Division of Pharmacology, Central Drug Research Institute, Lucknow - 226001, Uttar Pradesh, India.
Neuropharmacology. 2012 Nov;63(6):1161-71. doi: 10.1016/j.neuropharm.2012.05.041. Epub 2012 Jun 6.
Ketamine, an NMDA receptor antagonist has been shown to induce aberrant behaviour phenotypes in rodents, some of which are known to simulate the behaviour abnormalities observed in patients suffering from schizophrenia. Thus, developing ketamine-induced animal models became an important tool of choice to study the mechanistic details of some critical symptoms associated with schizophrenia. In this study, our goal was to characterize and correlate the ketamine-induced changes in the behavioural phenotypes to the changes in neurochemical and molecular profile(s) in the brain tissues implicated in the pathophysiology of schizophrenia. We studied the effects of ketamine in mice using 'acute' and 'chronic' treatment regimens along with the 'drug withdrawal' effects on their biochemical and molecular parameters in the pre-frontal cortex, hippocampus, and striatum. Our results demonstrated that the acute and chronic ketamine administration, differentially and site specifically, modulated the levels of acetylcholine, dopamine, serotonin and noradrenaline. In addition, the chronic ketamine doses dramatically suppressed the levels of glycine among some of the amino acids examined and induced alternations in gene expression of the key neurotransmitter receptor systems, including some members of the dopamine and the serotonin receptor families. The acute and chronic ketamine treatment induced "signature" neurochemical and gene-expression patterns that are implicated in the pathophysiology of schizophrenia. Our analyses tend to support the "chronic ketamine" mice model for experimental psychosis as a tool for deeper investigation of the mechanistic paradigm associated with the schizophrenia spectrum disorder and for screening next-generation antipsychotic drugs.
氯胺酮是一种 NMDA 受体拮抗剂，已被证明可在啮齿动物中诱导异常行为表型，其中一些已知可模拟精神分裂症患者观察到的行为异常。因此，开发氯胺酮诱导的动物模型成为研究与精神分裂症相关的一些关键症状的机制细节的重要选择工具。在这项研究中，我们的目标是描述并将氯胺酮诱导的行为表型变化与大脑组织中神经化学和分子特征的变化相关联，这些大脑组织与精神分裂症的病理生理学有关。我们使用“急性”和“慢性”治疗方案以及“药物戒断”对小鼠进行氯胺酮研究，研究其对前额叶皮质、海马体和纹状体中生化和分子参数的影响。我们的结果表明，急性和慢性氯胺酮给药会以不同的方式和特定的部位调节乙酰胆碱、多巴胺、血清素和去甲肾上腺素的水平。此外，一些检查的氨基酸中，慢性氯胺酮剂量会显著抑制甘氨酸的水平，并诱导关键神经递质受体系统的基因表达发生变化，包括多巴胺和血清素受体家族的一些成员。急性和慢性氯胺酮处理诱导了与精神分裂症病理生理学相关的“特征”神经化学和基因表达模式。我们的分析倾向于支持“慢性氯胺酮”小鼠模型作为实验性精神病的工具，用于更深入地研究与精神分裂症谱系障碍相关的机制范例，并用于筛选下一代抗精神病药物。
