Effects of short-acting hypnotics on sleep latency in rats placed on grid suspended over water

The present study was performed to develop a new sleep disturbance model for evaluating hypnotic potencies by placing rats on a grid suspended over water up to 1 cm under the grid surface. When rats were placed on the grid, significant increases in sleep latency and amount of wakefulness were observed compared with those of rats placed on sawdust. However, the amounts of non-rapid eye movement (non-REM) sleep and rapid eye movement (REM) sleep of rats placed on the grid were significantly decreased compared with those of rats placed on sawdust. Four short-acting hypnotics (triazolam, zopiclone, brotizolam, lormetazepam) caused significant decreases in sleep latency, and the effects of hypnotics in rats placed on the grid were more potent than those in rats placed on sawdust. In conclusion, the present model can serve as a new sleep disturbance model and may also be useful for evaluating the sleep-inducing effects of short-acting hypnotics.     

Effects of three hypnotics on the sleep-wakefulness cycle in sleep-disturbed rats

Rationale New sleep disturbance model in rats is useful for estimating the characteristics of some hypnotics.Objectives The present study was undertaken to investigate the utility of a sleep disturbance model by placing rats on a grid suspended over water using three kinds of hypnotics, that is, short-acting benzodiazepine (triazolam), intermediate-acting benzodiazepine (flunitrazepam) and long-acting barbiturate (phenobarbital).Methods Electrodes for measurement of EEG and EMG were implanted into the frontal cortex and the dorsal neck muscle of rats. EEG and EMG were recorded with an electroencephalogram. SleepSign ver.2.0 was used for EEG and EMG analysis. Total times of wakefulness, non-REM and REM sleep were measured from 0900 to 1500 hours.Results In rats placed on the grid suspended over water up to 1 cm under the grid surface, not only triazolam but also flunitrazepam and phenobarbital caused a shortening of sleep latency. Both flunitrazepam and phenobarbital were effective in increasing of total non-REM sleep time in rats placed on sawdust or the grid, and the effects of both drugs in rats placed on the grid were larger than those in rats placed on sawdust. Measurement of the hourly non-REM sleep time was useful for investigating the peak time and duration of effect of the three hypnotics. Phenobarbital showed a decrease in total REM sleep time in rats placed on the grid, although both triazolam and flunitrazepam were without effect.Conclusions The present insomnia model can be used as a sleep disturbance model for testing not only the sleep-inducing effects but also the sleep-maintaining effects including non-REM sleep and REM sleep of hypnotics.     

Characteristic Effects of Anti-dementia Drugs on Rat Sleep Patterns

The present study was undertaken to clarify the effects of anti-dementia drugs on sleep pattern in rats. Electrodes were chronically implanted into the frontal cortex and the dorsal neck muscle of rats for the electroencephalogram (EEG) and electromyogram (EMG), respectively. EEG and EMG were recorded with an electroencephalograph. SleepSigh ver. 2.0 was used for analysis of the sleep–wake state. Total times of waking, non-rapid eye movement (non-REM) sleep, and rapid eye movement (REM) sleep were measured from 10:30 to 16:30. Galantamine had no significant influence on the sleep pattern. On the other hand, donepezil and memantine showed significant increases in sleep latency and total waking time and a decrease in total non-REM sleep time. Furthermore, memantine decreased total REM sleep time. To investigate the characteristics of non-REM sleep in detail, non-REM sleep was classified as stage 1, 2, or 3 according to the depth of sleep. Different from donepezil and galantamine, memantine significantly decreased stage 1 and increased stage 3 in non-REM sleep. From these findings, it can be concluded that galantamine caused no sleep disturbance, different from donepezil and memantine.     

