小鼠无线头皮脑电图技术平台的建立及其在睡眠研究中的应用与验证

目的 建立小鼠无线头皮脑电图(EEG)记录平台。方法 小鼠颅骨表面植入EEG/肌电图(EMG)底座,术后恢复7 d开始实验。分别在第1天18∶00 ip给予溶剂(1%DMSO)和第2天同一时间ip给予镇静催眠药地西泮(DZP)1.0 mg·kg^-1,随后采用Pinnacle EEG/EMG无线记录系统采集自由活动小鼠ip注射后3 h内EEG和EMG数据,最后使用睡眠分析软件Sirenia^?Sleep pro分析EEG和EMG信号,判读睡眠-觉醒时相,通过MATLAB软件分析滤波后数据的功率谱。结果 该平台可高效且准确地采集和解析小鼠睡眠-觉醒行为。与溶剂组相比,DZP 1.0 mg·kg^-1增加非快眼动睡眠和总睡眠时间,减少觉醒时间(P<0.05);同时,降低睡眠期δ和θ波功率谱(P<0.05,P<0.01),增加睡眠期慢波振荡-睡眠纺锤波相位-振幅耦合度(P<0.05)。结论 成功建立小鼠无线头皮EEG技术平台,此平台可用于研究睡眠障碍发病机制及筛选新药。     

白芍总甙对大白鼠睡眠节律的影响

白芍总甙(TGP)每日ig 50mg·kg~(-1),连续7d可延长正常大鼠慢波睡眠(SWS)的持续时间.并能使咖啡因(12.5 mg·kg~(-1),ip)诱导的失眠大鼠睡眠各参数恢复到接近正常水平。TGP 50mg·kg~(-1)×3d)还可明显延长游泳大鼠(水温25±1℃.游泳时间30min)SWS和异相睡眠的总时间。上述实验结果提示TGP可改善不同功能状态下的大鼠睡眠。     

癫痫与睡眠关系的脑电图分析

目的探讨癫痫与睡眠时相的关系及癫痫对睡眠结构的影响。方法对20例确诊为颞叶癫痫患者和20名与之相匹配的健康者进行多导睡眠仪监测,并对结果进行分析。结果癫痫组与健康组相比,睡眠潜伏期明显延长,差异有统计学意义（P〈0．05）;癫痫患者睡眠中每小时唤醒次数增加,差异有统计学意义（P〈0．05）;癫痫患者的睡眠结构明显发生了变化,以浅睡期[非快速眼动（NREM）Ⅰ、Ⅱ期]所占时间比例比健康对照组明显延长（P〈0．01）,深睡期（NREMⅢ、Ⅳ期）时间（P〈0．01）和快速眼动（REM期）时间均缩短（P=0．01）;癫痫患者的睡眠纺锤波密度要明显低于健康者（P〈0．01）。结论癫痫患者存在明显的睡眠结构改变,睡眠期间的癫痫发作,可加重睡眠障碍。     

儿童癫痫患者剥夺睡眠—自然睡眠脑电图检查分析

为提高癫痫脑电图的阳性率，我院在1998—03—2004-03共对94例临床诊断为癫痫，而常规清醒时脑电图未见异常的患者进行了剥夺睡眠一自然睡眠时的脑电图监测。现将结果报告如下。     

一种新的大鼠睡眠自动分析系统

目的　建立一种有效的大鼠睡眠自动分析系统。方法　采用数据采集软件记录大鼠脑电图、肌电图和眼电图，原始图形经去噪声压缩后用数据分析软件进行振幅分析和混合波导联分析，然后根据睡眠各时相特点，并利用一定的逻辑判断对睡眠成分进行分析。结果　人工分析和系统自动分析符合率达８５ ％ 以上；给予大鼠选择性增加深睡眠药物ｒｉｔａｎｓｅｒｉｎ，经自动系统分析所得结果与文献报道一致；随机选择相同大鼠对其ｄ １ 和ｄ ５ 相同时间段的睡眠时间进行比较，发现变化很小。结论　经检验，本系统具有的可信、稳定和准确等优点都达到国外同类软件先进水平     

长期精神紧张对睡眠脑电图的影响

国际精神卫生和神经科学基金会选定每年的3月21日为"世界睡眠日",旨在唤起全球人民对睡眠的重视。我国今年"世界睡眠日"的主题是"良好睡眠,健康人生"。良好的睡眠能更好地形成并巩固记忆、促进规律分泌激素、放松内脏器官、     

剥夺睡眠脑电图在小儿癫痫诊断中的应用价值

目的:探讨剥夺睡眠脑电图在小儿癫痫诊断中的应用价值.方法:对152例疑诊癫痫患儿进行清醒脑电图及剥夺睡眠脑电图检查,作自身对照.比较两种方法痫样放电检出率.结果:两种状态下描记的脑电图痫样放电的阳性率分别为清醒脑电图32%、剥夺睡眠脑电图为53%.结论:剥夺睡眠脑电图是提高小儿癫痫的诊断水平的简单易行的方法,具有重要的临床应用价值.     

