D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats
D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats
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DOI：
10.1016/j.bbr.2007.07.033
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发表时间：
2008-01-10
影响因子：
2.7
通讯作者：
Chaki, Shigeyuki
中科院分区：
文献类型：
--
作者：
Karasawa, Jun-Ichi;Hashimoto, Kenji;Chaki, Shigeyuki
已报道增强N-甲基-D-天冬氨酸（NMDA）谷氨酸受体功能的化合物改善认知缺陷。由于认知缺陷被认为是精神分裂症的核心症状，因此增强NMDA受体功能代表了治疗精神分裂症的有希望的方法。本研究探讨了D-丝氨酸或甘氨酸转运体抑制剂N-[3-（4 ′-氟苯基）-3-（4 ′-苯基苯氧基）丙基]肌氨酸（NFPS）是否能改善MK-801诱导的大鼠认知功能障碍，并与非典型抗精神病药物氯氮平和典型抗精神病药物氟哌啶醇进行了比较。以评估认知功能。我们在大鼠中使用了新物体识别测试，该测试测量了新物体与熟悉物体配对时的自发探索活动。然后，我们评估了化合物对由NMDA受体拮抗剂MK-801治疗诱导的认知缺陷的影响。氯氮平预处理（1，5 mg/kg，i. p.）而氟哌啶醇（0.03，0.1mg/kg，i. p.）显著改善MK-801诱导的认知缺陷。用800mg/ka（i.p.）或NFPS（0.3，ling/k，a，i.p.）显著改善MK-801诱导的认知缺陷。这些发现表明，MK-801在新物体识别试验中诱导的对新物体的偏好受损可能是一种有用的动物模型，可用于评估针对精神分裂症患者中观察到的认知缺陷的化合物的疗效。结果还表明，提高NMDA受体功能是治疗精神分裂症相关认知功能障碍的有效途径。(c)2007 Elsevier B. V.保留所有权利。
Compounds enhancing N-methyl-D-aspartate (NMDA) glutamate receptor function have been reported to improve cognitive deficits. Since cognitive deficits are considered to be the core symptom of schizophrenia, enhancing NMDA receptor function represents a promising approach to treating, schizophrenia. In the present study, we investigated whether D-serine or a glycine transporter inhibitor N-[3-(4'-fluorophenyl)-3-(4'phenylphenoxy)propyllsarcosine (NFPS), both of which enhance NMDA receptor function, could improve MK-801-induced cognitive deficits in rats, and compared their effects with those of the atypical antipsychotic clozapine and of the typical antipsychotic haloperidol. To assess cognitive function. we used a novel object recognition test in rats that measured spontaneous exploratory activity of a novel object when paired with a familiar object. We then evaluated the effects of the compounds on cognitive deficits induced by treatment with MK-801, the NMDA receptor antagonist. Pretreatment with clozapine (1, 5 mg/kg, i.p.) but not haloperidol (0.03, 0.1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits. Pretreatment with D-serine at 800 mg/ka (i.p.) or NFPS (0.3, 1 ing/k,a, i.p.) significantly improved MK-801-induced cognitive deficits under this test paradigm. These findings suggest that impaired preference for novel objects induced by MK-801 in the novel object recognition test could be a useful animal model for evaluating the efficacy of compounds targeting the cognitive deficits observed in schizophrenic patients. The results also suggest that enhancing NMDA receptor function is an effective way for treating the cognitive deficits associated with schizophrenia. (c) 2007 Elsevier B.V. All rights reserved.