Model Establishment And Theraputic Drug Evaluation Of Sleep Disorder At Altitude

So far,drug therapy is still the main means of preventing and treating sleep disorders at altitude,but the medication of same drug to treat sleep disorder at altitude still follows its pharmacodynamics research at sea level,lacking experimental date to support its application at hypoxia environment,and the therapeutic effect of drugs is far from ideal,so it is urgent to develop new therapeutic drugs or drug combinations.This study systematically evaluated the therapeutic effects of oxygen deprivation improvement drugs,sedative-hypnotic drugs,antihistamines and antidepressants on sleep disorders mouse model at altitude,providing experimental date for the selection and evaluation of drugs for the prevention and treatment of sleep disorder at altitude.Firstly,established the mice hypoxia insomnia model by raising the altitude to 5500 m,and the sleep status of mice was evaluated by the loss of righting reflex（LORR）experiment induced by upper-threshold pentobarbital sodium.It was found that expose at hypoxia environment for 1 or 2 days,the duration of LORR of mice were significantly shorter than that normoxia control group.The changes of glutamic acid（Glu）andγ-aminobutyric acid（GABA）neurotransmitters in the thalamus and hypothalamus brain regions of mice with sleep disorder at altitude were determined by high-performance liquid chromatography（HPLC）,and the results showed that Glu content in hypothalamus increased significantly after expose 1 day at hypoxia environment,and Glu/GABA ratio in both thalamus and hypothalamus had an ascend trend.In addition,the phosphorylation level of Ca²⁺/Calmodulin-dependent protein kinase IIβ（CaMKⅡβ）in the left cerebral cortex of mice also had an increased trend after 1-day hypoxia treatment.Based on the above results,determined to adopt 1-day exposing at hypoxia in the experiment.Secondly,based on this model,prevention of 25,50,100 mg/kg acetazolamide had prolonged duration of LORR by synergy upper-threshold pentobarbital sodium.Then,the LORR in combination with subthreshold or upper-threshold pentobarbital sodium were used to compare the sedative-hypnotic effect of antihistamines,antidepressants and sedative-hypnotic drugs at the normoxia and hypoxia environment,the results showed that the sedative-hypnotic effect were weakened at hypoxia environment among the drugs,and sedative-hypnotic effect of the trazodone was stronger than that of diphenhydramine,mirtazapine,amitriptyline,doxepin.In addition,trazodone,diazepam and zolpidem increased the percentage of LORR induced by subthreshold pentobarbital sodium,and prolonged the duration of LORR induced by upper-threshold pentobarbital sodium in a dose-dependent manner,but the sedative hypnotic effect of trazodone was weaken than that of diazepam and zolpidem.Besides,HPLC results showed that zolpidem dose-dependently decreased Glu content in thalamus and hypothalamus under normoxia environment,and 40 mg/kg zolpidem significantly decreased Glu/GABA ratio in hypothalamus of mice.Compared with normoxia control group,mice treated with hypoxia significantly increased the Glu content and Glu/GABA ratio in hypothalamus and zolpidem dose-dependently decreased their elevation.At the same time,after zolpidem administration,CaMKⅡα/βand its phosphorylation increased in a dose-dependent manner,while extracellular signal-regulated kinase（ERK 1/2）phosphorylation decreased significantly.Finally,we found that after treatment with acetazolamide and zolpidem in hypoxia condition,the percentage of LORR in mice was increased than that treated with zolpidem alone.In conclusion,this study successfully built a simple and fast altitude sleep disorder model,and the results of pharmacodynamic evaluation showed that acetazolamide,diazepam and zolpidem had certain prevention and treatment effects on sleep disorders at high altitude,the combination of acetazolamide and zolpidem may further improve the efficacy of sedative hypnotics.