日间自然睡眠脑电图与常规脑电图对癫痫诊断的对比研究

目的探讨日间自然睡眠脑电图与常规脑电图对癫痫诊断情况。方法分析我院收治的癫痫患者80例临床资料,依据患者年龄不同分为未成年组30例和成年组50例。结果 80例癫痫患者清醒脑电图痫样放电检出率明显低于睡眠脑电图,未成年组痫样放电检出率明显高于成人组,P<0.05,差异均有统计学意义。结论日间自然睡眠脑电图可以明显提高痫样波的检出率、明确癫痫发作类型,其检出率明显高于常规脑电图,可以为指导临床用药和判断预后提供可靠的理论依据,值得临床推广应用。     

多巴胺D2受体调控睡眠-觉醒研究进展

脑内多巴胺（dopamine,DA）参与觉醒相关的运动、认知和奖赏等行为调控。DA能神经元主要位于黑质致密部和腹侧被盖区。DA受体（receptor,R）包括：D1R、D2 R（D2S和D2L）、D3R、D4R和D5R五种亚型。中枢神经内D1R和D2R数目占绝对优势,D2R对内源性DA的亲和力显著高于D1R。近年来,药理学和基因剔除动物等研究发现：D2R是维持觉醒的重要受体,本文综述其研究进展。     

D1/D2 receptor-targeting L-stepholidine, an active ingredient of the Chinese herb Stephonia, induces non-rapid eye movement sleep in mice

L-stepholidine, an active ingredient of the Chinese herb Stephonia, is the first compound known to have mixed dopamine D₁ receptor agonist/D₂ antagonist properties and to be a potential treatment medication for schizophrenia. In schizophrenic patients insomnia is a common symptom and could be partly related to the presumed over-activity of the dopaminergic system. To elucidate whether stepholidine modulates sleep behaviors, we observed its effects on sleep-wake profiles in mice. The results showed that stepholidine administered i.p. at doses of 20, 40 or 80 mg/kg significantly shortened the sleep latency to non-rapid eye movement (non-REM, NREM) sleep, increased the amount of NREM sleep, and prolonged the duration of NREM sleep episodes, with a concomitant reduction in the amount of wakefulness. Stepholidine at doses of 40 and 80 mg/kg increased the number of state transitions from wakefulness to NREM sleep and subsequently from NREM sleep to wakefulness. However, stepholidine had no effect on either the amount of REM sleep or electroencephalogram power density of either NREM or REM sleep. Immunohistochemistry study showed that stepholidine dose-dependently increased c-Fos expression in neurons of the ventrolateral preoptic area, a sleep center in the anterior hypothalamus, as compared with the vehicle control. These results indicate that stepholidine initiates and maintains NREM sleep with activation of the sleep center in mice, suggesting its potential application for the treatment of insomnia.     

Effect of Withania somnifera on Sleep-Wake Cycle in Sleep-Disturbed Rats: Possible GABAergic Mechanism

Sleep deprivation disrupts significantly sleep pattern and cause poor quality of sleep. The aim the present study was to explore role of Withania somniferra root extract in sleep-disturbed rats. Male wistar rats (n=5-6/group) were sleep deprived for 24 h using grid suspended over water method. Withania somniferra extract (100 mg/kg) was administered intraperitoneally (i.p.) 30 min before actual recording (EEG and EMG) recording and electrophysiological recordings are further classified as- sleep latency, slow wave sleep, paradoxical sleep, total sleep, wakefulness. One day (24 h) sleep deprivation delayed latency sleep, reduced duration of slow wave sleep, rapid eye movement sleep, total sleep time and increased total waking as compared to animals placed on saw dust (P<0.05). Pretreatment with Withania somniferra extract (100 mg/kg) and diazepam (0.5 mg/kg) significantly improved electrophysiological parameters, which was further reversed by picrotoxin (2 mg/kg) and potentiated by muscimol (0.05 mg/kg). Flumazenil (2 mg/kg) did not produce any significant effect on the sleep parameters of Withania somnifera root extract. Present study suggests the involvement of GABAergic mechanism in the sleep promoting effect of Withania somniferra in sleep-disturbed state.     

