Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India.
Division of Biomedical Sciences, Indian Council of Medical Research, Ministry of Health and Family Welfare, Government of India, V. Ramalingaswamy Bhawan, New Delhi 110029, India.
J Environ Pathol Toxicol Oncol. 2020;39(1):1-12. doi: 10.1615/JEnvironPatholToxicolOncol.2019030362.
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.
谷氨酸 N-甲基-D-天冬氨酸（NMDA）受体在几种神经和精神疾病中具有关键作用。地卓西平（MK-801）是一种与 NMDA 受体偶联阳离子通道相关的苯环利定识别位点配体，在该通道中，它作为中枢谷氨酸受体的有效非竞争性拮抗剂发挥作用。在这项研究中，我们研究了氯氮平对 MK-801 诱导的小鼠前额叶皮层神经化学和神经行为改变的影响。急性给予 NMDA 非竞争性拮抗剂 MK-801 会损害运动协调、握力和运动活动。氯氮平是唯一一种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物中的疗效最好；然而，其机制尚不清楚。为了了解其机制，我们研究了氯氮平对 NMDA 受体拮抗剂 MK-801 引起的运动协调、运动活动和握力的影响。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 引起的作用（0.2 毫克/千克体重）。由 MK-801 改变的运动协调和握力范式被氯氮平恢复。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，氯氮平治疗降低了大脑皮质中神经元活性标志物 c-fos 的过度表达。目前研究的结果确定，氯氮平通过胆碱能和神经机制改善了 MK-801 治疗的小鼠的认知。这些发现表明氯氮平具有增强精神分裂症等疾病认知的潜力。
