Olanzapine and risperidone block a high dose of methamphetamine-induced schizophrenia-like behavioral abnormalities and accompanied apoptosis in the medial prefrontal cortex

This study aims to propose a comprehensive new model for schizophrenia, which shows PPI disruption at baseline state as an endophenotype, the development of cross-sensitization to an NMDA receptor antagonist, MK-801 as a clinical phenotype of the progression into treatment-resistance, and accompanied induction of apoptosis in the medial prefrontal cortex as a critical possibility during the progression. Repeated administration of a high dose of methamphetamine (METH) (2.5 mg/kg), which could increase glutamate levels in the medial prefrontal cortex (mPFC), induced TUNEL-positive cells in this region, accompanied development of behavioral cross-sensitization to MK-801 in response to a challenge injection of MK-801, and PPI disruption at baseline state without a challenge injection. Olanzapine (OLZ) (1.0 mg/kg) and risperidone (RIS) (0.1 mg/kg), which inhibited and remarkably attenuated METH (2.5 mg/kg)-induced increases in glutamate levels, respectively, blocked not only the induction of TUNEL-positive cells in the mPFC but also the accompanied development of above behavioral abnormalities. These findings suggest that repeating the METH-induced glutamate release produces behavioral abnormalities as a clinical phenotype of schizophrenia, accompanied apoptosis as a critical possibility during the progression, and suggest that sufficient dose of olanzapine and risperidone can block the development of these behavioral abnormalities and accompanied apoptosis during the progression.