Effects of some H1-antagonists on the sleep-wake cycle in sleep-disturbed rats

The present study was undertaken to investigate the effects of some H(1)-antagonists on the sleep-wake cycle in sleep-disturbed rats in comparison with those of nitrazepam. Electrodes were chronically implanted into the frontal cortex and the dorsal neck muscle of rats for the electroencephalogram (EEG) and electromyogram (EMG), respectively. EEG and EMG were recorded with an electroencephalograph. SleepSign ver. 2.0 was used for EEG and EMG analysis. The total times of waking, non-rapid eye movement (non-REM), and rapid eye movement (REM) sleep were measured from 10:00 to 16:00. Nitrazepam showed a significant decrease in sleep latency, total waking time, and delta activity and an increase in the total non-REM sleep time. A significant decrease in the sleep latency was observed with diphenhydramine, chlorpheniramine, and cyproheptadine. Cyproheptadine also caused a significant decrease in the total waking time and increases in total non-REM sleep time, REM sleep time, slow wave sleep, and delta activity, although no remarkable effects were observed with diphenhydramine and chlorpheniramine. In conclusion, cyproheptadine can be useful as a hypnotic, having not only sleep inducing-effects, but also sleep quantity- and quality-increasing effects.     

Effects of kava-kava extract on the sleep–wake cycle in sleep-disturbed rats

Rationale Kava-kava extract may be useful as an herbal medicine for treatment of insomnia and anxiety.Objectives The present study was undertaken to investigate the effects of kava-kava extract on the sleep–wake cycle in comparison with that of flunitrazepam using sleep-disturbed rats.Methods Electrodes for measurement of electroencephalogram (EEG) and electromyogram (EMG) were implanted into the frontal cortex and the dorsal neck muscle of rats. EEG and EMG were recorded with an electroencephalogram. SleepSign ver.2.0 was used for EEG and EMG analysis. Total times of wakefulness, non-rapid eye movement (non-REM) and REM sleep were measured from 09:00 to 15:00.Results A significant shortening of the sleep latency in sleep-disturbed rats was observed following the administration of kava-kava extract at a dose of 300 mg/kg, while no effects were observed on the total waking and non-REM sleep time. On the other hand, flunitrazepam showed a significant shortening in sleep latency, decrease in total waking time and increase in total non-REM sleep time. Although the effects of flunitrazepam were antagonized by the benzodiazepine receptor antagonist flumazenil, the effect of kava-kava extract was not antagonized by flumazenil. Kava-kava extract showed a significant increase in delta activity during non-REM sleep in sleep-disturbed rats, whereas a significant decrease in delta power during non-REM sleep was observed with flunitrazepam. Flumazenil caused no significant effect on the changes in delta activity induced by both kava-kava extract and flunitrazepam.Conclusions Kava-kava extract is an herbal medicine having not only hypnotic effects, but also sleep quality-enhancement effects.     

Studies on somnolence in the daytime caused by drugs used for neuropathic pain

In the present study, the characteristics of the sleep features of amitriptyline, mexiletine, and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyradine-1(2H)-carbox-amide (BCTC) were studied. Electrodes were chronically implanted into the frontal cortex and the dorsal neck muscles of rats for electroencephalogram (EEG) and electromyogram (EMG) measurements, respectively. EEG and EMG were recorded with an electroencephalograph, and SleepSign ver. 2.0. was used for sleep-wake state analysis. Recordings were performed from 11:00 to 17:00. Amitriptyline caused significant decreases in sleep latency and total wake time and an increase in total non-rapid eye movement (non-REM) sleep time. Mexiletine caused a significant decrease in sleep latency, but no significant effect was observed in total wake time and total non-REM sleep time. On the other hand, BCTC, which is an antagonist of transient receptor potential vaniloid 1 (TRPV1), showed no significant effect on sleep latency, total wake time, total non-REM sleep time, and total REM sleep time. From these results, it can be concluded that a TRPV1 antagonist may become a useful drug for neuropathic pain without sedative side effects in the daytime, different from amitriptyline and mexiletine.     

Hypnotic activities of chamomile and passiflora extracts in sleep-disturbed rats

In the present study, we investigated hypnotic activities of chamomile and passiflora extracts using sleep-disturbed model rats. A significant decrease in sleep latency was observed with chamomile extract at a dose of 300 mg/kg, while passiflora extract showed no effects on sleep latency even at a dose of 3000 mg/kg. No significant effects were observed with both herbal extracts on total times of wakefulness, non-rapid eye movement (non-REM) sleep and REM sleep. Flumazenil, a benzodiazepine receptor antagonist, at a dose of 3 mg/kg showed a significant antagonistic effect on the shortening in sleep latency induced by chamomile extract. No significant effects were observed with chamomile and passiflora extracts on delta activity during non-REM sleep. In conclusion, chamomile extract is a herb having benzodiazepine-like hypnotic activity.     

