Uttl Libor, Petrasek Tomas, Sengul Hilal, Svojanovska Marketa, Lobellova Veronika, Vales Karel, Radostova Dominika, Tsenov Grygoriy, Kubova Hana, Mikulecka Anna, Svoboda Jan, Stuchlik Ales
Department of Developmental Epileptology, Institute of Physiology, Czech Academy of Sciences, Prague, Czechia.
Department of Experimental Neurobiology, National Institute of Mental Health, Klecany, Czechia.
Front Pharmacol. 2018 Feb 12;9:42. doi: 10.3389/fphar.2018.00042. eCollection 2018.
The role of NMDA receptors in learning, memory and hippocampal function has long been recognized. Post-mortem studies have indicated that the expression or subunit composition of the NMDA glutamate receptor subtype might be related to the impaired cognitive functions found in schizophrenia patients. NMDA receptor antagonists have been used to develop animal models of this disorder. There is accumulating evidence showing that not only the acute but also the chronic application of NMDA receptor antagonists may induce schizophrenia-like alterations in behavior and brain functions. However, limited evidence is available regarding the consequences of NMDA receptor blockage during periods of adolescence and early adulthood. This study tested the hypothesis that a 2-week treatment of male Long-Evans and Wistar rats with dizocilpine (MK-801; 0.5 mg/kg daily) starting at postnatal days (PD) 30 and 60 would cause a long-term cognitive deficit and changes in the levels of NMDA receptor subunits. The working memory version of the Morris water maze (MWM) and active place avoidance with reversal on a rotating arena (Carousel) requiring cognitive coordination and flexibility probed cognitive functions and an elevated-plus maze (EPM) was used to measure anxiety-like behavior. The western blot method was used to determine changes in NMDA receptor subunit levels in the hippocampus. Our results showed no significant changes in behaviors in Wistar rats. Slightly elevated anxiety-like behavior was observed in the EPM in Long-Evans rats with the onset of treatment on PD 30. Furthermore, Long-Evans rats treated from PD 60 displayed impaired working memory in the MWM. There were; however, no significant changes in the levels of NMDA receptor subunits because of MK-801 administration. These findings suggest that a 2-week treatment starting on PD 60 in Long-Evans rats leads to long-term changes in working memory, but this deficit is not paralleled by changes in NMDA receptor subunits. These results support the face validity, but not construct validity of this model. We suggest that chronic treatment of adolescent and adult rats does not constitute a plausible animal model of schizophrenia.
N-甲基-D-天冬氨酸（NMDA）受体在学习、记忆及海马功能中的作用早已得到认可。尸检研究表明，NMDA谷氨酸受体亚型的表达或亚基组成可能与精神分裂症患者认知功能受损有关。NMDA受体拮抗剂已被用于建立该疾病的动物模型。越来越多的证据表明，不仅NMDA受体拮抗剂的急性应用，而且其慢性应用都可能诱发行为和脑功能的精神分裂症样改变。然而，关于青春期和成年早期NMDA受体阻断的后果，现有证据有限。本研究检验了以下假设：从出生后第30天和第60天开始，对雄性Long-Evans和Wistar大鼠进行为期2周的地佐环平（MK-801；每日0.5 mg/kg）治疗，会导致长期认知缺陷以及NMDA受体亚基水平的变化。采用Morris水迷宫（MWM）的工作记忆版本以及在旋转竞技场（转盘）上进行主动位置回避并反转，以探究认知协调和灵活性，从而探测认知功能，并使用高架十字迷宫（EPM）来测量焦虑样行为。采用蛋白质免疫印迹法测定海马中NMDA受体亚基水平的变化。我们的结果显示，Wistar大鼠的行为没有显著变化。在出生后第30天开始治疗的Long-Evans大鼠中，EPM中观察到焦虑样行为略有增加。此外，从出生后第60天开始治疗的Long-Evans大鼠在MWM中表现出工作记忆受损。然而，由于给予MK-801，NMDA受体亚基水平没有显著变化。这些发现表明，从出生后第60天开始对Long-Evans大鼠进行为期2周的治疗会导致工作记忆的长期变化，但这种缺陷与NMDA受体亚基的变化并不平行。这些结果支持了该模型的表面效度，但不支持其结构效度。我们认为，对青春期和成年大鼠进行慢性治疗并不能构成一个合理的精神分裂症动物模型。
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