5-羟色胺和环磷酸腺苷对睡眠的影响

目的研究杏仁核中５ 羟色胺（５ ＨＴ）和环磷酸腺苷（ｃＡＭＰ）对大鼠睡眠的影响。方法多导睡眠描记和杏仁核微量注射。结果５ ＨＴ前体５ 羟色氨酸（５ ＨＴＰ）引起慢波睡眠、快波睡眠和总睡眠时间增多,入睡潜伏期缩短;５ 羟色胺受体阻断剂二甲麦角新碱（ＭＳ）对睡眠无直接影响,但可完全阻断５ ＨＴＰ的促睡眠效应;ｃＡＭＰ可引起慢波睡眠和总睡眠时间延长,入睡潜伏期缩短。结论杏仁核参与睡眠 觉醒调节,杏仁核中５ ＨＴ和ｃＡＭＰ有明显的促睡眠效应。     

Effects of the selective activation of 5-HT3 receptors on sleep: a polysomnographic study in healthy volunteers.

The respective role of various classes of central serotonin (5-HT) receptors in the regulation of sleep-wakefulness cycles has been the subject of many studies. Notably, it has been reported that 5-HT1A/B receptors are involved in the regulation of rapid eye movement sleep (REMS) and that 5-HT2A/C receptors participate in the control of slow wave sleep (SWS), but the role of 5-HT3 receptors is less well characterised. In this study we investigated the effects of SR 57227A, a potent and selective 5-HT3 agonist, on the sleep EEG of normal young male volunteers. SR 57227A (2.5, 5, 10, 20, 40 mg o.d. and 20 mg b.i.d.) or placebo were administered during 7 consecutive days in seven groups of ten subjects using a parallel group design. Sleep EEG recordings were performed on days 6 and 7 after an habituation session. SR 57227A produced a dose-dependent shift of REMS toward the end of the night without changing REMS and SWS duration nor altering sleep continuity. It suggests a role for the 5-HT3 receptor in the human sleep-wakefulness cycle and particularly in REMS regulation.     

Sleep improvement in dogs after oral administration of mioflazine,a nucleoside transport inhibitor

Mioflazine, a nucleoside transport inhibitor, was given PO to dogs at doses of 0.04–10 mg/kg. Sixteen hour polygraphic sleep recordings were made and analysis and sleep stage classification was done by computer. Mioflazine decreased wakefulness and increased slow wave sleep, but did not affect the latencies of either REM sleep or slow wave sleep. This increased sleep was due to an increase in the number of light and deep slow wave sleep epochs. The effect lasted for about 8 h. The decreased wakefulness and increased slow wave sleep could be antagonized by the adenosine antagonist caffeine (2.5 and 10 mg/kg, PO); however, there was not a pure antagonistic effect. It might be that the enhancement of slow wave sleep is due to an activation of brain adenosine receptors. This is the first report of a drug acting on adenosine that given orally improves sleep. Mioflazine might be the prototype of substances worth considering for the treatment of a variety of sleep disorders.     

Effects of seganserin, a 5-HT2 antagonist, and temazepam on human sleep stages and EEG power spectra

The effects of seganserin, a specific 5HT2 antagonist, on human sleep were assessed in two experiments and compared to the effects of temazepam and sleep deprivation. During daytime recovery sleep after sleep deprivation, seganserin did not significantly enhance visually scored slow wave sleep (SWS, stages 3 + 4) or the EEG power density in the delta frequencies. Under these conditions temazepam reduced the power density in the delta and theta frequencies. During nighttime sleep after a nap in the evening, seganserin caused an increase in SWS, a reduction in intermittent wakefulness, and an enhancement of the power density in the delta and theta frequencies during non-rapid eye movement (NREM) sleep. Temazepam induced a reduction in the power density in the delta and theta frequencies. It is concluded that the 5HT2 antagonist, seganserin, can induce SWS. However, since the spectral results showed that the changes in the sleep EEG were not identical to those induced by sleep deprivation it seems premature to conclude that 5HT2 receptors are primarily involved in NREM sleep regulation.     

