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

对于难治性精神分裂症，我们可以使用NMDA受体功能障碍模型，对于精神分裂症的治疗反应模型，可以使用甲基苯丙胺模型。我们推测，大剂量甲基苯丙胺引起的内侧前额叶皮质(MPFC)和伏隔核(NA)谷氨酸水平的升高在NMDA受体拮抗剂的行为交叉敏化发展中起重要作用。我们已经证明，蛋白激酶C抑制剂星形孢子素和GABA激动剂丙戊酸盐可以阻断地佐西平的交叉增敏作用。丙戊酸盐、奥氮平和利培酮可有效抑制大剂量甲基苯丙胺诱导的mPFC和NA中谷氨酸水平的延迟性升高。这些结果表明，丙戊酸盐、奥氮平和利培酮可能阻止精神分裂症耐药的发展。

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.