Effect of paliperidone and risperidone on extracellular glutamate in the prefrontal cortex of rats exposed to prenatal immune activation or MK-801.
Effect of paliperidone and risperidone on extracellular glutamate in the prefrontal cortex of rats exposed to prenatal immune activation or MK-801.
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DOI：
10.1016/j.neulet.2011.06.011
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发表时间：
2011-08-18
影响因子：
2.5
通讯作者：
Richtand NM
中科院分区：
文献类型：
--
作者：
Roenker NL;Gudelsky G;Ahlbrand R;Bronson SL;Kern JR;Waterman H;Richtand NM
精神分裂症的 NMDA 谷氨酸功能减退模型部分基于 NMDA 受体阻断对人类和啮齿动物的急性影响。一些实验室报告了产前暴露于免疫挑战后谷氨酸系统异常，免疫挑战是精神分裂症的已知环境危险因素。在此，我们报告产前免疫激活后 NMDA 谷氨酸受体功能减退的指标，以及青春期期间使用非典型抗精神病药物利培酮和帕潘立酮治疗的效果。怀孕的 Sprague-Dawley 大鼠在妊娠第 14 天注射聚肌苷：聚胞苷酸 (poly I:C) 或盐水。在出生后第 35 天至 56 天（青春期）期间，通过饮用水和载体、利培酮（0.01 mg/kg/天）或帕潘立酮（0.01 mg/kg/天）和细胞外谷氨酸口服治疗雄性后代前额皮质中的水平通过 PD 56 时的微透析测定。与 NMDA 受体功能下降一致，MK-801 诱导的细胞外谷氨酸浓度增加在产前免疫激活后明显减弱。进一步表明 NMDA 受体功能低下，Poly I:C 处理的母鼠的后代中前额皮质基底细胞外谷氨酸显着升高（P<0.05）。用低剂量帕潘立酮或利培酮（0.01 mg/kg/天，产后第 35-56 天）进行预处理，可使前额皮质基础细胞外谷氨酸正常化（与聚 I:C 载体治疗相比，P<0.05）。用帕潘立酮和利培酮预处理也可以防止 MK-801 诱导的细胞外谷氨酸的急性增加。这些观察结果表明，在产前免疫激活后的青春期期间，NMDA 受体功能下降和细胞外谷氨酸升高，这是精神分裂症 NMDA 谷氨酸受体功能低下模型的两个关键特征。使用非典型抗精神病药物帕潘立酮和利培酮进行治疗，使基础细胞外谷氨酸正常化。作为产前免疫激活的早期发育结果，谷氨酸异常与精神分裂症 NMDA 谷氨酸受体功能低下模型一致，这提供了一个模型来识别针对谷氨酸系统的新型早期干预措施，谷氨酸系统在精神分裂症的阳性和阴性症状中都发挥着重要作用。
The NMDA glutamate hypofunction model of schizophrenia is based in part upon acute effects of NMDA receptor blockade in humans and rodents. Several laboratories have reported glutamate system abnormalities following prenatal exposure to immune challenge, a known environmental risk factor for schizophrenia. Here we report indices of NMDA glutamate receptor hypofunction following prenatal immune activation, as well as the effects of treatment during periadolescence with the atypical antipsychotic medications risperidone and paliperidone. Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or saline on gestational day 14. Male offspring were treated orally via drinking water with vehicle, risperidone (0.01 mg/kg/day), or paliperidone (0.01 mg/kg/day) between postnatal days 35 and 56 (periadolescence) and extracellular glutamate levels in the prefrontal cortex were determined by microdialysis at PD 56. Consistent with decreased NMDA receptor function, MK-801 – induced increases in extracellular glutamate concentration were markedly blunted following prenatal immune activation. Further suggesting NMDA receptor hypofunction, prefrontal cortex basal extracellular glutamate was significantly elevated (P<0.05) in offspring of Poly I:C treated dams. Pretreatment with low dose paliperidone or risperidone (0.01 mg/kg/day postnatal days 35–56) normalized prefrontal cortical basal extracellular glutamate (P<0.05 vs. poly I:C vehicle-treatment). Pretreatment with paliperidone and risperidone also prevented the acute MK-801-induced increase in extracellular glutamate. These observations demonstrate decreased NMDA receptor function and elevated extracellular glutamate, two key features of the NMDA glutamate receptor hypofunction model of schizophrenia, during periadolescence following prenatal immune activation. Treatment with the atypical antipsychotic medications paliperidone and risperidone normalized basal extracellular glutamate. Demonstration of glutamatergic abnormalities consistent with the NMDA glutamate receptor hypofunction model of schizophrenia as an early developmental consequence of prenatal immune activation provides a model to identify novel early interventions targeting glutamatergic systems which play an important role in both positive and negative symptoms of schizophrenia.
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影响因子：
17.7
作者：
Clarke, Mary C.;Tanskanen, Antti;Cannon, Mary
通讯作者：
Cannon, Mary
影响因子：
11
作者：
Meyer, U.;Murray, P. J.;Feldon, J.
通讯作者：
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影响因子：
7.4
作者：
Lante, Fabien;Meunier, Johann;Barbanel, Gerard
通讯作者：
Barbanel, Gerard
影响因子：
7.6
作者：
Meyer, Urs;Nyffeler, Myriel;Feldon, Joram
通讯作者：
Feldon, Joram
DOI：
10.1017/s1461145708009267
发表时间：
2009-05-01
影响因子：
4.8
作者：
Lopez-Gil, Xavier;Artigas, Francesc;Adell, Albert
通讯作者：
Adell, Albert