A STUDY ON CLASSIFICATION OF ANTIPSYCHOTIC DRUGS BY MEANS OF THEIR ABILITY TO INDUCE THE RELEASE OF NEUROTRANSMITTERS

1. 采用微透析技术建立了实时监测大鼠内侧前额叶皮层胞外谷氨酸水平的体内方法，并考察了不同类型的抗精神病药物对前额叶谷氨酸释放的影响。非典型抗精神病药物如氯氮平、奥氮平和利培酮至少服用一剂，但非典型抗精神病药物氟哌啶醇，可减弱高K^+诱导的内侧前额叶皮层细胞外谷氨酸水平。这一发现提示急性给予非典型抗精神病药物可能抑制前额叶谷氨酸能活性。由于非典型抗精神病药物选择性地减弱了苯环利定治疗大鼠内侧前额叶皮层和伏隔核中立即-早期基因弧的表达，这种精神分裂症动物模型可能有助于阐明这些药物的作用部位。然而，多巴胺能神经传递的改变可能不是非典型抗精神病药物减轻苯环利定诱导的arc表达的作用机制的主要原因。结合其他实验室先前的报告，急性给药氯氮平、利培酮和奥氮平可能增加大鼠前额皮质多巴胺、去甲肾上腺素和乙酰胆碱的释放。这些非典型抗精神病药物至少在一次剂量时可减少前额叶谷氨酸释放，而利培酮可促进血清素释放，而氯氮平或奥氮平则无此作用。氟哌啶醇可能对两种神经递质的前额叶释放影响极小。根据其诱导多巴胺、去甲肾上腺素和乙酰胆碱的区域特异性释放的能力，抗精神病药物可分为三种类型：1 .以前额叶为主的氯氮平；非显性前额叶型如利培酮和III型。主要是皮层下型，如氟哌啶醇。前两类抗精神病药在临床疗效上是不典型的，而第二类药物在高剂量下缺乏其非典型性。少

1. We established the in vivo method of monitoring in real-time extracellular glutamate levels in rat medial prefrontal cortex by employing the microdialysis technique and then examined the effect of different types of antipsychoic drugs on prefrontal glutamate release. The atypical antipsychotic drugs such as clozapine, olanzapine and risperidone at at least one dose, but not the typical antipsychotic haloperidol, attenuated high K^+-induced extracellular glutamate levels in the medial prefrontal cortex. This finding suggests that acute administration of atypical antipsychotics may inhibit prefrontal glutamatergic activity.2. Since atypical antipsychotic drugs selectively attenuated the expression of the immediate-early gene arc in the medial prefrontal cortex and nucleus accumbens of phencyclidine-treated rats, this animal model of schizophrenia may be useful for elucidating the sites of action of these drugs. However, alteration of dopaminergic neurotransmission may not contribute t … More o the mechanism of action of atypical antipsychotic drugs in regard to their ability to attenuate phencyclidine-induced arc expression.3. Taken together with previous reports from other laboratories, acute administration of clozapine, risperidone and olanzapine may increase the release of dopamine, norepinephrine and acetylcholine in rat prefrontal cortex. These atypical antipsychotics may decrease prefrontal glutamate release at at least one dose, whereas risperidone, but not clozapine or olanzapine, may facilitate serotonin release. Haloperidol may have minimal effect on the prefrontal release of either neurotransmitters.4. By means of the ability to induce the region-specific release of dopamine, norepinephrine and acetylcholine, antipsychotic drugs may be classified into three types: I. dominantly prefrontal type such as clozapine, II. Non-dominantly prefrontal type such as risperidone, and III. Dominantly subcortical type such as haloperidol. The former two types are atypical antipsychotics in regard to the clinical effects, although the type II drugs at high doses lack their atypicality. Less