The D1 dopamine receptor antagonist SCH 23390 enhances REM sleep in the rat

The effect of the D1 dopamine receptor antagonist SCH 23390 on sleep patterns was studied in rats by means of the electroencephalographic (EEG) technique. Haloperidol, an established D2 antagonist neuroleptic, was used for comparison. Over a very small dose range (0.003-0.03 mg/kg, subcutaneously), SCH 23390 significantly increased the time spent in total sleep, including rapid eye movement (REM) and non-REM sleep. The magnitude of the overall change of REM sleep was considerably greater than that of non-REM sleep. Enhancement of the amount of REM was characterized by increase in number of episodes but no change of latency to the first period of REM. Haloperidol increased non-REM sleep at 0.3-3 mg/kg, orally, but did not affect other measures of REM. Considering the small dose range at which SCH 23390 was effective, and the fact that REM and non-REM sleep may be unrelated events, it is suggested that promotion of REM sleep is a specific effect induced by selective blockade of D1 receptors.     

The flower pot technique of Rapid Eye Movement (REM) sleep deprivation

This technique of REM sleep deprivation may make data interpretation difficult because it can lack selectivity, and because controls may suppress some REM sleep. To correct these difficulties, EEG recordings were made of rats placed in 4 situations for 96 hours: (1) baseline, (2) on 6.5 cm, or (3) 12.5 cm inverted flowerpots surrounded by water, (4) swimming in 10 cm water for 1 hr per 24 hr. Rats on the 6.5 cm pots had 57% as much REM sleep as baseline with no change in non-REM sleep. Rats on 12.5 cm pots initially had 55% as much REM sleep baseline, but by the fourth day increased to baseline levels. The swimming rats had no reduction in REM or non-REM sleep at any time, and thus seem to be a better control. The smaller the platform relative to the size of the rat, the greater the reduction in REM sleep - but at one point, non-REM sleep is decreased. The combination used here depresses REM sleep by about one half but does not reduce non-REM sleep.     

Rebound insomnia induced by abrupt withdrawal of hypnotics in sleep-disturbed rats

The present study was performed to examine whether or not rebound insomnia is caused by an abrupt withdrawal of benzodiazepine hypnotics and tandospirone in rats. Etizolam and triazolam caused a significant shortening of sleep latency, increase in non-REM sleep time, and decrease in wake time in a dose-dependent manner. Etizolam and triazolam caused a significant shortening of sleep latency during drug administration (for 7 days), whereas a significant prolongation of sleep latency was observed by the abrupt withdrawal of these drugs. Tandospirone caused a shortening of sleep latency, whereas no effect was observed on non-REM sleep time and wake time during drug administration (for 7 days). On the other hand, tandospirone showed no significant effect on sleep latency through its abrupt withdrawal, differing from etizolam and triazolam. From these findings, a rebound phenomenon in terms of sleep latency was confirmed with etizolam and triazolam in rats. Furthermore, the 5-HT(1A) agonist, tandospirone, caused no rebound phenomenon regarding sleep latency in rats.     

Cholecystokinin-B (CCK-B) receptor antagonists improve "aged" sleep: a new class of sleep modulators?

Sleep disorders are a major, although often minimized and underdiagnosed, medical problem. Current therapy is based on the use of hypnotics, mainly benzodiazepines, which disrupt the sleep pattern often suppressing rapid-eye-movement (REM) sleep. Here, new types of pharmacological tools such as cholecystokinin (CCK) receptor antagonists are examined. In particular, since the awake-sleep rhythm is mainly altered in old age in humans, the influence of these compounds over REM and non-REM sleep has been studied in aged rats (21 months) vs. young rats (5 months) prepared for electroencephalographic (EEG) recordings. Basal EEG data indicated that REM and non-REM sleep was reduced in aged rats vs. young rats. GV-150013, a selective CCK-B receptor antagonist, was found to increase REM sleep, as well as non-REM sleep, and therefore total sleep (non-REM + REM) mainly in aged rats. The dose-range of activity (0.5-60 micrograms/kg) together with the evidence that another CCK-B receptor antagonist, L-365,260 (5 micrograms/kg) increased, while devazepide (a CCK-A receptor antagonist; 20 micrograms/kg) decreased non-REM sleep and total sleep time, support the original hypothesis that the activity of GV-150013 on sleep progress through CCK-B receptors. Furthermore, no tolerance was detected after chronic treatments with GV-150013. In contrast, typical EEG modifications (decrease of REM) and the development of tolerance towards benzodiazepines were monitored following chronic treatment with triazolam (400 micrograms/kg). These results suggest that the CCKergic compounds studied are involved via a different mechanism of action than benzodiazepines in the modulation of the awake-sleep rhythm. A further observation is that the total sleep time recorded in aged rats after treatment with GV-150013 reached the value of the total sleep time of young untreated rats also prepared for EEG. Finally, this work suggests that CCK receptor antagonists, GV-150013 in particular, are more effective in aged resulting in an improvement of sleep quality towards that of young rats.     

