唑吡坦对低压低氧致失眠模型小鼠的镇静催眠作用OACSTPCD
Sedative and hypnotic effects of zolpidem on insomnia model mice induced by hypoxia
目的 研究唑吡坦的镇静催眠作用及对丘脑和下丘脑氨基酸类神经递质含量的影响.方法 模拟海拔5500 m低压低氧环境,通过阈上剂量(50 mg·kg-1,ip)戊巴比妥钠诱导小鼠翻正反射消失(LORR)实验建立低压低氧致失眠模型.采用LORR实验观察常压常氧和低压低氧条件下唑吡坦(0.33,1,3,9和27 mg·kg-1,ip)与戊巴比妥钠镇静催眠阈下(20 mg·kg-1,ip)和阈上剂量的协同效应及唑吡坦(10,13,17,20,23,30和40 mg·kg-1,ip)的镇静催眠效应.运用高效液相荧光检测法测定常压常氧和低压低氧条件下给予唑吡坦(10,20和40 mg·kg-1,ip)1 h后,小鼠丘脑和下丘脑谷氨酸(Glu)和γ-氨基丁酸(GABA)含量.结果 低压低氧处理1d显著缩短阈上剂量戊巴比妥钠诱导小鼠LORR持续时间(P<0.05).与常压常氧溶媒组和低压低氧致失眠溶媒组相比,常压常氧唑吡坦9和27 mg·kg-1组和低压低氧致失眠模型+唑吡坦9和27 mg·kg-1组均显著缩短阈下及阈上剂量戊巴比妥钠诱导LORR的潜伏期(P<0.01,P<0.05),同时显著延长LORR持续时间(P<0.01,P<0.05);常压常氧唑吡坦组和低压低氧致失眠模型+唑吡坦组致小鼠LORR的半数有效剂量(ED50)分别为16.21和20.55 mg·kg-1.神经递质水平检测结果表明,与常压常氧溶媒组相比,常压常氧唑吡坦40 mg·kg-1组显著降低丘脑和下丘脑Glu含量及下丘脑Glu/GABA比值(P<0.01,P<0.05);与常压常氧溶媒组相比,低压低氧致失眠模型组小鼠下丘脑Glu含量及Glu/GABA比值显著升高(P<0.01,P<0.05),低压低氧致失眠模型+唑吡坦40 mg·kg-1组显著逆转其升高(P<0.05).结论 在低压低氧条件下,唑吡坦的镇静催眠效应减弱,唑吡坦对下丘脑中Glu和GABA水平的调节可能在其镇静催眠效应中发挥重要作用.
OBJECTIVE To study the sedative and hypnotic effects of zolpidem and the content of amino acid neurotransmitters in the thalamus and hypothalamus after treatment with zolpidem.METHODS Experiments on the loss of righting reflex(LORR)induced by the upper-threshold dose pentobarbital sodium(50 mg·kg-1,ip)were conducted to establish a hypoxic insomnia model in mice by simulating an altitude of 5500 m.Based on this model,the synergistic effect of zolpidem(0.33,1,3,9 and 27 mg·kg-1,ip)and the subthreshold(20 mg·kg-1,ip)and upper-threshold pentobarbital sodium,as well as the sedative hypnotic effect of zolpidem(10,13,17,20,23,30 and 40 mg·kg-1,ip)were evaluated via the LORR in normoxic and hypoxic environments.One hour after ip given zolpidem,the levels of glutamic acid(Glu)and γ-aminobutyric acid(GABA)in the thalamus and hypothalamus of mice in either environment were determined by the high-performance liquid chromatography(HPLC)with fluorescence detection.RESULTS One-day treatment with hypoxia significantly shortened the duration of LORR induced by the upper-threshold dose pentobarbital sodium.Compared with normoxia vehicle and hypoxia induced insomnia vehicle groups,zolpidem 9 and 27 mg·kg-1 significantly shortened the latency to LORR(P<0.01,P<0.05)and prolonged duration of LORR induced by subthreshold and upper-threshold pentobarbital sodi-um(P<0.01,P<0.05).The median effective dose(ED50)of LORR induced by zolpidem was 16.21 and 20.55 mg·kg-1 in normoxic and hypoxic environments,respectively.The results of neurotransmitter level detection showed that Glu contents in the thalamus and hypothalamus and the ratio of Glu/GABA in the hypothalamus were decreased after treatment with zolpidem 40 mg·kg-1 in a normoxic environment(P<0.01,P<0.05).Compared with the normoxia control group,Glu content and the ratio of Glu/GABA in the hypothalamus were significantly increased after treatment with hypoxia(P<0.01,P<0.05),and zolpidem 40 mg·kg-1 could reverse their elevation.CONCLUSION The sedative-hypnotic effect of zolpidem is weakened in a hypoxic environment,and the effect of zolpidem on the levels of Glu and GABA in the hypothalamus may play an important role in the sedative-hypnotic effect of zolpidem.
梁欢欢;许琳;俞纲;苏瑞斌;李明媛
天津科技大学生物工程学院,天津市透明质酸应用研究企业重点实验室,天津 300457||军事科学院军事医学研究院毒物药物研究所,抗毒药物与毒理学国家重点实验室,北京 100850天津科技大学生物工程学院,天津市透明质酸应用研究企业重点实验室,天津 300457军事科学院军事医学研究院毒物药物研究所,抗毒药物与毒理学国家重点实验室,北京 100850
药学
低压低氧唑吡坦翻正反射谷氨酸γ-氨基丁酸
hypoxiazolpidemrighting reflexglutamic acidγ-aminobutyric acid
《中国药理学与毒理学杂志》 2024 (002)
81-88 / 8
天津市教委"十三五综投"项目(2018KJ124);天津市透明质酸应用研究企业重点实验室开放基金(KTRDHA-Y201906) Tianjin Education Commission"13th Five-Year Comprehensive Investment"project(2018KJ124);and Tianjin Laboratory of Hyaluronic Acid Applied Research Enterprise Open Fund(KTRDHA-Y201906)
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