酸枣仁汤对血虚小鼠的镇静催眠作用

目的:观察机体在血虚模型状况下,酸枣仁汤的镇静催眠作用。方法:①实验于2004-03/05在中国药科大学中医药教研室实验室完成。选用昆明种雄性小鼠246只。②观察酸枣仁汤(酸枣仁、甘草、知母、茯苓、川芎经煎煮制成酸枣仁汤颗粒。酸枣仁颗粒溶于蒸馏水,制成0.6,1.2,2.4g/mL溶液)对血虚小鼠戊巴比妥钠致睡眠时间的影响:取昆明种小鼠60只,随机分为5组:正常对照组、模型组(灌服生理盐水),酸枣仁汤低、中、高剂量组(灌服酸枣仁汤生药量6,12,24g/kg),每组12只。除正常对照组以外,其余各组造失血性贫血模型:小鼠眼眶放血0.5mL,24h后给药,连续给药5d,最后1d给药1h后,腹腔注射戊巴比妥钠35mg/kg。15min内翻正反射消失达30s以上为进入睡眠,翻正反射恢复为清醒,其间为睡眠时间,记录各组小鼠的睡眠潜伏期和睡眠期。③观察酸枣仁汤对血虚小鼠戊巴比妥钠阈下催眠剂量的影响:取昆明种小鼠66只,随机分成5组:正常对照组、模型组(n=12,21),酸枣仁汤低、中、高剂量组(n=11,12,10)。每组干预时间及干预措施同睡眠时间实验。分别腹腔注射戊巴比妥钠27mg/kg。腹腔注射后15min内翻正反射消失1min(睡眠)记为阳性(+),否则(清醒)记为阴性(-)。④观察酸枣仁汤对血虚小鼠自发活动的影响:每组小鼠只数、干预措施及干预时间同“睡眠时间”观察,进行旷野法实验:将小鼠放入直径30cm,高20cm的圆柱型笼中,笼底部分为19格,笼上方1m处放置60W白炽灯,描记小鼠在笼内2min的活动轨迹,轨迹与笼底格线相交记为1次。⑤观察酸枣仁汤对血虚小鼠血红蛋白的影响:每组小鼠只数、干预措施及干预时间同“睡眠时间”观察。用HiCN法测血红蛋白含量,给药第1天,第6天分别测血红蛋白含量,比较血红蛋白的变化值。⑥计数结果差异比较采用χ2Test孙氏直接概率法,组间计量结果比较采用t检验。结果:小鼠246只均进入结果分析。①酸枣仁汤低、高剂量组睡眠潜伏期明显短于模型组(P<0.01,0.05),睡眠期明显长于模型组(P<0.05)。②酸枣仁汤高、低剂量组睡眠小鼠只数明显多于模型组(P<0.05),清醒小鼠只数明显少于模型组(P<0.05)。③模型组小鼠自发活动次数明显少于对照组(P<0.01),酸枣仁汤中剂量组小鼠自发活动次数明显多于模型组(P<0.05)。④治疗前模型组小鼠血红蛋白含量明显低于对照组,治疗后酸枣仁汤中、高剂量组小鼠血红蛋白含量变化值明显高于模型组(P<0.05)。结论:①酸枣仁汤对机体在血虚小鼠具有镇静催眠作用。②酸枣仁汤能提高血虚小鼠血红蛋白含量,改善血虚症状,该作用具有剂量依赖性。     