Functional role of 5-HT2 receptors in the regulation of sleep and wakefulness in the rat

Recently developed agents specifically acting on different 5-hydroxytryptamine (5-HT) receptor populations were used to analyze the functional role of 5-HT₂ receptor subtypes in the sleep-wakefulness cycle of the rat. The 5-HT₂ receptor antagonist ritanserin injected intraperitoneally (IP) (0.04–2.5 mg/kg) induced an increase in deep slow wave sleep (SWS2) duration at the expense of wakefulness (W), light slow wave sleep (SWS1) and paradoxical sleep (PS). The stimulation of 5-HT₂ receptors by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) produced a dose-related increase in W and a dose-dependent decrease in both SWS2 and PS. Pretreatment with ritanserin (0.16–2.5 mg/kg) or with cinanserin (2.5–5 mg/kg), another 5-HT₂ receptor antagonist, dose-dependently reversed the W enhancement and the SWS2 deficit produced by DOM, but not the PS deficit. Sleep-wakefulness alterations (increase in W and SWS1 combined with a suppression of SWS2 and PS) observed after IP injection of two putative 5-HT₁ receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (2.5 mg/kg) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969) (0.63 mg/kg), were not modified by ritanserin pretreatment (0.16–2.5 mg/kg). These results further support the hypothesis that the serotonergic system plays an active role in the regulation of the sleep-wakefulness cycle in the rat and that 5-HT₂ receptors are involved in this action. In addition it is suggested that 5-HT₁ receptor subtypes are unlikely to interact with 5-HT₂ receptors in the sleep-wakefulness modulation mediated through 5-HT₂ receptors.     

Increased slow wave sleep with 5-HT2 receptor antagonists: detection by ambulatory EEG recording and automatic sleep stage analysis

The effect on slow wave sleep (SWS) of 5-HT antagonists with different affinities for 5-HT(1) and 5-HT(2) receptors was investigated using ambulatory EEG monitoring in normal volunteers. The selective 5-HT( 2) antagonists, ritanserin and cypropheptadine, increased SWS while the non-selective 5-HT antagonist metergoline did not. The histamine H( 1)-receptor antagonist, mepyramine, was similarly without effect on SWS. These findings suggest that home ambulatory monitoring with automatic sleep stage analysis may be useful in detecting the effect of selective 5-HT( 2) receptor antagonists on SWS.     

Estazolam逆转结节乳头体核组胺引发的觉醒

目的观察增加γ-氨基丁酸(gamma-aminobutyricacid,GABA)受体与GABA亲和力的Estazolam对结节乳头体核(tuberomammillary nucleus,TMn)组胺(histamine,HA)产生觉醒的作用,探究GABA与TMn的HA对睡眠-觉醒周期的调节。方法♂SD大鼠随机分为对照组,生理盐水组,Estazolam组,HA组,以及HA+Estazolam(2.5mg)组,HA+Estazolam(5mg)组。颅骨和颈肌植入脑电图(EEG)和肌电图(EMG)电极,带芯的不锈钢导管植入TMn邻近区以备微量注射药物。术后恢复7d,各组分别记录24h的EEG和EMG,分析睡眠-觉醒周期中各时相的变化。结果:TMn内注射HA(1μg.kg-1)在24h中觉醒时间增加(P<0.01),慢波睡眠被抑制,但不影响异相睡眠(paradoxicalsleep,PS)。灌胃给予Estazolam(5mg.kg-1)产生以深度慢波睡眠(SWS2)增加(P<0.01)为主要特征的总睡眠时间增加。在HA引起的觉醒达高峰(2h)的时候分别灌胃给予Estazolam2.5mg.kg-1与5mg.kg-1,使觉醒转为睡眠,并呈剂量依赖性。结论TMn内HA能神经元促进和维持觉醒,作用于GABA神经元末梢的苯二氮类(benzodiazepine,BZD)1受体的Estazolam,通过增加SWS2而增加总睡眠时间,并逆转HA引起的觉醒状态。     

Lithium increases slow wave sleep: possible mediation by brain 5-HT2 receptors?

The effect of lithium on slow wave sleep (SWS) was studied in ten normal male volunteers using home based cassette sleep recording and automatic sleep stage analysis. Lithium increased SWS, an effect consisten with a reduction in brain 5-HT₂ receptor function.     

