Different effects of a single and repeated administration of clozapine on phencyclidine-induced hyperlocomotion and glutamate releases in the rat medial prefrontal cortex at short- and long-term withdrawal from this antipsychotic
Different effects of a single and repeated administration of clozapine on phencyclidine-induced hyperlocomotion and glutamate releases in the rat medial prefrontal cortex at short- and long-term withdrawal from this antipsychotic
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DOI：
10.1007/s00210-007-0154-x
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发表时间：
2007-06-01
影响因子：
3.6
通讯作者：
Koyama, Tsukasa
中科院分区：
文献类型：
--
作者：
Abekawa, Tomohiro;Ito, Koki;Koyama, Tsukasa
氯氮平是非典型抗精神病药的原型，不仅能阻断 D-2/5-HT2A 受体，还能增强 N-甲基-D-天冬氨酸 (NMDA) 受体介导的谷氨酸能神经传递。这项研究假设单次和重复服用氯氮平对 NMDA 受体介导的神经传递有不同的影响，并检查了短期和长期停用这种抗精神病药后，氯氮平的这些治疗对非竞争性 NMDA 受体拮抗剂苯环己哌啶 (PCP) 诱导的过度运动和内侧前额叶皮质 (mPFC) 谷氨酸水平急剧增加的影响。分别通过红外传感器和体内微透析测量运动活性和谷氨酸的细胞外水平。注射氯氮平后 48 小时（但不是 11 天），单次施用氯氮平可减弱 PCP 诱导的过度运动，并阻止 PCP 诱导的 mPFC 中谷氨酸水平的增加。重复施用氯氮平不仅在 48 小时内，而且在最后一次注射氯氮平后 11 天减弱了 PCP 诱导的过度运动，并阻止了 PCP 诱导的 mPFC 中谷氨酸水平的增加。在氯氮平治疗后 48 小时或 11 天，单次和重复施用氯氮平对甲基苯丙胺 (METH) 诱导的过度运动没有影响。考虑到氯氮平与多巴胺 D-2 受体的快速解离以及单次或重复施用氯氮平对 METH 诱导的过度运动没有影响，单次和重复氯氮平治疗减弱的 PCP 诱导的过度运动不能用氯氮平占据多巴胺 D-2 受体来解释。重复但单次施用氯氮平可抑制 5-HT2A/2C 激动剂，即最后一次注射氯氮平后 11 天 DOI 诱导的 mPFC 增加。这些发现表明，亚慢性治疗氯氮平诱导的 5-HT2A 受体长期下调可能会阻止 PCP 诱导的神经化学和行为变化的增强。
Clozapine is a prototype of atypical antipsychotics that has a profile not only to block D-2/5-HT2A receptors but also to enhance N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission. This study hypothesized different effects between a single and repeated administration of clozapine on NMDA receptor-mediated neurotransmission, and examined effects of these treatments of clozapine on a non-competitive NMDA receptor antagonist, phencyclidine (PCP)-induced hyperlocomotion and acute increases in glutamate levels in the medial prefrontal cortex (mPFC), after short- and long-term withdrawal from this antipsychotic. Locomotor activity and extracellular levels of glutamate were measured by an infrared sensor and in vivo microdialysis respectively. A single administration of clozapine attenuated PCP-induced hyperlocomotion and blocked PCP-induced increases in glutamate levels in the mPFC at 48 hours, but not 11 days after the injection of clozapine. Repeated administration of clozapine attenuated PCP-induced hyperlocomotion not only at 48 hours, but also 11 days after the last injection of clozapine, with blocking PCP-induced increases in glutamate levels in the mPFC. Both a single and repeated administration of clozapine had no effect on methamphetamine (METH)-induced hyperlocomotion at 48 hours or 11 days after the treatment of clozapine. Considering fast dissociation of clozapine from dopamine D-2 receptors and no effect of a single or repeated administration of clozapine on METH-induced hyperlocomotion, the attenuated PCP-induced hyperlocomotion by a single and repeated clozapine treatments cannot be explained by clozapine occupancy of dopamine D-2 receptors. Repeated but not a single administration of clozapine inhibited a 5-HT2A/2C agonist, DOI-induced increases in the mPFC 11 days after the last injection of clozapine. These findings suggest that subchronically treated clozapine-induced long-lasting downregulation of 5-HT2A receptors may block the enhanced PCP-induced neurochemical and behavioral changes.