Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine
Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine
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DOI：
10.1073/pnas.0704848104
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发表时间：
2007-09-11
影响因子：
11.1
通讯作者：
Artigas, Francesc
中科院分区：
文献类型：
--
作者：
Kargieman, Lucila;Santana, Noemi;Artigas, Francesc
NMDA受体(NMDA-R)拮抗剂被广泛用于精神分裂症模型，因为它们能够引起阳性和阴性症状以及与疾病类似的认知障碍。精神分裂症的认知缺陷与前额叶皮质(PFC)异常有关。这些缺陷特别令人感兴趣，因为认知能力的早期改善预示着更好的长期临床结果。在这里，我们研究了非竞争性NMDA-R拮抗剂苯环利定(PCP)对PFC功能的影响，以了解参与其分裂行为的细胞和网络元件。PCP可引起大鼠PFC活动的显著破坏，分别使45%和33%的锥体神经元的活动增加和降低(22%的神经元未受影响)。同时，通过记录局部场电位，PCP显著降低了德尔塔频率范围(0.3-4赫兹)的皮质同步性。随后给予的抗精神病药物氟哌啶醇和氯氮平逆转了PCP对锥体细胞放电和皮质同步化的影响。PCP可增加PFC锥体神经元c-fos的表达，氯氮平可阻止这种作用。PCP还增强了丘脑中央内侧核和内侧背核(但不是网状核)中c-fos的表达，提示丘脑皮质兴奋性输入的增强参与了这一过程。这些结果阐明了PFC参与了NMDA-R拮抗剂的拟分裂行为，并表明抗精神病药物可能通过使PFC活动正常化而部分发挥其治疗作用，这一作用可能会增加皮质下多巴胺受体的阻断。
NMDA receptor (NMDA-R) antagonists are extensively used as schizophrenia models because of their ability to evoke positive and negative symptoms as well as cognitive deficits similar to those of the illness. Cognitive deficits in schizophrenia are associated with prefrontal cortex (PFC) abnormalities. These deficits are of particular interest because an early improvement in cognitive performance predicts a better long-term clinical outcome. Here, we examined the effect of the noncompetitive NMDA-R antagonist phencyclidine (PCP) on PFC function to understand the cellular and network elements involved in its schizomimetic actions. PCP induces a marked disruption of the activity of the PFC in the rat, increasing and decreasing the activity of 45% and 33% of the pyramidal neurons recorded, respectively (22% of the neurons were unaffected). Concurrently, PCP markedly reduced cortical synchrony in the delta frequency range (0.3-4 Hz) as assessed by recording local field potentials. The subsequent administration of the antipsychotic drugs haloperidol and clozapine reversed PCP effects on pyramidal cell firing and cortical synchronization. PCP increased c-fos expression in PFC pyramidal neurons, an effect prevented by the administration of clozapine. PCP also enhanced c-fos expression in the centromedial and mediodorsal (but not reticular) nuclei of the thalamus, suggesting the participation of enhanced thalamocortical excitatory inputs. These results shed light on the involvement of PFC in the schizomimetic action of NMDA-R antagonists and show that antipsychotic drugs may partly exert their therapeutic effect by normalizing a disrupted PFC activity, an effect that may add to subcortical dopamine receptor blockade.