Depletion of brain serotonin by 5,7-DHT: effects on the 8-OH-DPAT-induced changes of sleep and waking in the rat

The effect of 5-HT_1A receptor agonist 8-OH-DPAT on sleep and wakefulness was studied in rats with selective serotonin depletion after ICV administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Injection of 8-OH-DPAT to vehicle-treated animals induced biphasic effects, such that low doses (0.010 mg/kg) which act perferentially on the somatodendritic autoreceptor decreased wakefulness (W) and increased slow wave sleep (SWS), while higher doses (0.375 mg/kg) which stimulate postsynaptic receptors caused opposite effects. REM sleep was suppressed irrespective of the dosage given. Injection of the 0.010 mg/kg dose in the 5,7-DHT-treated rats did not result in significant changes in sleep or W. On the other hand, the 0.375 mg/kg dose produced changes in sleep variables which were similar to those described in the vehicle-treated animals. Our findings tend to indicate that increased SWS after low doses of 8-OH-DPAT depends upon the activation of inhibitory somatodendritic 5-HT_1A receptors, while increased W after higher doses of the compound is related to stimulation of postsynaptic receptors.     

Role of adenosine in sleep and temperature regulation in the preoptic area of rats.

We have examined the effects on sleep and brain temperature of bilateral microinjections of adenosine and adenosine analogs to the preoptic area (PO) of rats. Administration of adenosine (12.5 nmoles), a nonselective adenosine A1/A2 receptor agonist NECA (N-ethyl-carboxamido-adenosine, 1.0 nmole), and the selective adenosine A1 receptor agonist CPA (cyclopentyladenosine, 0.25, 0.5 nmoles) increased total sleep primarily through an enhancement in deep slow-wave sleep (SWS2), while adenosine also increased REM sleep. Administration of 12.5 nmoles adenosine and 0.25 nmoles CPA did not affect brain temperature, while 1.0 nmole NECA and 0.5 nmoles CPA caused a transient and prolonged hypothermia, respectively. Administration of the selective adenosine A2 receptor agonist CV-1808 (2-phenylaminoadenosine, 5, 10 nmoles) had no effect on sleep or brain temperature. The present results demonstrate a site for the central hypnotic action of adenosine, and a functional role for adenosine A1 receptors in the hypothalamus.     

The influence of chronic caffeine administration on sleep parameters in the cat

Caffeine (20 mg/kg/day) was administered per os to 5 cats for 21 days and sleep parameters were measured both during drug administration and over the withdrawal phase. The initial effect of caffeine was a marked increase in waking. As the animal habituated to the stimulant action of the methylxanthine, however, total sleep time normalized, although time spent in Stage II slow wave sleep (S2) remained below, and Stage I slow wave sleep (S1) above, control levels throughout the period of drug administration. In contrast, a significant increase in the S2/S1 ratio was recorded as soon as caffeine treatment ended, and this parameter remained elevated for about 30 days. Chronic caffeine administration has been previously shown to increase the number of central adenosine receptors, and it has also been reported that adenosine agonists increase S2 at the expense of S1. The present data were thus interpreted as indicating that the action of caffeine on sleep may be mediated at a central adenosine receptor site. Results also imply that changes induced in this receptor population by chronic caffeine administration last for at least 30 days after the drug is withdrawn.     

Basic sleep mechanisms: an integrative review

Regulation of the sleep-waking cycle is complex and involves diverse brain circuits and molecules. On one hand, an interplay among many neuroanatomical and neurochemical systems including acetylcholine, dopamine, noradrenaline, serotonin, histamine, and hypocretin has been shown to control the waking state. On the other hand the sleep-onset is governed by the activity of sleep-promoting neurons placed in the anterior hypothalamus that utilize GABA to inhibit wake-promoting regions. Moreover, brainstem regions inhibited during wakefulness (W) and slow wave sleeps (SWS) become active during rapid eye movement (REM) sleep. Further complexity has been introduced by the recognition of sleep-promoting molecules that accumulate in the brain in prolonged W as well as the physiological role of gene expression during sleep. The sleep-wake cycle is currently undergoing intense research with many new findings leading to new paradigms concerning sleep regulation, brain organization and sleep function. This review provides a broader understanding of our present knowledge in the field of sleep research.     

