Study of model for pathophysiology and mechanism for the treatment of the treatment resistant schizophrenia

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We can use an NMDA receptor dysfunction model for the treatment-resistant schizophrenia, and methamphetamine model for the treatment-responsive model for schizophrenia. We hypothesized that increased glutamate levels in the medial prefrontal cortex(mPFC) and the nucleus accumbens(NA) induced by high dose of methamphetamine play an important role for the development of behavioral cross-sensitization to an NMDA receptor antagonist. We have shown that a protein kinase C inhibitor, staurosporine and a GABA stimulant, valproate block the development of the cross-sensitization to dizocilpine. Valproate and olanzapine potently, and risperidone moderately inhibited high dose of methamphetamine-induced delayed increases in glutamate levels in the mPFC and the NA.These findings suggest that valproate, olanzapine, and risperidone may block the development of the treatment-resistance of schizophrenia.