酸枣仁汤对血虚小鼠的镇静催眠作用

目的：观察机体在血虚模型状况下，酸枣仁汤的镇静催眠作用。 方法：①实验于2004—03／05在中国药科大学中医药教研室实验室完成。选用昆明种雄性小鼠246只。（④观察酸枣仁汤（酸枣仁、甘草、知母、茯苓、川芎经煎煮制成酸枣仁汤颗粒。酸枣仁颗粒溶于蒸馏水，制成0．6，1．2，2．4g／mL溶液）对血虚小鼠戊巴比妥钠致睡眠时间的影响：取昆明种小鼠60只，随机分为5组：正常对照组、模型组（灌服生理盐水），酸枣仁汤低、中、高剂量组（灌服酸枣仁汤生药量6，12，24g／kg），每组12只。除正常对照组以外，其余各组造失血性贫血模型刊、鼠眼眶放血0．5mL，24h后给药，连续给药5d，最后1d给药1h后，腹腔注射戊巴比妥钠35mg／kg。15min内翻正反射消失达30s以上为进入睡眠，翻正反射恢复为清醒，其间为睡眠时间，记录各组小鼠的睡眠潜伏期和睡眠期。③观察酸枣仁汤对血虚小鼠戊巴比妥钠阈下催眠剂量的影响：取昆明种小鼠66只，随机分成5组：正常对照组、模型组（n=12，21），酸枣仁汤低、中、高剂量组（n=11，12，10）。每组干预时间及干预措施同睡眠时间实验。分别腹腔注射戊巴比妥钠27mg／kg。腹腔注射后15min内翻正反射消失1min（睡眠）记为阳性（＋），否则（清醒）记为阴性（-）。④观察酸枣仁汤对血虚小鼠自发活动的影响：每组小鼠只数、干预措施及干预时间同“睡眠时间”观察，进行旷野法实验：将小鼠放人直径30cm，高20cm的圆柱型笼中，笼底部分为19格，笼上方1m处放置60W白炽灯，描记小鼠在笼内2min的活动轨迹，轨迹与笼底格线相交记为1次。⑤观察酸枣仁汤对血虚小鼠血红蛋白的影响：每组小鼠只数、干预措施及干预时间同“睡眠时间”观察。用HiCN法测血红蛋白含量，给药第1天，第6天分别测血红蛋白含量，比较血红蛋白的变化值。⑥计数结果差异比较采用χ^2Test孙氏直接概率法，组间计量结果比较采用t检验。 结果：小鼠246只均进入结果分析。①酸枣仁汤低、高剂量组睡眠潜伏期明显短于模型组（P〈0.01，0．05），睡眠期明显长于模型组（P〈0．05）。②酸枣仁汤高、低剂量组睡眠小鼠只数明显多于模型组（P〈0．05），清醒小鼠只数明显少于模型组（P〈0．05）。③模型组小鼠自发活动次数明显少于对照组（P〈0．01），酸枣仁汤中剂量组小鼠自发活动次数明显多于模型组（P〈0．05）。④治疗前模型组小鼠血红蛋白含量明显低于对照组，治疗后酸枣仁汤中、高剂量组小鼠血红蛋白含量变化值明显高于模型组（P〈0．05）。 结论：①酸枣仁汤对机体在血虚小鼠具有镇静催眠作用。②酸枣仁汤能提高血虚小鼠血红蛋白含量，改善血虚症状，该作用具有剂量依赖性。     

薰衣草精油对小鼠镇静催眠作用的实验研究

目的验证薰衣草精油芳香疗法的镇静、催眠作用。方法将20只小鼠分为对照组和薰衣草组,熏衣草组分别给予10-3、10-4浓度的薰衣草精油香薰,计数运动时间和运动次数、移动格子数及站立次数。另将30只小鼠分为对照组、薰衣草10-3组和薰衣草10-4组,给予阈剂量戊巴比妥钠诱导睡眠,记录睡眠潜伏期和睡眠时间。结果薰衣草精油香薰后小鼠的运动时间和运动次数少于对照组(P<0.05),移动格子数和站立次数少于对照组(P<0.05);与对照组相比,香薰各组的睡眠潜伏期均缩短(P<0.05),睡眠时间均延长(P<0.01);不同浓度精油香薰的两组相比,睡眠潜伏期没有明显差异(P>0.05),而薰衣草10-3组睡眠时间长于薰衣草10-4(P<0.01)。结论薰衣草精油香薰疗法有镇静催眠作用。     

眠安方对小鼠镇静催眠作用的实验研究

目的观察眠安方灌胃给药后对小鼠的镇静催眠作用。方法采用阈上和阈下剂量戊巴比妥钠致小鼠睡眠的方法,观察眠安方不同剂量对小鼠自主活动及睡眠时间等影响。结果眠安方能明显减少小鼠自主活动次数,增加阈下剂量戊巴比妥钠致小鼠睡眠只数,改善阈上剂量戊巴比妥钠致小鼠睡眠时间。结论眠安方有明显的镇静催眠作用。     

