Glutamatergic N-methyl-D-aspartate (NMDA) receptors have critical roles in several neurological and psychiatric diseases. Dizocilpine (MK-801) is a ligand at phencyclidine recognition sites that is associated with NMDA receptor-coupled cation channels, where it acts as a potent noncompetitive antagonist of central glutamate receptors. In this study, we investigate the effect of clozapine on MK-801-induced neurochemical and neurobehavioral alterations in the prefrontal cortex of mice. Acute administration of NMDA noncompetitive antagonist MK-801 impairs motor coordination, grip strength, and locomotor activity. Clozapine is the only medication that is indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents; however, its mechanism is not well understood. To understand its mechanism, we investigated the effects of clozapine on motor coordination, locomotor activity, and grip strength in mice against the NMDA receptor antagonist MK-801. MK-801 induced elevations in acetylcholinesterase (AChE) activity, monoamine oxidase (MAO) activity, and c-fos expression. The administration of clozapine inhibited the effects caused by MK-801 (0.2 mg/kg body weight). Motor coordination and grip strength paradigms that had been altered by MK-801 were restored by clozapine. Moreover, clozapine also ameliorated MK-801-induced elevation in AChE and MAO activity. Our immunostaining results demonstrated that clozapine treatment reduced overexpression of the neuronal activity marker c-fos in cortices of the brain. Results of the current study determine that clozapine ameliorated cognition in MK-801-treated mice via cholinergic and neural mechanisms. These findings show that clozapine possesses the potential to augment cognition in diseases such as schizophrenia.

中文翻译：

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氯氮平改善了MK-801诱导的精神分裂症小鼠模型的行为和生化结果。

谷氨酸能N-甲基-D-天冬氨酸（NMDA）受体在几种神经系统疾病和精神疾病中具有关键作用。Dizocilpine（MK-801）是在苯环利定识别位点的配体，与NMDA受体偶联的阳离子通道相关，在其中它充当中枢谷氨酸受体的有效非竞争性拮抗剂。在这项研究中，我们调查了氯氮平对小鼠前额叶皮层MK-801诱导的神经化学和神经行为改变的影响。NMDA非竞争性拮抗剂MK-801的急性给药会损害运动协调性，抓地力和运动能力。氯氮平是唯一可用于治疗难治性精神分裂症的药物，因为它在所有抗精神病药中均具有优越的疗效。但是，其机理尚不十分清楚。要了解其机制，我们研究了氯氮平对小鼠针对NMDA受体拮抗剂MK-801的运动协调，自发活动和握力的影响。MK-801诱导乙酰胆碱酯酶（AChE）活性，单胺氧化酶（MAO）活性和c-fos表达升高。氯氮平的给药抑制了由MK-801（0.2 mg / kg体重）引起的作用。氯氮平恢复了由MK-801改变的运动协调性和抓地力范例。此外，氯氮平还改善了MK-801诱导的AChE和MAO活性升高。我们的免疫染色结果表明，氯氮平治疗可减少大脑皮层神经元活性标记c-fos的过表达。目前的研究结果确定，氯氮平可通过胆碱能和神经机制改善MK-801治疗小鼠的认知。