Chen Long, Yang Charles R
Neuroscience Discovery, Eli Lilly and Co., Indianapolis, Indiana 46285-0510, USA.
J Neurophysiol. 2002 May;87(5):2324-36. doi: 10.1152/jn.2002.87.5.2324.
The atypical antipsychotic drug clozapine effectively alleviates both negative and positive symptoms of schizophrenia via unclear cellular mechanisms. Clozapine may modulate both glutamatergic and dopaminergic transmission in the prefrontal cortex (PFC) to achieve part of its therapeutic actions. Using whole cell patch-clamp techniques, current-clamp recordings in layers V-VI pyramidal neurons from rat PFC slices showed that stimulation of local afferents (in 2 microM bicuculline) evoked mixed [AMPA/kainate and N-methyl-D-aspartate (NMDA) receptors] glutamate receptor-mediated excitatory postsynaptic potentials (EPSPs). Clozapine (1 microM) potentiated polysynaptically mediated evoked EPSPs (V(Hold) = -65 mV), or reversed EPSPs (rEPSP, V(Hold) = +20 mV) for >30 min. The potentiated EPSPs or rEPSPs were attenuated by elevating Ca(2+) (7 mM), by application of NMDA receptor antagonist 2-amino5-phosphonovaleric acid (50 microM), or by pretreatment with dopamine D1/D5 receptor antagonist SCH23390 (1 microM) but could be further enhanced by a dopamine reuptake inhibitor bupropion (1 microM). Clozapine had no significant effect on pharmacologically isolated evoked NMDA-rEPSP or AMPA-rEPSPs but increased spontaneous EPSPs without changing the steady-state resting membrane potential. Under voltage clamp, clozapine (1 microM) enhanced the frequency, and the number of low-amplitude (5-10 pA) AMPA receptor-mediated spontaneous EPSCs, while there was no such changes with the mini-EPSCs (in 1 microM TTX). Taken together these data suggest that acute clozapine can increase spike-dependent presynaptic release of glutamate and dopamine. The glutamate stimulates distal dendritic AMPA receptors to increase spontaneous EPSCs and enabled a voltage-dependent activation of neuronal NMDA receptors. The dopamine released stimulates postsynaptic D1 receptor to modulate a lasting potentiation of the NMDA receptor component of the glutamatergic synaptic responses in the PFC neuronal network. This sequence of early synaptic events induced by acute clozapine may comprise part of the activity that leads to later cognitive improvement in schizophrenia.
非典型抗精神病药物氯氮平可通过尚不清楚的细胞机制有效缓解精神分裂症的阴性和阳性症状。氯氮平可能调节前额叶皮质（PFC）中的谷氨酸能和多巴胺能传递，以实现其部分治疗作用。使用全细胞膜片钳技术，对大鼠PFC切片中V-VI层锥体神经元进行电流钳记录，结果显示，刺激局部传入神经（在2 microM荷包牡丹碱中）可诱发混合的[AMPA/海人藻酸和N-甲基-D-天冬氨酸（NMDA）受体]谷氨酸受体介导的兴奋性突触后电位（EPSP）。氯氮平（1 microM）增强多突触介导的诱发EPSP（钳制电压V（Hold）=-65 mV），或翻转EPSP（rEPSP，钳制电压V（Hold）=+20 mV），持续时间超过30分钟。增强的EPSP或rEPSP可通过提高细胞外钙离子浓度Ca(2+)（7 mM）、应用NMDA受体拮抗剂2-氨基-5-磷酸戊酸（50 microM）或用多巴胺D1/D5受体拮抗剂SCH23390（1 microM）预处理而减弱，但可被多巴胺再摄取抑制剂安非他酮（1 microM）进一步增强。氯氮平对药理学分离的诱发NMDA-rEPSP或AMPA-rEPSP无显著影响，但增加了自发EPSP，而不改变稳态静息膜电位。在电压钳制下，氯氮平（1 microM）增加了频率以及低幅度（5-10 pA）AMPA受体介导的自发兴奋性突触后电流（EPSC）的数量，而微小兴奋性突触后电流（在1 microM河豚毒素中）则无此变化。综合这些数据表明，急性给予氯氮平可增加谷氨酸和多巴胺的锋电位依赖性突触前释放。谷氨酸刺激树突远端的AMPA受体，增加自发EPSC，并使神经元NMDA受体发生电压依赖性激活。释放的多巴胺刺激突触后D1受体，调节PFC神经元网络中谷氨酸能突触反应的NMDA受体成分的持久增强。急性氯氮平诱导的这一系列早期突触事件可能是导致精神分裂症后期认知改善的部分活动。
