Fine-tuning of awake prefrontal cortex neurons by clozapine: Comparison with haloperidol and N-desmethylclozapine
Fine-tuning of awake prefrontal cortex neurons by clozapine: Comparison with haloperidol and N-desmethylclozapine
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DOI：
10.1016/j.biopsych.2006.05.016
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发表时间：
2007-03-01
影响因子：
10.6
通讯作者：
Moghaddam, Bita
中科院分区：
文献类型：
--
作者：
Homayoun, Houlman;Moghaddam, Bita
背景：氯氮平对精神分裂症更好的临床疗效的机制仍然知之甚少。前额叶皮层（PFC）被认为是氯氮平治疗效果的主要部位;然而，在行为相关的背景下，缺乏氯氮平如何影响PFC神经元活性的证据。方法：采用灌胃单单位记录法，观察了清醒大鼠PFC神经元对氯氮平及其主要代谢产物N-去甲基氯氮平（DMCIz）的反应，和典型的抗精神病药物氟哌啶醇在基线条件下和治疗后与N-甲基-D-天冬氨酸拮抗剂MK 801。结果：氯氮平和DMClz对PFC细胞的自发放电率有活性依赖性影响，但氟哌啶醇对PFC细胞的自发放电率无影响：它们增加低基线放电率神经元的活性，降低高基线放电率神经元的活性。氯氮平和DMClz也逆转了MK 801对PFC神经元放电的影响，但氟哌啶醇未逆转。这种逆转与阻断MK 801诱导的行为stereotypy.Conclusions：这些研究结果表明，氯氮平有能力微调自发和中断活动的PFC神经元。这种效应可能有助于，在一定程度上，氯氮平治疗精神分裂症的疗效。
Background: Mechanisms underlying clozapine's better clinical efficacy in schizophrenia remain poorly understood. The prefrontal cortex (PFC) has been implicated as a primary site for the therapeutic effects of clozapine; however, evidence for how clozapine influences the activity of PFC neurons in behaviorally relevant contexts is lacking.Methods: Ensemble single unit recording in awake rats was used to measure the activity of PFC neurons in response to clozapine, its main metabolite N-desmethylclozapine (DMCIz), and the typical antipsychotic drug haloperidol during baseline conditions and after treatment with the N-methyl-D-aspartate antagonist MK801. Behavioral stereotypy was scored during recording.Results: Clozapine and DMClz but not haloperidol had an activity-dependent influence on spontaneous firing rate of PFC cells: they increased the activity of neurons with low baseline firing rates and decreased the activity of neurons with higher firing rates. Clozapine and DMClz but not haloperidol also reversed the effect of MK801 on PFC neuronal firing. This reversal was strongly correlated with blockade of MK801-induced behavioral stereotypy.Conclusions: These findings indicate that clozapine has the capacity to fine-tune spontaneous and disrupted activity of PFC neurons. This effect might contribute, in part, to the therapeutic efficacy of clozapine in schizophrenia.