Effects of ritanserin and chlordiazepoxide on sleep-wakefulness alterations in rats following chronic cocaine treatment

The effects of ritanserin, a 5-hydroxytryptamine-2 (5-HT₂) receptor antagonist, and chlordiazepoxide, a benzodiazepine agonist, on sleep-wakefulness disturbances in rats after acute administration of cocaine and after discontinuation of chronic cocaine treatment were examined. Intraperitoneal (IP) injection of chlordiazepoxide (10 mg/kg) but not ritanserin (0.63 mg/kg) prevented the increase of wakefulness (W) and the reduction of light slow wave sleep (SWS1) and deep slow wave sleep (SWS2) induced by an acute injection of cocaine (20 mg/kg IP). Daily injection of cocaine (20 mg/kg for 5 days, then 30 mg/kg for 5 days IP) at the onset of the light phase elicited an increase of W and a concomitant decrease of SWS1, SWS2 and paradoxical sleep (PS) in the light phase, followed by a rebound in SWS2 and PS in the subsequent dark phase. Following cocaine discontinuation, the circadian distribution of sleep-wakefulness states remained disturbed in saline-treated rats for at least 5 days. Both ritanserin (0.63 mg/kg IP/day) and chlordiazepoxide (10 mg/kg IP/day) reduced the alteration in the distribution of W and SWS2 throughout the light-dark cycle from the first day of administration on, but failed to prevent PS alterations. The mechanisms by which both compounds exert their effect are probably quite different. For chlordiazepoxide sedative and sleep-inducing properties probably play a major role. In contrast, for ritanserin SWS2-increasing properties and its ability to reverse preference for drugs of abuse without inducing aversion might be key factors.     

A review of sodium oxybate and baclofen in the treatment of sleep disorders

Studies examining GABA(B) receptor agonists have reported effects on sleep including decreased sleep onset latency (SOL), increased sleep consolidation and increases in slow wave sleep (SWS). γ-hydroxybutyrate (GHB) is proposed to act as a GABA(B) receptor agonist; however, the mechanism of action of GHB is controversial. In addition, the GABA(B) receptor agonist, baclofen, has also been proposed to exert similar effects on sleep. The aim of this paper is to provide a review of the human clinical studies of sodium oxybate and baclofen regarding sleep and the treatment of sleep disorders including narcolepsy and insomnia, as well as other disorders involving disrupted sleep such as fibromyalgia.     

Effect of a highly selective central CCK-B receptor agonist: BC-264 on rat sleep

The possible involvement of the CCK-B receptor type in the atypical somnolence and EEG changes induced by low doses of CCK-B was investigated by intraperitoneal administration of three different doses (8, 16 and 32 micrograms/kg) of the new highly potent and selective CCK-B agonist, BC-264, on sleep parameters in the fasted rat. At the dose of 8 micrograms/kg BC-264 induced a significant increase in waking in the second 120 min of recording without effect on slow wave sleep (SWS). BC-264 did not modify the others sleep parameters. Taken all together these results suggest that CCK-B type receptors are probably not critically involved in satiety and sleep.     

5-HT 2C receptor sensitivity during treatment with selective serotonin re-uptake inhibitors

We studied the effect of repeated treatment with selective serotonin re-uptake inhibitors (SSRIs) on the sensitivity of brain 5-HT(2C) receptors, by measuring the decrease in slow wave sleep (SWS) that follows administration of meta-chlorophenylpiperazine (mCPP) (7.5 mg orally). mCPP significantly lowered SWS both in patients taking SSRIs and in a group of healthy controls. There was, however, no difference in the response between the two groups. The results do not support the suggestion that repeated SSRI treatment alters the sensitivity of 5-HT(2C) receptors in the human brain. The present study, however, cannot exclude the possibility that a decrease in 5-HT(2C) receptor sensitivity was offset by higher plasma levels of mCPP in the SSRI-treated group.     

