Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs
Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs
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DOI：
10.1073/pnas.0806669105
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发表时间：
2008-11-18
影响因子：
11.1
通讯作者：
Moghaddam, Bita
中科院分区：
文献类型：
--
作者：
Homayoun, Hournan;Moghaddam, Bita
直到最近，所有已知的抗精神病药物都被认为是阻断多巴胺D2受体。代谢型谷氨酸2/3（mGlu 2/3）受体激动剂改善精神分裂症的精神病和情感症状的新证据表明，具有不同分子靶点的化合物可能作用于共同的细胞靶点来治疗精神分裂症。我们假设正常化眶额皮质（OFC）神经元的活动，这是一个越来越多地涉及精神分裂症的病理生理学的区域，提出了这样一个目标。我们中断OFC活动的行为大鼠与使用依赖性NMDA拮抗剂模型的NMDA功能减退状态，可能会发生在精神分裂症。这种全身性治疗增加了大多数锥体细胞的活性，同时抑制了推定的抑制性GABA中间神经元的活性并增加了行为刻板性。安非他明后观察到类似的OFC放电中断模式，安非他明模拟精神分裂症中的多巴胺多动状态，并产生不同于其他前额叶皮层区域中NMDA拮抗剂的放电中断模式。抗精神病药物氟哌啶醇和氯氮平，其目标是单胺受体，以及mGlu 2/3激动剂和mGlu 5受体调节剂提出具有抗精神病疗效，逆转了NMDA功能减退对OFC细胞和行为的影响。当在安非他明之后给予治疗时，观察到OFC活性正常化的类似模式。因此，具有不同作用机制的已证实或推定的抗精神病药物类似地降低了NMDA功能减退和多巴胺功能亢进对OFC神经元的影响，表明这些神经元是抗精神病药物治疗效果的候选靶点。
Until recently, all known antipsychotic drugs were thought to block the dopamine D2 receptor. New evidence that agonists of the metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate psychotic and affective symptoms of schizophrenia suggests that compounds with different molecular targets may act on a common cellular target to treat schizophrenia. We hypothesized that normalizing the activity of neurons in the orbitofrontal cortex (OFC), a region that is increasingly implicated in the pathophysiology of schizophrenia, presents such a target. We disrupted OFC activity in behaving rats with a use-dependent NMDA antagonist to model the NMDA hypofunction state that may occur in schizophrenia. This systemic treatment increased the activity of most pyramidal cells while inhibiting the activity of putative inhibitory GABA interneurons and increasing behavioral stereotypy. A similar pattern of OFC firing disruption was observed after amphetamine, which models a dopamine hyperactivity state in schizophrenia and which produces a pattern of firing disruption different from those of NMDA antagonists in other prefrontal cortex regions. Antipsychotic drugs haloperidol and clozapine, which target monoamine receptors, as well as an mGlu2/3 agonist and an mGlu5 receptor modulator proposed to have antipsychotic efficacy, reversed the impact of NMDA hypofunction on OFC cells and on behavior. A similar pattern of normalization of OFC activity was observed when treatments were given after amphetamine. Thus, proven or putative antipsychotic drugs with different mechanisms of action similarly reduced the impact of NMDA hypofunction and dopamine hyperfunction on OFC neurons, suggesting that these neurons are a candidate target for the therapeutic effects of antipsychotic medications.