Bimodal effects of MK-801 on locomotion and stereotypy in C57BL/6 mice

Rationale Systemic injection of the non-competitive NMDA (N-methyl-d-aspartate) receptor antagonist MK-801 (dizocilpine maleate) causes both increased locomotion in rodents and various stereotypic behaviors that are proposed to model certain aspects of schizophrenic symptoms in humans.Objectives This study presents a comprehensive characterization of the bimodal effects of MK-801 on locomotion and stereotypy in the C57BL/6 mouse strain, a strain commonly used for genetically modified mice.Results We found that it is important to analyze both locomotion and stereotypy in parallel, as MK-801-induced stereotypy results in abnormal movements that are recorded as locomotion by automated beam detection systems. Furthermore, it is important to analyze the bimodal effects of MK-801 over an extended time span, rather than the commonly used narrower time window, as at higher doses (e.g., above 0.3 mg/kg) the hyperlocomotion phase develops only after the stereotypic phase subsides. We also observed that the apparent dose–response curve is very sensitive to the particular time window chosen for analysis because MK-801 affects both the time course and maximum value of stimulated locomotion. We show that analyzing the absolute peak value of locomotion induced for each animal, rather than group-averaged time courses, provides a measure that is sensitive over a wider range of MK-801 doses. Interestingly, MK-801 even at a very low dose of 0.02 mg/kg suppressed rather than enhanced rearing behavior, differing in this regard from amphetamine.Conclusions The non-competitive NMDA receptor antagonist MK-801 induces a complex pattern of behavioral modification in mice with respect to both the time course and the dose–response relationship of behavioral changes. The results of this study provide a foundation and frame of reference for the growing interest in studying MK-801-induced behavior in mice.The first three authors contributed equally to this work.Co-corresponding authors: Guoping Zhao, Meilei Jin, Lei Yu     

Discovery and development of orexin receptor antagonists as therapeutics for insomnia

Insomnia persistently affects the quality and quantity of sleep. Currently approved treatments for insomnia primarily target γ-aminobutyric acid-A (GABA-A) receptor signalling and include benzodiazepines and GABA-A receptor modulators. These drugs are used to address this sleep disorder, but have the potential for side effects such as tolerance and dependence, making them less attractive as maintenance therapy. Forward and reverse genetic approaches in animals have implicated orexin signalling (also referred to as hypocretin signalling) in the control of vigilance and sleep/wake states. Screening for orexin receptor antagonists using in vitro and in vivo methods in animals has identified compounds that block one or other of the orexin receptors (single or dual orexin receptor antagonists [SORAs and DORAs], respectively) in animals and humans. SORAs have primarily been used as probes to further elucidate the roles of the individual orexin receptors, while a number of DORAs have progressed to clinical development as pharmaceutical candidates for insomnia. The DORA almorexant demonstrated significant improvements in a number of clinically relevant sleep parameters in animal models and in patients with insomnia but its development was halted. SB-649868 and suvorexant have demonstrated efficacy and tolerability in Phase II and III trials respectively. Furthermore, suvorexant is currently under review by the Food and Drug Administration for the treatment of insomnia. Based on the publication of recent non-clinical and clinical data, orexin receptor antagonists potentially represent a targeted, effective and well-tolerated new class of medications for insomnia.Linked ArticlesThis article is part of a themed section on Orexin Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-2     

Interactions between metoclopramide and morphine: enhanced antinociception and motor dysfunction in rats

1. Opioid analgesics and anti-emetics are often used concomitantly to treat pain and nausea and vomiting in people with malignant disease. We investigated interactions between the opioid analgesic morphine and the anti-emetic metoclopramide, a dopamine D2 receptor antagonist, on nociception and gross motor function. 2. To assess for antinociceptive interactions, 11 Sprague-Dawley rats were injected intraperitoneally with morphine (5.0 mg/kg) or saline in combination with metoclopramide (0.5, 1.5 and 5.0 mg/kg) or saline and, 30 min later, the tail-flick latencies to a noxious thermal stimulus (49 degrees C water) were measured. Immediately thereafter we induced reperfusion hyperalgesia in the rats' tails using a tourniquet cuff and tested nociception again. Because, in addition to its ability to block D2 receptors, metoclopramide is also a weak 5-HT(3) receptor antagonist, we assessed in a further 11 rats whether any antinociceptive interactions occurred between morphine (5.0 mg/kg) and ondansetron (0.2 and 2.0 mg/kg), an anti-emetic that selectively antagonizes 5-HT(3) receptors. To assess for motor interactions, we injected another group of nine rats with morphine (5.0 mg/kg) or saline in combination with metoclopramide (0.5 and 5.0 mg/kg) or saline and tested the ability of the animals to run on an 80 mm diameter rod rotating at 25 r.p.m. for 30 min. 3. Metoclopramide was not inherently analgesic or antihyperalgesic, but the highest dose of metoclopramide (5.0 mg/kg) enhanced the analgesic and antihyperalgesic effects of morphine. Neither dose of ondansetron was analgesic or antihyperalgesic or enhanced the antinociceptive actions of morphine. 4. Only the high dose of metoclopramide compromised running performance when administered with saline. However, coadministering morphine with metoclopramide (both doses) decreased motor performance. 5. Therefore, metoclopramide, possibly through its actions on D2 receptors and not 5-HT(3) receptors, enhances the analgesic and antihyperalgesic effects of morphine, but morphine exacerbates metoclopramide-induced motor dysfunction in rats.     

