Stevens J R, Denney D, Szot P
Department of Neurology, Oregon Health Sciences, University of Portland 97201, USA.
Epilepsy Res. 1996 Dec;26(1):295-304. doi: 10.1016/s0920-1211(96)00061-7.
Clozapine is an 'atypical' neuroleptic that improves symptoms of many patients with schizophrenia whose illness is resistant to treatment with other neuroleptics. Unlike the 'typical neuroleptics (chlorpromazine, haloperidol), clozapine does not induce extrapyramidal symptoms such as Parkinsonism and tardive dyskinesia in humans or catalepsy in the rat. However, clozapine frequently causes epileptiform EEG changes and causes seizures in 3-5% of patients treated with this drug in therapeutic doses. Clozapine also induces dose dependent myoclonus in the partially restrained rat. In the experiments reported here, partially restrained rats were administered repeated alternate day or weekly low, fixed doses of clozapine (1 mg/kg). This dose initially caused no behavioral change. Following the third and subsequent administrations, the same dose elicited an increasing number of myoclonic seizure-like jerks reaching 140/h following the 15th injection in rats receiving the same low dose of clozapine on alternate days and 160/h following the 9th injection in animals that received the same dose once weekly. These effects are consistent with kindling, i.e. a progressive increase of brain excitability following repeated administration of a fixed subconvulsive dose of an excitatory agent. Clozapine kindled animals exhibited a significantly different pattern of early gene expression in ventral tegmental area, origin of the mesolimbic-mesocortical dopamine system and in the anterior thalamic nuclei, compared with saline treated controls subjected to exactly the same recording conditions. The evidence of central nervous system excitation with clozapine may be important to the unique therapeutic effect of this atypical antipsychotic in the treatment of symptoms, especially the deficit symptoms, of schizophrenia.
氯氮平是一种“非典型”抗精神病药物，可改善许多对其他抗精神病药物治疗无效的精神分裂症患者的症状。与“典型”抗精神病药物（氯丙嗪、氟哌啶醇）不同，氯氮平不会在人类中诱发锥体外系症状，如帕金森氏症和迟发性运动障碍，也不会在大鼠中诱发僵住症。然而，氯氮平经常导致癫痫样脑电图改变，并在3%至5%接受该药物治疗剂量的患者中引发癫痫发作。氯氮平还会在部分受限的大鼠中诱发剂量依赖性肌阵挛。在本文报道的实验中，对部分受限的大鼠每隔一天或每周重复给予低剂量、固定剂量的氯氮平（1毫克/千克）。该剂量最初未引起行为变化。在第三次及后续给药后，相同剂量引发的肌阵挛样抽搐数量不断增加，在每隔一天接受相同低剂量氯氮平注射的大鼠中，第15次注射后达到每小时140次，在每周接受一次相同剂量注射的动物中，第9次注射后达到每小时160次。这些效应与点燃现象一致，即反复给予固定亚惊厥剂量的兴奋性药物后，大脑兴奋性逐渐增加。与在完全相同记录条件下接受生理盐水处理的对照组相比，氯氮平点燃的动物在腹侧被盖区、中脑边缘 - 中脑皮质多巴胺系统的起源以及前丘脑核中表现出明显不同的早期基因表达模式。氯氮平引起中枢神经系统兴奋的证据可能对这种非典型抗精神病药物在治疗精神分裂症症状，尤其是缺陷症状方面的独特治疗效果具有重要意义。
