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目的:观察长期应用地西泮小鼠对药物的耐受性及不同安神药对对其的抑制作用,并初步探讨其机制。方法:将小鼠分为空白组、模型组、法半夏-秫米组(3.25 g·kg-1·d-1)、磁石-朱砂组(0.33 g·kg-1·d-1)、黄连-阿胶组(2.73 g·kg-1·d-1)、黄连-肉桂组(2.15 g·kg-1·d-1)、栀子-淡豆豉组(1.69 g·kg-1·d-1),每天灌胃(ig)1次,连续60 d。给药期间,除空白组外,各组隔2日于ig给药30 min后每3天1次ip地西泮注射液25 mg·kg-1,造成地西泮耐受。持续监测小鼠睡眠潜伏期,测定自主活动次数和时间,并用荧光定量PCR测定小鼠全脑γ-氨基丁酸受体(GABAA-R)mRNA、谷氨酸脱羧酶65(GAD65)mRNA的表达。结果:用药期间,模型组睡眠潜伏期逐渐延长,黄连-肉桂组、黄连-阿胶组睡眠潜伏期变化不大;用药2个月后,与模型组比较,黄连-肉桂组、黄连-阿胶组睡眠潜伏期明显缩短(P<0.01),黄连-肉桂组、黄连-阿胶组、法半夏-秫米组小鼠自主活动次数、活动时间显著性减少(P<0.05,P<0.01),黄连-肉桂组、黄连-阿胶组、半夏-秫米组、磁石-朱砂组和栀子-淡豆豉组小鼠脑组织GABAA-R mRNA,GAD65 mRNA表达显著性上调(P<0.05,P<0.01)。结论:黄连-阿胶、黄连-肉桂和法半夏-秫米具有抑制长期单独应用地西泮而致药效下降机体耐受的作用,其机制可能与上调脑内GABAA-R和GAD65有关。
OBJECTIVE: To observe the long-term use of diazepam in mice to drug tolerance and different antipsychotic drugs on its inhibition, and to explore its mechanism. Methods: The mice were divided into three groups: blank control group, model group, Banxia Xiajiu group (3.25 g · kg -1 · d -1), magnetite-cinnabar group (0.33 g · kg -1 · d -1) Coptidis -concentration (2.73 g · kg-1 · d-1), berberine-cinnamon group (2.15 g · kg-1 · d-1) 1), gavage (ig) 1 times a day for 60 days. During the administration, diazepam was tolerated with 25 mg · kg-1 of ip diazepam injection once every 3 days for every 3 days except for the blank group except for the blank group. The sleep latency of mice was continuously monitored. The frequency and time of spontaneous activity were measured. The expression of GABAA-R mRNA and glutamate decarboxylase 65 (GAD65) mRNA in whole brain of mice was detected by fluorescence quantitative PCR. Results: During the treatment, the sleep latency of the model group was gradually prolonged, and the sleep latency of Coptis-Cinnamon and Coptis-Ejiao did not change much. After two months of treatment, the latency to sleep of Coptis-Cinnamon, Coptis-Ejiao showed significant (P <0.01), the number of spontaneous activity and the time of activity in the Coptis-Cinnamon, Coptis-Ejiao-Pinellia and Pinellia-Mi-Mi groups decreased significantly The expression of GABAA-R mRNA and GAD65 mRNA in the Huanglian-Ejiao, Pinellia-Shenmi, Magnet-Zhuzha and Zhizi-Diantan groups were significantly increased (P <0.05, P <0.01). CONCLUSION: Coptis-gelatin, berberine-cinnamon and French pinellia tuber can inhibit the long-term use of diazepam and reduce the tolerance of the body. The mechanism may be related to the upregulation of GABAA-R and GAD65.