D-丝氨酸与奎硫平联合治疗谷氨酸功能低下精神分裂症模型小鼠研究

Effects of quetiapine combination with D-serine on the hypoglutamatergic schizophrenia model in mice

目的观察D-丝氨酸与奎硫平联合治疗谷氨酸功能低下精神分裂症（SZ）模型小鼠的效果，为临床治疗提供实验依据。方法使用昆明种小鼠做实验动物，采用腹腔注射地卓西平马来酸盐（MK-801）溶液（0．25mg／kg）建立SZ模型，使用奎硫平（6．0mg／kg）、D-丝氨酸（0．3mg／kg）或者D-丝氨酸（0．3mg／kg）＋奎硫平（6．0mg／kg）＋MK-801（0．25mg／kg）组合治疗，观察小鼠自主活动、刻板行为，检测脑组织NMDA受体亚单位基因（Grin1，Grin2a，Grin2b）转录以及神经递质（谷氨酸、多巴胺和5-羟色胺）浓度。结果单纯应用奎硫平可阻止MK-801引起小鼠自主活动增加、减少MK-801引起的小鼠刻板行为、阻止MK-801引起NMDA受体亚单位基因（Grin1，Grin2a，Grin2b）转录，但对脑组织神经递质（谷氨酸、多巴胺和5-HT）浓度的影响较少；单纯应用D-丝氨酸可调节脑组织神经递质（谷氨酸、DA和5-HT）浓度，但对MK-801引起小鼠自主活动、刻板行为以及NMDA受体亚单位基因转录的变化不如奎硫平；D-丝氨酸＋奎硫平合用则不仅可阻止MK-801引起小鼠自主活动增加、减少MK-801引起的小鼠刻板行为、阻止MK-801引起NMDA受体亚单位基因转录，而且可增加调节脑组织神经递质（谷氨酸、DA和5-HT）浓度。结论D-丝氨酸＋奎硫平联合治疗谷氨酸功能低下精神分裂症模型小鼠，其作用机制具有互补协同作用。

Objective To observe the effects of quetiapine combination with N-methyl-D-aspartate （NMDA） receptor agonist D-serine on Dizocilpine maleate （MK-801） induced hypoglutamatergic schizophrenia model in mice for treatment of clinic schizophrenia. Methods Kunming mice were used in the experiment. Dizocilpine maleate （MK-801） （0.25 mg/kg） induced hypoglutamatergic schizophrenia model in mice through intraperitoneal injection. D-serine （0.3 mg/kg）, quetiapine（6.0 mg/kg）, or quetiapine（6.0 mg/kg） and D-serine （0.3 mg/kg） combination were used to treat the mice. Spontaneous activity, stereotyped behavior, transcription of NMDA receptor subunit genes （Grin1, Grin2a, and Grin2b）, and concentration of brain neurotransmitters （glutamic acid, DA and 5-HT） were examined. Results Quetiapine significantly inhibited spontaneous activity, stereotyped behavior, and transcription of NMDA receptor subunit genes induced by MK-801, but no effect on concentration of brain neurotransmitters. D-serine regulated concentration of brain neurotransmitters, but less effect on spontaneous activity, stereotyped behavior, and transcription of NMDA receptor subunit genes. Quetiapine combination with D-serine not only significantly inhibited spontaneous activity, stereotyped behavior, and transcription of NMDA receptor subunit genes, but also regulated concentration of brain neurotransnitters （P 〈0. 01 ）. Conclusion Quetiapine combination with D-serine on hypoglulutarmtergic schizophrenia model in mice has conpement each other.