益眠达片治疗失眠的药效学研究

目的观察益眠达片对小鼠的镇静催眠作用,观察小鼠对催眠及阈下催眠剂量戊巴比妥钠作用的影响,及益眠达片对小鼠自主活动的影响。方法实验小鼠随机分为:益眠达片高剂量组、中剂量组、低剂量组,安神补脑液组,艾司唑仑片组,空白对照组,按照实验要求给药,观察记录入睡潜伏期和睡眠持续时间,观察记录30min内翻正反射消失达1min以上的小鼠数以及末次给药30min后,2min内小鼠自发活动次数。结果益眠达片缩短戊巴比妥钠致小鼠入睡的潜伏时间,延长睡眠持续时间,增加阈下催眠剂量戊巴比妥钠小鼠入睡率;益眠达片可抑制小白鼠自发活动次数。结论益眠达片具有镇静催眠作用。     

绞股蓝改善睡眠有效成分的研究

目的：探究绞股蓝改善睡眠的有效成分。方法：通过直接睡眠试验、延长戊巴比妥钠睡眠时间试验、戊巴比妥钠阈下剂量催眠试验、巴比妥钠睡眠潜伏期试验,评价绞股蓝水提物、绞股蓝皂苷、绞股蓝多糖对小鼠睡眠作用的影响。结果表明,绞股蓝水提物、绞股蓝皂苷、绞股蓝多糖各剂量组对正常小鼠均无直接睡眠作用,绞股蓝皂苷各剂量组均可以延长戊巴比妥钠诱导的小鼠睡眠时间(P<0.05或P<0.001),增加戊巴比妥钠阈下催眠剂量入睡小鼠只数(P<0.05或P<0.01),缩短小鼠的睡眠潜伏期(P<0.05或P<0.001)。绞股蓝皂苷、绞股蓝水提物高剂量组在延长戊巴比妥钠睡眠时间、增加小鼠戊巴比妥钠阈下剂量催眠只数、缩短巴比妥钠睡眠潜伏期方面效果优于绞股蓝多糖组(P<0.05)。此外,绞股蓝皂苷高剂量组小鼠下丘脑及血清中的5-羟色胺(5-HT)及γ-氨基丁酸(GABA)含量均显著高于对照组(P<0.001),多巴胺(DA)含量均显著低于对照组(P<0.01)。结论：绞股蓝水提物、绞股蓝皂苷、绞股蓝多糖均可在一定程度上改善小鼠睡眠,绞股蓝皂苷是改善睡眠的主要功效成分...     

夜交藤提取物对小鼠中枢神经系统作用的实验研究

目的观察夜交藤提取物对小鼠中枢神经系统的作用。方法清洁级小鼠80只,随机分为4组。其中每组各设夜交藤组(灌服夜交藤提取物)和对照组(灌服等体积生理盐水),每组10只。4组分别观察夜交藤提取物对小鼠自主活动的影响、对延长异戊巴比妥钠诱导的小鼠睡眠时间、对异戊巴比妥钠致小鼠睡眠率的影响以及对士的宁中枢兴奋作用的影响。结果夜交藤提取物对小鼠自主活动呈明显抑制作用,可延长异戊巴比妥钠诱导的小鼠睡眠时间,对阈下催眠剂量的异戊巴比妥钠有协同作用,能显著降低士的宁引起的惊厥率。结论夜交藤提取物对小鼠有明显的镇静、催眠作用。     