Hypnotic action of flunitrazepam in the rat: Does 5-HT mechanism play a role?

This study examined whether pharmacological manipulation of serotonergic (5-HT) systems would affect the hypnotic action of flunitrazepam in rats. Flunitrazepam, a potent hypnotic, was used alone or combined with parachlorophenylalanine (pCPA), an inhibitor of the synthesis of 5-HT, 8-OH-DPAT, a 5-HT_1A receptor agonist and fluvoxamine, an inhibitor of the reuptake of 5-HT. Flunitrazepam increased the amount of orthodox sleep, the latency of rapid eye movement (REM) sleep and decreased the amount of REM sleep. The drug pCPA decreased the total sleep time and the amount of orthodox and REM sleep. Administration of flunitrazepam to pCPA-pretreated rats induced orthodox sleep in an identical way to that found in the controls. The drug 8-OH-DPAT increased wakefulness and the latency of REM sleep. The association of flunitrazepam with 8-OH-DPAT abolished the increase in waking seen after 8-OH-DPAT alone. In contrast, the combined treatment with flunitrazepam and 8-OH-DPAT resulted in a lengthening of the latency of REM sleep significantly greater than that observed with the same dose of each drug alone. Fluvoxamine increased the latency and decreased the amount of REM sleep. The association of fluvoxamine with flunitrazepam induced a decrease in REM sleep, equal to the sum of the effects of the two drugs alone. Fluvoxamine did not modify the other effects of flunitrazepam. The present experiments demonstrate that the association of pCPA, 8-OH-DPAT and fluvoxamine, did not alter the hypnogenic effect of flunitrazepam. The possibility of an involvement of 5-HT mechanisms in the effect of flunitrazepam on the phasic events in sleep is questionable.     

Extract of Ganoderma lucidum potentiates pentobarbital-induced sleep via a GABAergic mechanism

Ganoderma lucidum has been used for the treatment of a variety of diseases. For the first time here we report a detailed study on the mechanisms and effects of G. lucidum aqueous extract (GLE) on sleep and its sedative activity. GLE showed no effects on sleep architecture in normal rats at doses of 80 and 120 mg/kg. However, GLE significantly decreased sleep latency, increased sleeping time, non-REM sleep time and light sleep time in pentobarbital-treated rats. Suppression of locomotor activity in normal mice induced by GLE was also observed. Flumazenil, a benzodiazepine receptor antagonist, at a dose of 3.5 mg/kg showed a significant antagonistic effect on the shortening in sleep latency, increase in sleeping time, non-REM sleep time or light sleep time in pentobarbital-treated rat induced by GLE. Significant effect was also observed with GLE on delta activity during non-REM sleep and flumazenil did not block this effect. In conclusion, GLE may be a herb having benzodiazepine-like hypnotic activity at least in part.     

