Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.
Department of Radiology, McMaster University, Hamilton, Ontario, Canada.
Neuropharmacology. 2014 Feb;77:325-33. doi: 10.1016/j.neuropharm.2013.10.001. Epub 2013 Oct 18.
Functional imaging studies in schizophrenic patients have demonstrated metabolic brain abnormalities during cognitive tasks. This study aimed to 1) introduce a novel analysis of brain metabolic function in live animals to characterize the hypo- and hyperfrontality phenomena observed in schizophrenia and following NMDA antagonist exposure, and 2) identify a robust and representative MK-801 treatment regimen that effectively models brain metabolic abnormalities as well as a range of established behavioural abnormalities representative of schizophrenia.
The validity of the MK-801 animal model was examined across several established pre-clinical tests, and a novel assessment of brain metabolic function using PET/CT fused imaging. In the present study, MK-801 was administered acutely at 0.1 mg/kg and 0.5 mg/kg, and sub-chronically at 0.5 mg/kg daily for 7 days.
Acute treatment at 0.5 mg/kg-disrupted facets of memory measured through performance in the 8-arm radial maze task and generated abnormalities in sensorimotor gating, social interaction and locomotor activity. Furthermore, this treatment regimen induced hyperfrontality (increased brain metabolic function in the prefrontal area) observed via PET/CT fused imaging in the live rat.
While PET and CT fused imaging in the live rat offers a functional representation of metabolic function, more advanced PET/CT integration is required to analyze more discrete brain regions.
These findings provide insight on the effectiveness of the MK-801 pre-clinical model of schizophrenia and provide an optimal regimen to model schizophrenia. PET/CT fused imaging offers a highly translatable tool to assess hypo- and hyperfrontality in live animals.
精神分裂症患者的功能影像学研究表明，在认知任务期间大脑代谢存在异常。本研究旨在：1）引入一种新的活体动物大脑代谢功能分析方法，以描述精神分裂症及 NMDA 拮抗剂暴露后观察到的低额叶和高额叶现象；2）确定一种有效的、有代表性的 MK-801 治疗方案，该方案能有效模拟大脑代谢异常，以及一系列具有代表性的精神分裂症行为异常。
通过多项已建立的临床前测试来检验 MK-801 动物模型的有效性，并使用 PET/CT 融合成像对大脑代谢功能进行新的评估。在本研究中，MK-801 以 0.1mg/kg 和 0.5mg/kg 的剂量进行急性处理，以 0.5mg/kg 的剂量每天进行亚慢性处理，持续 7 天。
0.5mg/kg 的急性处理破坏了 8 臂放射迷宫任务中记忆的各个方面，并导致感觉运动门控、社会互动和运动活动异常。此外，这种治疗方案通过活体大鼠的 PET/CT 融合成像观察到了高额叶现象（前额区域大脑代谢功能增加）。
虽然活体大鼠的 PET 和 CT 融合成像提供了代谢功能的功能表现，但需要更先进的 PET/CT 整合来分析更离散的脑区。
这些发现为 MK-801 精神分裂症临床前模型的有效性提供了深入了解，并为模拟精神分裂症提供了最佳方案。PET/CT 融合成像提供了一种高度可转化的工具，可在活体动物中评估低额叶和高额叶现象。
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