西洋参改善睡眠有效成分的研究

目的：探究西洋参改善睡眠的有效成分。方法：通过直接睡眠试验、延长戊巴比妥钠睡眠时间试验、戊巴比妥钠阈下剂量催眠试验、巴比妥钠睡眠潜伏期试验,评价西洋参水提物、西洋参皂苷、西洋参多糖对小鼠睡眠作用的影响。结果：西洋参水提物、西洋参皂苷、西洋参多糖各剂量组对正常小鼠均无直接睡眠作用。西洋参皂苷各剂量组均可以延长戊巴比妥钠诱导的小鼠睡眠时间,差异有统计学意义(P<0.05或P<0.01),增加戊巴比妥钠阈下催眠剂量入睡小鼠只数,差异有统计学意义(P<0.05或P<0.01),缩短小鼠的睡眠潜伏期,差异有统计学意义(P<0.05或P<0.001)。西洋参皂苷、西洋参水提物高剂量组在延长戊巴比妥钠睡眠时间、缩短巴比妥钠睡眠潜伏期方面效果优于西洋参多糖组,差异有统计学意义(P<0.05)。此外,西洋参皂苷高剂量组小鼠下丘脑及血清中的5-羟色胺(5-HT)及γ-氨基丁酸(GABA)含量均显著高于对照组,差异有统计学意义(P<0.01或P<0.001),多巴胺(DA)含量均显著低于对照组,差异有统计学意义(P<0.01)。结论：西洋参水提物、...     

久强脑立清对昆明种小鼠行为的影响

目的评价久强脑立清 (JNQ)对昆明种小鼠行为的作用。方法采用自发运动、Morris水迷宫、转杆实验、对咖啡因引起的兴奋作用、戊巴比妥钠睡眠时间、戊巴比妥钠阈下催眠剂量实验以及对戊四唑引起的惊厥作用等方法对小鼠的行为进行评价。结果和对照组相比 ,JNQ低剂量组可增加小鼠自发运动 ,中、高剂量组可以延长小鼠在转杆上的运动时间 ;脑立清各剂量组可以延长戊巴比妥钠睡眠时间 ,增加戊巴比妥钠阈下催眠剂量时的睡眠百分数 ,并拮抗咖啡因的兴奋作用。结论JNQ对昆明种小鼠具有镇静、安眠作用 ,并能增强其在运动中的平衡协调能力     

植物油提取新工艺得到的五味子提取物对小鼠睡眠影响的实验研究

目的观察植物油提取新工艺得到的五味子提取物的改善睡眠作用。方法采用植物油提取新工艺得到五味子提取物,昆明种雄性小鼠随机分为对照组及五味子提取物低、中、高剂量组,对照组给予橄榄油20 ml/kg/d灌胃,五味子提取物低、中、高剂量组分别给予五味子提取物150、3006、00 mg/kg/d,连续灌胃15 d,通过直接睡眠实验、延长戊巴比妥钠睡眠时间实验、戊巴比妥钠阈下剂量催眠实验和巴比妥钠睡眠潜伏期实验,观察对小鼠直接睡眠、阈剂量戊巴比妥钠睡眠时间、戊巴比妥钠阈下剂量睡眠发生率及巴比妥钠诱导睡眠潜伏期的影响。结果采用植物油提取新工艺得到的五味子提取物可明显延长戊巴比妥钠诱导的小鼠睡眠时间,提高戊巴比妥钠诱导的小鼠睡眠发生率,缩短巴比妥钠诱导的小鼠睡眠潜伏期,对小鼠入睡动物数及睡眠时间均无明显影响。结论采用植物油提取新工艺得到的五味子提取物具有明显改善睡眠作用,有开发利用价值。     

Evaluation of the anxiolytic effect of Nepeta persica Boiss. in mice

The aim of the present study was to evaluate the anxiolytic effects of hydroalcoholic extract (HE) of Nepeta persica Boiss. (Lamiaceae) on the elevated plus-maze (EPM) model of anxiety. The extract of arial parts of the plant was administered intraperitoneally to male NMRI mice, at various doses, 30 min before behavioural evaluation. The HE extract of N. persica at the dose of 50 mg kg(-1) significantly increased the percentage of time spent and percentage of arm entries in the open arms of the EPM. This dose of plant extract affected neither animal's locomotor activity nor ketamine-induced sleeping time. The 50 mg kg(-1) dose of the plant extract seemed to be the optimal dose in producing the anxiolytic effects, lower or higher doses of the plant produce either sedative or stimulant effects. At 100 mg kg(-1), the plant extract increased the locomotor activity. These results suggested that the extract of N. persica at dose of 50 mg kg(-1) possess anxiolytic effect with less sedative and hypnotic effects than that of diazepam and causes a non-specific stimulation at 100 mg kg(-1).     

