Olanzapine Reverses MK-801-Induced Cognitive Deficits and Region-Specific Alterations of NMDA Receptor Subunits.
Olanzapine Reverses MK-801-Induced Cognitive Deficits and Region-Specific Alterations of NMDA Receptor Subunits.
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奥氮平可逆转 MK-801 引起的认知缺陷和 NMDA 受体亚基的区域特异性改变。
DOI：
10.3389/fnbeh.2017.00260
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发表时间：
2017
影响因子：
3
通讯作者：
Si T
中科院分区：
文献类型：
--
作者：
Liu X;Li J;Guo C;Wang H;Sun Y;Wang H;Su YA;Li K;Si T
认知功能障碍是精神分裂症的一个重要组成部分，它在疾病的病理生理学中早期出现，并与患者的生活质量密切相关。为了开发有效的治疗认知缺陷，重要的是要了解其神经生物学原因，并确定潜在的治疗靶点。本研究采用MK-801重复治疗作为精神分裂症动物模型，研究抗精神病药物奥氮平和氟哌啶醇是否可以逆转MK-801诱导的认知缺陷，以及逆转过程如何招募参与大鼠内侧前额叶皮层（mPFC）和海马谷氨酸神经传递的蛋白质。我们发现，低剂量长期MK-801治疗损害了Morris水迷宫中的情境中物体识别记忆和逆转学习，使参考记忆相对不受影响，并且这些认知缺陷可以通过奥氮平而不是氟哌啶醇治疗部分逆转。在分子水平上，MK-801长期给药导致大鼠mPFC和奥氮平（而非氟哌啶醇）中多种N-甲基-D-天冬氨酸（NMDA）受体亚单位减少，给药恢复了该区域的GluN 1和磷酸化GluN 2B水平。总之，MK-801诱导的认知缺陷可能与NMDA受体亚基的区域特异性变化相关，特定NMDA受体亚基的逆转可能是奥氮平认知增强效应的基础。
Cognitive dysfunction constitutes an essential component in schizophrenia for its early presence in the pathophysiology of the disease and close relatedness to life quality of patients. To develop effective treatment of cognitive deficits, it is important to understand their neurobiological causes and to identify potential therapeutic targets. In this study, adopting repeated MK-801 treatment as an animal model of schizophrenia, we investigated whether antipsychotic drugs, olanzapine and haloperidol, can reverse MK-801-induced cognitive deficits and how the reversal processes recruited proteins involved in glutamate neurotransmission in rat medial prefrontal cortex (mPFC) and hippocampus. We found that low-dose chronic MK-801 treatment impaired object-in-context recognition memory and reversal learning in the Morris water maze, leaving reference memory relatively unaffected, and that these cognitive deficits can be partially reversed by olanzapine, not haloperidol, treatment. At the molecular level, chronic MK-801 treatment resulted in the reduction of multiple N-methyl-D-aspartate (NMDA) receptor subunits in rat mPFC and olanzapine, not haloperidol, treatment restored the levels of GluN1 and phosphorylated GluN2B in this region. Taken together, MK-801-induced cognitive deficits may be associated with region-specific changes in NMDA receptor subunits and the reversal of specific NMDA receptor subunits may underlie the cognition-enhancing effects of olanzapine.
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