Neurochemical and pharmacological studies on the noves mode of action mechanisms of antipsychotic drugs : Preferential dopaminergic activation in the prefrontal cortex.

为了阐明非典型抗精神病药物（APDs）的作用模式和机制，我们进行了一系列的实验研究。(1)某组非典型抗精神病药物在体内表现为5-羟色胺（5-HT） _<2A>受体高占用，多巴胺d2受体低或极低占用。(2)与其他apd治疗相比，氯氮平或齐拉西酮治疗诱导的前额皮质多巴胺释放量显著增加。(3)只有氯氮平和齐拉西酮抑制前额皮质突触体对去甲肾上腺素的再摄取。前额叶皮层的优先多巴胺能激活可能与氯氮平或齐拉西酮抑制去甲肾上腺素转运体多巴胺的交叉再摄取有关。(4)不同典型apd的慢性治疗均使纹状体d2受体数量增加，而非典型apd的纹状体d2受体数量没有增加。5-HT_<2A>拮抗剂与氟哌啶醇联合使用可减弱D_2受体的上调。(5)非典型apd以剂量依赖性抑制条件性恐惧诱导冻结的获得。ED_<50 bb0 s与D_4受体的Ki值显著相关。这些结果为以下假设提供了证据：非典型apd在前额皮质的优先多巴胺能激活和5-HT_<2A>或D_4受体的拮抗作用可能是典型apd的一个或多个临床优势的原因。

A series of experiments was conducted to clarify the mode of action mechanisms of atypical antipsychotic drugs (APDs)(1) A certain group of atypical APD was characterized by high occupancy of serotonin (5-HT) _<2A> receptor with lower or minimal occupancy of dopamine D_2 receptor in vivo.(2) The treatment of clozapine or ziprasidone induced the significantly greater increases in dopamine release in the prefrontal cortex, when compared to the treatment of other APDs.(3) Only clozapine and ziprasidone inhibited the reuptake of noradrenaline in the synaptosomes from the prefrontal cortex. The preferential dopaminergic activation in the prefrontal cortex might be related the inhibition of crossed reuptake of dopamine at the noradrenaline transporter by clozapine or ziprasidone.(4) Chronic treatment with various typical APDs increased the number of striatal D_2 receptors, while no increase was observed with the atypical APDs. Coadministration of 5-HT_<2A> antagonist with haloperidol attenuated the D_2 receptor up-regulation.(5) The atypical APDs dose-dependently inhibited the acquisition of conditioned fearinduced freezing. the ED_<50>s for this effect significantly correlated with the Ki values for D_4 receptors.These results provide evidence for the hypothesis that the preferential dopaminergic activation in the prefrontal cortez and the antagonism of 5-HT_<2A> or D_4 receptors by the atypical APDs might account for one or more of the clinical advantage of the etypical APDs.