The effects of linalool acupoint application therapy on sleep regulation

The Shenque acupoint is located in the umbilicus of the human body. In the human body meridians, the Shenque acupoint can regulate body functions. The Shenque acupoint was one of the important acupuncture acupoints for the treatment of insomnia. However, the effect of linalool applied at the Shenque acupoint to improve sleep was unknown. This study explored the hypnotic and sedative effects of the main component of lavender, linalool, on the Shenque acupoint of mice and rats. The effects on the sleep latency and sleep duration were studied with the supra-threshold dose of pentobarbital sodium, and the effects on the sleep rate were studied with the sub-threshold dose of pentobarbital sodium. In order to further study the feasibility and superiority of linalool administered at the Shenque acupoint, a pharmacokinetic study was carried out. The pharmacodynamic results showed that the mice and rats treated with linalool at Shenque had the highest sleep rate, the shortest sleep latency, and the longest sleep duration compared with other groups. The T_max and t_1/2 of the LS were longer than those of the LO, and had the characteristics of sustained release. The relative bioavailability of LS was 323.0 ± 31.66%. This showed that the combination of linalool and the Shenque acupoint had greater medicinal effects. This development will provide a new direction for improving sleep.

This study explored the hypnotic and sedative effects of the main component of lavender, linalool, when applied to the Shenque acupoint of mice and rats.     

Study on the hypnotic effect of rare protopanaxadiol-type and protopanaxatriol-type ginsenosides

Ginsenosides, as major active components of ginseng, possess various pharmacological activities, including anti-tumor, anti-diabetic and hypotensive effects. However, the sedative and hypnotic effect of ginsenosides and the involved mechanism remain unclear. In the present study, the hypnotic effect of rare protopanaxadiol-type (PD) ginsenosides, consisting of Rg3, Rk1, Rg5, and protopanaxatriol-type (PT) ginsenosides, consisting of Rh1, Rk3, Rh4, was investigated and compared in rodent models through behavioral pharmacology methods. Both rare PD and PT ginsenosides decreased spontaneous locomotion activity in normal mice and reduced sleep latency, and extended sleep duration in pentobarbital-treated mice. Moreover, PD and PT ginsenosides attenuated the insomnia induced by caffeine in mice. These hypnotic effects of PD and PT ginsenosides were potentiated by 5-hydroxytryptophan (5-HTP), a precursor of serotonin, and inhibited by p-chlorophenylalanine (PCPA), a 5-HT synthesis inhibitor. Flumazenil (FLU, a specific gamma aminobutyric acid (GABA) antagonist) also impaired the hypnotic effect of both PD and PT ginsenosides. The aforementioned results indicated that PD and PT ginsenosides exhibit sedative and hypnotic activity, and PT ginsenosides show higher activity than PD ginsenosides at high doses (96 mg kg⁻¹). Furthermore, the bioactivity of these two types of ginsenosides might be mediated via the serotonergic and GABAergic systems.

Ginsenosides, as major active components of ginseng, possess various pharmacological activities, including anti-tumor, anti-diabetic and hypotensive effects.     

Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of alcohol and other drugs

Enhancement of the activation of GABAA receptors is a common feature of many sedative and hypnotic drugs, and it is probable that the GABAA receptor complex is a molecular target for these drugs in the mammalian central nervous system. We set out to elucidate the role of the two predominant (alpha1 and beta2) subunits of GABAA receptor in sedative drug action by studying mice lacking these two subunits. Both alpha1 (-/-) and beta2 (-/-) null mutant mice showed markedly decreased sleep time induced by nonselective benzodiazepine, flurazepam, and GABAA agonist, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol. The sleep time induced by the beta-selective drug etomidate was decreased only in beta2 (-/-) knockout mice. In contrast, alpha1 (-/-) mice were more resistant to the alpha1-selective drug zolpidem than beta2 (-/-) or wild-type animals. Knockout mice of both strains were similar to wild-type mice in their responses to pentobarbital. The duration of loss of the righting reflex produced by ethanol was decreased in male mice for both null alleles compared with wild-type mice, but there were no differences in ethanol-induced sleep time in mutant females. Deletion of either the alpha1 or beta2 subunits reduced the muscimol-stimulated 36Cl36 influx in cortical microsacs suggesting that these mutant mice have reduced number of functional brain GABAA receptors. Our results show that removal of either alpha1 or beta2 subunits of GABAA receptors produce strong and selective decreases in hypnotic effects of different drugs. Overall, these data confirm the crucial role of the GABAA receptor in mechanisms mediating sedative/hypnotic effects.     