Warm sensitive neurons of the preoptic area regulate ambient temperature related changes in sleep in the rat

Warm sensitive neurons (WSN) play a major role not only in body temperature regulation, but also in sleep regulation. The present study was undertaken to investigate the role of WSN of the preoptic area (POA) in mediating the ambient temperature (T(amb)) related changes in sleep. The effect of T(amb) changes on sleep and body temperature was studied in rats before and after destruction of WSN of the POA by local intracerebral injection of capsaicin. Though the rats preferred 27 degrees C T(amb), they slept maximum at 30 degrees C. After destruction of WSN of the POA, slow wave sleep (SWS) peak was brought down to 27 degrees C, which was the preferred T(amb) of the rats. This indicates that WSN of the POA mediate the increase in SWS, at temperatures higher than preferred T(amb). On the other hand, in WSN destroyed rats, rapid eye movement (REM) sleep was maximum at 33 degrees C. It suggests that the REM sleep generation is under inhibitory control of the WSN of the POA. The study supports several earlier reports that the neurons of the POA play a key role in coordinating sleep and body temperature regulation.     

Differential effects of the new antipsychotic risperidone on sleep and wakefulness in the rat

The effects of risperidone, a new antipsychotic with potent 5-hydroxytryptamine₂ (5-HT₂) and dopamine-D₂ (DA-D₂) antagonistic properties, were studied on sleep-wakefulness patterns in rats. Administration of low doses (0.01–0.16 mg/kg i.p.) resulted in a significant increase of deep slow wave sleep (SWS2) and a decrease of wakefulness (W) and light slow wave sleep (SWSl). High doses (0.63–2.5 mg/kg) produced opposite effects. Paradoxical sleep (PS) was significantly reduced over the dose range tested. The increase of SWS2 after low doses of risperidone could be related to a predominant and potent 5-HT₂ receptor blocking activity.     

中缝背核投射到基底外侧杏仁核的5-羟色胺能纤维对睡眠的调节作用

目的　观察大鼠中缝背核 (DRN)到基底外侧杏仁核(BLA)的 5 HT能纤维投射在睡眠 -觉醒调节中的作用。方法　采用脑立体定位 ,核团微量注射和多导睡眠描记 (PSG)方法。结果　DRN内微量注射L Glu ,可使觉醒 (W )增加 ,慢波睡眠 (SWS)和异相睡眠 (PS)明显减少。在双侧BLA微量注射非选择性 5 HT受体阻断剂麦角新碱 (MS)可以逆转DRN内微量注射L Glu的效应 ,SWS增加 ,W减少 ,但PS没有变化 ;DRN内微量注射PCPA ,导致SWS增加 ,W减少 ,但当在DRN内微量注射PCPA后 ,双侧BLA内微量注射 5 HTP可以逆转PCPA所引起的睡眠增加效应 ,使SWS减少 ,W增加 ,但PS没有变化。结论　DRN对睡眠 -觉醒的调节作用部分通过DRN到BLA的 5 HT能纤维投射介导的     

Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat

The effects of the dopamine (DA) receptor agonists apomorphine, bromocriptine and pergolide were compared with those produced by a DA receptor antagonist, haloperidol, in rats implanted with electrodes for chronic sleep recordings. Apomorphine (0.025–2.0 mg/kg) and bromocriptine (0.25–6.0 mg/kg) induced biphasic effects such that low doses decreased wakefulness (W) and increased slow wave sleep (SWS) and REM sleep (REMS), while large doses induced opposite effects. The effects of pergolide (0.05–0.5 mg/kg) on W and SWS were also biphasic, while REMS was suppressed over the range of dosages given. At 0.040 mg/kg, haloperidol increased W, while at 0.160 mg/kg it produced the opposite effect. Pretreatment with haloperidol (0.020 mg/kg) in a dose which preferentially acts at presynaptic sites reversed the effects of low doses of apomorphine, bromocriptine or pergolide on sleep and W. However, the compound differed substantially in its ability to block agonist effects.The increase in sleep after low doses of apomorphine, bromocriptine or pergolide could be related to activation of presynaptic D-2 receptors located on DA axons of mesolimbic and mesocortical systems. In addition, inhibition of norepinephrine and acetylcholine neurons having inhabitory D-2 receptors could contribute to the increase of sleep after small doses of the DA agonists.