A comparison between astemizole and other antihistamines on sleep-wakefulness cycles in dogs

The effects of four reference antihistamines: ketotifen, diphenhydramine, chlorpheniramine and pyrilamine and of astemizole, a new potent and long-acting antihistamine, were studied on 16 hr sleep-wakefulness patterns in the same dogs. Using a computer-based on-line analysis and automatic stage classification, a differentiation was made between wakefulness, transition to sleep (drowsiness), slow wave sleep and rapid eye movement (REM) sleep. The reference antihistamines significantly increased non-REM sleep. The reference antihistamines significantly increased non-REM sleep: diphenhydramine and chlorpheniramine increased drowsiness, ketotifen increased slow-wave sleep and pyrilamine increased both. All, but astemizole, significantly prolonged the latency to the first REM period, prolonged the interval between successive REM periods and suppressed the total amount of REM sleep. With all antihistamines, the effects were most pronounced for the first 4 hr and there was no within-night rebound. Chlorpheniramine had long-lasting effects throughout the night, especially on REM sleep. The effects on non-REM sleep might be due to a blockage of brain histamine H₁ receptors, whereas the effects on REM sleep might be due to the anticholinergic properties of the antihistamines. Astemizole was devoid of any significant effect on the sleep-wakefulness pattern, in spite of its long-lasting antihistamine effects, suggesting that the common clinical side-effects of antihistamines, such as sedation and dryness of mucosal surfaces, will be lacking.     

Effects of N-cyclopentyladenosine and caffeine on sleep regulation in the rat

To study the role of adenosine in sleep regulation, the adenosine A₁ receptor agonist N⁶-cyclopentyladenosine (CPA) and the antagonist caffeine were administered to rats. Intraperitoneal (i.p.) CPA 1 mg/kg but not 0.1 mg/kg, suppressed rapid-eye-movement (REM) sleep and enhanced electroencephalographic (EEG) slow-wave activity (power density 0.75–4.0 Hz) in non-REM sleep. The latter effect was remarkably similar to the response to 6-h sleep deprivation. The effects persisted when CPA-induced hypothermia was prevented. Caffeine (10 and 15 mg/kg i.p.) elicited a dose-dependent increase in waking followed by a prolonged increase of slow-wave activity in non-REM sleep. The combination of caffeine (15 mg/kg) and sleep deprivation caused less increase in slow-wave activity than sleep deprivation alone, indicating that caffeine may reduce the buildup of sleep pressure during waking. The results are consistent with the involvement of adenosine in the regulation of non-REM sleep.     

Effect of valerian extract preparation (BIM) on the sleep-wake cycle in rats

In the present study, we studied the effect of valerian extract preparation (BIM) containing valerian extract, golden root (Rhodiola rosea L.) extract and L-theanine (gamma-glutamylethylamide) on the sleep-wake cycle using sleep-disturbed model rats in comparison with that of valerian extract. A significant shortening in sleep latency was observed with valerian extract and the BIM at a dose of 1000 mg/kg. On the other hand, valerian extract and the BIM caused no significant effects on total times of wakefulness, non-rapid eye movement (non-REM) sleep and REM sleep. Valerian extract and the BIM at a dose of 1000 mg/kg also had no significant effect on delta activity. In conclusion, it became clear that the BIM could be useful as a herbal medicine having a sleep-inducing effect without causing an alteration of the sleep-wakefulness cycle.     

Correlations between depression behaviors and sleep parameters after repeated corticosterone injections in rats

Aim： Disrupted sleep may be a prodromal symptom or a predictor of depressive disorders. In this study we investigated the relationship between depression symptoms and disrupted sleep using a novel model of stress-mimicked sleep disorders in rats. Methods： SD rats were injected with corticosterone （10, 20 or 40 mg/kg, sc） or vehicle for 7 d. Their sleep-wake behavior was monitored through implanted EEG and EMG electrodes. Their depressive behaviors were assessed using forced swim test, open field test and sucrose preference test. Results： The corticosterone-treated rats showed significantly reduced sleep time, disinhibition of rapid-eye-movement （REM） sleep and altered power spectra during non-REM sleep. All depressive behavioral tests did not show significant difference across the groups. However, individual correlation analysis revealed statistically significance： the immobility time （despair） was negatively correlated with REM sleep latency, slow wave sleep （SWS） time ratio, SWS bouts and delta power density, and it was positively correlated with REM sleep bouts and beta power density. Meanwhile, sucrose preference （anhedonia） was positively correlated with total sleep time and light sleep bouts, and it was negatively correlated with the REM sleep time ratio. Conclusion： In stress-mimicked rats, sleep disturbances are a predictor of depressive disorders, and certain symptoms of depression may be related to the disruption of several specific sleep parameters.     

