and haloperidol on MK-801-induced memory impairment and neurogenesis in mice. Methods: MK-801 (0.1 mg/kg) was administered 20 minutes prior to behavioral testing over 9 days. Beginning on the sixth day of MK-801 treatment, either olanzapine (0.05 mg/kg) or haloperidol (0.05 mg/kg) was administered 40 minutes prior to MK-801 for the final 4 days. Spatial memory performance was measured using a Morris water maze (MWM) test for 9 days (four trials/day). Immunohistochemistry with bromodeoxyuridine (BrdU) was used to identify newborn cells labeled in tissue sec-tions from the dentate gyrus of the hippocampus. Results: MK-801 administration over 9 days significantly impaired memory performance in the MWM test compared to untreated controls ( p ＜0.05) and these deficits were blocked by treatment with olanzapine ( p ＜0.05) but not haloperidol. The administration of MK-801 also resulted in a decrease in the number of BrdU-labeled cells in the dentate gyrus (28.6%; p ＜0.01), which was prevented by treatment with olanzapine ( p ＜0.05) but not haloperidol. Conclusion: These results suggest that olanzapine has a protective effect against cognitive impairments induced by MK-801 in mice via the stimulating effects of neurogenesis.