Arvanov V L, Liang X, Schwartz J, Grossman S, Wang R Y
Department of Psychiatry, State University of New York at Stony Brook, 11794-8790, USA.
J Pharmacol Exp Ther. 1997 Oct;283(1):226-34.
The effects of the antipsychotic drugs haloperidol and clozapine on N-methyl-D-aspartate (NMDA) and non-NMDA receptor-mediated neurotransmission were examined and compared in pyramidal cells of the medial prefrontal cortex in rat brain slices by using the techniques of intracellular recording and single-electrode voltage-clamp. The bath administration of either haloperidol or clozapine produced a marked facilitation (300-400%) of NMDA-evoked responses in a concentration-dependent manner. The EC50 values of haloperidol and clozapine were 38 and 14 nM, respectively. At concentrations of > or =100 nM, clozapine, but not haloperidol, produced bursts of excitatory postsynaptic potentials (EPSPs), which were blocked by glutamate receptor antagonists, suggesting that these EPSPs were the result of increasing release of excitatory amino acids. Haloperidol, but not clozapine, produced a concentration-dependent inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced current with an EC50 value of 37 nM. Haloperidol significantly decreased the amplitude of EPSPs evoked by the electrical stimulation of the forceps minor, whereas clozapine increased the amplitude of these EPSPs. The study of current-voltage relationship indicates that clozapine preferentially potentiates NMDA receptor-mediated transmission, whereas haloperidol depresses the non-NMDA receptor-mediated response, which probably obscures its potentiating effect on NMDA receptor-mediated EPSPs.
采用细胞内记录和单电极电压钳技术，在大鼠脑片内侧前额叶皮质的锥体细胞中，检测并比较了抗精神病药物氟哌啶醇和氯氮平对N-甲基-D-天冬氨酸（NMDA）和非NMDA受体介导的神经传递的影响。浴槽给药氟哌啶醇或氯氮平均可浓度依赖性地显著促进（300 - 400%）NMDA诱发的反应。氟哌啶醇和氯氮平的EC50值分别为38 nM和14 nM。在浓度≥100 nM时，氯氮平而非氟哌啶醇可产生兴奋性突触后电位（EPSP）爆发，该爆发可被谷氨酸受体拮抗剂阻断，提示这些EPSP是兴奋性氨基酸释放增加的结果。氟哌啶醇而非氯氮平可浓度依赖性地抑制α-氨基-3-羟基-5-甲基-4-异恶唑丙酸诱导的电流，其EC50值为37 nM。氟哌啶醇显著降低了小钳夹电刺激诱发的EPSP幅度，而氯氮平则增加了这些EPSP的幅度。电流-电压关系研究表明，氯氮平优先增强NMDA受体介导的传递，而氟哌啶醇则抑制非NMDA受体介导的反应，这可能掩盖了其对NMDA受体介导的EPSP的增强作用。