4-Hydroxybenzyl alcohol derivatives and their sedative–hypnotic activities

4-Hydroxybenzyl alcohol (HBA), one of the characteristic active components of Gastrodia elata, exhibits obvious effects on the human central nervous system. In order to acquire compounds with superior bioactivity, 10 derivatives of HBA were synthesized from HBA and carboxylic acids. The sedative effects of the 10 HBA derivatives were evaluated using a spontaneous locomotor activity test (SLT) in mice, and their hypnotic effects were determined to be synergistic with pentobarbital-induced sleep. The results showed that 4-hydroxybenzyl alcohol 3-furancarboxylic acid diester (2FHBA, 10 mg kg⁻¹) exhibited the strongest sedative–hypnotic activity among HBA and its derivatives, and 2FHBA could reverse the insomnia caused by p-chlorophenylalanine (pCPA), flumazenil (FLU) and thiosemicarbazide (TSC). Meanwhile, 2FHBA and 5-hydroxytryptophan (5-HTP) showed a synergistic effect. The results suggested that 2FHBA might be a potential agent against insomnia, which might be mediated by the serotonergic and GABAergic systems.

2FHBA, a derivative of HBA, exerts sedative and hypnotic effects through the serotonergic and GABAergic systems.     

In vivo pharmacological characterization of indiplon, a novel pyrazolopyrimidine sedative-hypnotic

Indiplon (NBI 34060; N-methyl-N-[3-[3-(2-thienylcarbonyl)-pyrazolo[1,5-alpha]pyrimidin-7-yl]phenyl]acetamide), a novel pyrazolopyrimidine and high-affinity allosteric potentiator of GABA(A) receptor function, was profiled for its effects in rodents after oral administration. In mice, indiplon inhibited locomotor activity (ED(50) = 2.7 mg/kg p.o.) at doses lower than the nonbenzodiazepine hypnotics zolpidem (ED(50) = 6.1 mg/kg p.o.) and zaleplon (ED(50) = 24.6 mg/kg p.o.), a sedative effect that was reversed by the benzodiazepine site antagonist flumazenil. Indiplon inhibited retention in the mouse passive avoidance paradigm over a dose range and with a temporal profile that coincided with its sedative activity. Indiplon, zolpidem, and zaleplon were equally effective in inhibiting locomotor activity in the rat and produced dose-related deficits on the rotarod. In a rat vigilance paradigm, indiplon, zolpidem, and zaleplon produced performance deficits over a dose range consistent with their sedative effects, although indiplon alone showed no significant increase in response latency. Indiplon produced a small deficit in the delayed nonmatch to sample paradigm at a dose where sedative effects became apparent. Indiplon was active in the rat Vogel test of anxiety, but it showed only a sedative profile in the mouse open field test. The pharmacokinetic profile of indiplon in both rat and mouse was consistent with its pharmacodynamic properties and indicated a rapid T(max), short t(1/2), and excellent blood-brain barrier penetration. Therefore, indiplon has the in vivo profile of an efficacious sedative-hypnotic, in agreement with its in vitro receptor pharmacology as a high-affinity allosteric potentiator of GABA(A) receptor function, with selectivity for alpha1 subunit-containing GABA(A) receptors.     

Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem.