Clozapine alters sleep-wake behavior in rats.

Clozapine is an atypical antipsychotic agent showing therapeutic efficacy superior to that of classical neuroleptics. Clozapine has strong sedative effects, but detailed studies on the drug influencing sleep in rodents are lacking. We studied the effects of clozapine on sleep and body temperature in rats. Clozapine (0, 2.5, and 7.5 mg/kg) was given i.p. to male Wistar rats at the beginning of the rest period. After administration of 7.5 mg/kg clozapine, animals were significantly more awake during the first 2 h postinjection. In parallel, the slow-wave activity (SWA) was suppressed. In the following 2 h non-REM sleep was markedly increased, whereas the SWA returned to baseline. At both doses clozapine decreased overall wakefulness and increased non-REM sleep on the first treatment day, which was associated with prolonged non-REM sleep episodes. These effects were transiently present even after subchronic treatment (7 days). After acute treatment, 7.5 mg/kg clozapine significantly reduced REM sleep and pre-REM sleep due to an increase in REM sleep latency and a reduction in the number of REM sleep episodes. Furthermore, clozapine produced a transient decrease in brain temperature that was followed by a moderate, but long-lasting elevation. To conclude, clozapine affected sleep-wake behavior in a way comparable to its effects in humans, suggesting that the rat is a suitable model for further studies on the underlying mechanisms.     

Package inserts for antihypertensive drugs: use by the patients and impact on adverse drug reactions

Summary The effect of a single dose (30 mg) of Org 3770 (metirzapine) on human sleep was assessed in a double blind, placebo controlled, cross over study in 6 young, healthy male volunteers. The sleep stage classification was based on visual scoring of 24 h electroencephalographic recordings according to the criteria of Rechtschaffen and Kales.Org 3770 30 mg p.o. given 2 h before bedtime had a sleep promoting action in all subjects, resulting in a shortened time to the onset of sleep. Bedtime waking and dozing (Stage 1) were reduced in favour of deep, slow wave sleep (Stages 3 and 4). Org 3770 increased the latency of REM sleep with respect to Stage 2 sleep in all subjects. It also caused a minor reduction in waking periods during REM sleep and a lower frequency of awakenings after periods of movement. No effect of Org 3770 was observed in reaction and vigilance tests on the post treatment day.The observed effects of Org 3770 on normal human sleep suggest that it might ameliorate the sleep disturbances encountered in endogenous depression, which are characterized by a reduction in slow wave sleep, an increase in nighttime awakenings and shortening of REM sleep latency.     

颞叶癫痫患者的睡眠特征研究

目的 通过多导睡眠监测（PSG）研究颞叶癫痫（TLE）患者发作间期的睡眠特征。方法 选取 25 例 TLE 患者为 TLE 组，健康志愿者 18 例为对照组，对 2 组受试者分别进行 PSG，监测指标包括总卧床时间（TIB）、总睡眠时 间（TST）、睡眠效率（SE）、睡眠潜伏期（SL）、快速动眼睡眠期潜伏期（REML）、入睡后觉醒时间（WASO）、非快速动眼 睡眠（NREM）1、2、3 期以及快速动眼睡眠期（REM）时间占总睡眠期时间的百分比（以 N1%、N2%、N3%、REM%表 示）、呼吸暂停低通气指数（AHI）、低通气指数、平均血氧饱和度（SpO2）及最低 SpO2、觉醒指数、每小时周期性肢体运 动指数（PLMs/h）、每小时 REM 期 PLMs、总睡眠期转换次数（SSS）、每小时睡眠期转换次数（SSS/H）、NREM1、2、3 期 以及 REM、清醒期转换次数（以 N1、N2、N3、REM、W 表示）、N1、N2、N3、REM、清醒期转换次数占总睡眠期转换次数 百分比（以 N1/SSS、N2/SSS、N3/SSS、REM/SSS、W/SSS 表示）等睡眠指标。结果 与对照组相比，TLE 组 WASO 延长， 平均 SpO2降低，PLMs 增多，REM 期 PLMs 增多，SSS、SSS/H 及 N2 增多（P＜0.05）。结论 TLE 患者存在睡眠障碍， 主要表现为睡眠结构明显紊乱，睡眠相关呼吸、运动事件增多。