Zolpidem is a new, short-acting hypnotic of imidazopyridine structure which binds selectively to a subpopulation of receptors involved in the action of benzodiazepines [omega 1 (BZ1) sites of the gamma-aminobutyric acidA receptors]. The present study investigated whether tolerance and physical dependence develop after repeated treatment with zolpidem as is observed with benzodiazepines. Mice were given zolpidem or the benzodiazepine midazolam (2 x 30 mg/kg, p.o.) for 10 consecutive days. Tolerance to central depressant effects (evaluated by recording spontaneous locomotor activity) and to anticonvulsant effects (measured against pentylenetetrazole-, electroshock- and isoniazid-induced convulsions) was assessed 42 hr after the last administration. A decrease in the latency to isoniazid-induced convulsions was taken as an index of physical dependence and was evaluated 3, 6, 14, 24, 42 and 67 hr after the end of chronic drug treatment. Repeated treatment with midazolam produced tolerance to its sedative and anticonvulsant activities as indicated by shifts of the dose-response curves by a factor of 3 to 5. Fourteen hr after discontinuation of treatment, spontaneous withdrawal was observed and lasted 3 days. When flumazenil was given 3 or 6 hr after the final midazolam injection, precipitated withdrawal was observed. In contrast, after repeated treatment with zolpidem, there was no change in its ability to produce sedative and anticonvulsant effects. Moreover, neither spontaneous nor flumazenil-induced precipitated withdrawal was observed in zolpidem-treated mice.     

Syringin may exert sleep‐potentiating effects through the NOS/NO pathway

Sleep is essential for basic survival as well as for optimal physical and cognitive performance in both human beings and animals. To investigate the effect of syringin on sleep of anesthetized mice and the potential mechanisms, 35 male Kunming mice were randomly divided into six experimental groups (n = 5) and one control group (n = 5). Sleep latency and sleep duration, as well as nitric oxide (NO) content and nitric oxide synthase (NOS) activity, were determined after syringin administration. The NO precursor l ‐Arginine (l ‐Arg) or NOS inhibitor NG‐Nitro‐l ‐arginine methyl ester (l ‐NAME) was administered alone or in combination with syringin, and time for sleep latency and duration was recorded. After intragastric administration of syringin, sleep latency decreased in a dose‐ and time‐dependent manner, concomitant with increased sleep duration. The optimal sleep performance was obtained when syringin was given at a dose of 80 mg/kg for eight consecutive days. Syringin significantly reduced NO concentration and NOS activity. Administration of l ‐Arg prolonged sleep latency and shortened sleep duration, and the effects were fully reversed by syringin coadministration. Administration of L‐NAME induced a significant reduction in sleep latency and a corresponding increase in sleep duration, and coadministration of syringin further enhanced the effects. The finding of our study demonstrated that syringin could exert sleep‐potentiating effects on anesthetized mice in a time‐ and dose‐dependent manner, and these effects may be intimately correlated with the NO/NOS pathway.     

The potentiation of barbiturate-induced narcosis by procarbazine.

Procarbazine (MIH), N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide (NSC-77213), a clinically effective antineoplastic agent, induced sleep in mice at its optimally effective dose (400 mg/kg) and prolongs hexobarbital sleeping times. MIH (400 mg/kg) increased the period of sleep following hexobarbital (100 mg/kg) nearly 10-fold. Nonhypnotic doses of MIH also significantly prolonged hexobarbital-induced sleep. Hexobarbital half-life in plasma was prolonged 6 to 7 times by prior treatment with MIH (400 mg/kg). Liver microsomes from mice treated with MIH exhibited decreased metabolism of the following substrates in vitro: hexobarbital, aminopyrine, ethylmorphine, and aniline. Cytochrome P-450 levels were also decreased by MIH treatment. Maximal decreases in enzyme activity and P-450 content occurred between 4 and 8 hours following treatment. Pretreatment with phenobarbital decreased the effectiveness of MIH to prolong hexobarbital sleeping times while pretreatment with SKF 525A added to the potentiating effect of MIH. Two major metabolites of MIH had neither central nervous system hypnotic effect nor inhibited hepatic microsomal mixed-function oxidases. Therefore, MIH potentiation of hexobarbital-induces sleep is probably due both to its direct hypnotic effect and inhibition of mixed-function oxidase activity.