Biochemical studies support the assumption that dopamine plays a minor role in the EEG effects of nicotine

In a previous study, it was shown that a moderate dose of nicotine (0.2 mg/kg SC) produced a desynchronization in the EEG and a decrease of power which was not antagonized by blockade of D₁-like dopamine receptors, although this EEG pattern seemed to be characteristic for activation of D₁-like rather than D₂-like receptors. This seemed surprising, since nicotine is known to enhance dopaminergic neurotransmission in the basal ganglia. Since there is a strong reciprocal connection between the cortex and the striatum, dopaminergic effects on the striatum should lead to alterations in the cortical EEG. Therefore, the release of dopamine was studied in the striatum by using microdialysis in awake rats, and in parallel studies, the EEG was studied after administration of a larger dose of nicotine (0.4 mg/kg SC). This is a dose which does not induce toxic side effects. This dose produced a desynchronization in the EEG and a decrease of power. The increase in extracellular dopamine in the striatum was very moderate (by about 30%) and of shorter duration than the EEG effect. Therefore, activation of striatal dopaminergic neurotransmission does not seem to be relevant for the EEG effect studied. Received: 7 July 1996 /Final version: 15 September 1996     

α-Flupenthixol increases slow-wave sleep in rats: Effect of dopamine receptor blockade

α-Flupenthixol (0.2 mg/kg, i.p.). a dopamine receptor blocker, significantly increased slow-wave sleep and decreased wakefulness in rats when administered either at the onset of a 12-hr light period or a 12-hr dark period. The same dose of the drug strongly antagonized the dopamine-mediated stereotypy produced by an injection of apomorphine (1 mg/kg, i.p.) for at least 9-hr, indicating that dopamine receptors were blocked throughout most of the recording session. The results suggest a relationship between the blockade of dopamine receptors and the increase of slow-wave sleep time.     

Acute amphetamine and/or phencyclidine effects on the dopamine receptor specific binding in the rat brain

Psychotic-like behaviour was induced in rats with a single i.p. injection of AMPH (20 mg/kg b.w.) and/or PCP (10 mg/kg b.w.). The D₁ and D₂ dopamine receptor (DAR) specific binding of [³H]SCH 23390 and [³H]spiperone, respectively, during the 120 min period upon the treatment was examined on cryosections using computerized scanning and image analysis. AMPH, alone or in combination with PCP, induced a transient decrease of the D₁ receptor specific binding in the striatum (30 min; AMPH, −18%; AMPH+PCP, −31%) and nucleus accumbens (30 min; AMPH, −30%; AMPH+PCP, −40%), which was completely abolished at the 120 min point. Only AMPH persistently elevated nigral D₁ receptor specific binding. PCP-induced striatal and accumbal D₁ receptor down-regulation was intensive throughout the 120 min period, while in the s. nigra it was non-significant. A significant increase of the D₂ receptor specific binding was observed only 30 min after the treatment in striatum (AMPH, 15%; PCP, 16%; AMPH+PCP, 13%) and n. accumbens (AMPH, 16%). These alterations of DAR specific binding may reflect a regulation of the DAR and the changes in nigrostriatal and mesolimbic DA-ergic neurotransmission during an intensive drug-induced psychotic-like behavioral expression.     

左旋千金藤啶碱对外周血管多巴胺DA_1和DA_2受体亚型的作用

用家兔离体血管环方法，研究左旋千金藤啶碱（ｌＳＰＤ）对外周血管ＤＡ１和ＤＡ２受体亚型的作用。结果表明，ｌＳＰＤ使ＤＡ１受体激动剂ＦＯＤＡ诱发的肾、肺和肠动脉以及ＤＡ２受体激动剂ＰＢＤＡ诱发的肠和股动脉舒张反应的量效曲线非平行右移，最大反应（Ｅｍａｘ）降低，均呈非竞争性拮抗；ｌＳＰＤ本身还可使肾和肺血管产生轻度的浓度依赖性舒张反应，表现为ＤＡ１受体激动剂的作用特性。提示ｌＳＰＤ为外周血管ＤＡ１和ＤＡ２受体的混合性阻滞剂并兼有ＤＡ１受体部分激动剂的双重作用特性。     

The chemical basis for the blockade of the D-1 dopamine receptor by SCH 23390

SCH 23390 (R(+)-7-chloro-8-hydroxy-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1H-3 -benzazepine) is a potent, relatively selective antagonist of the D-1 dopamine receptor ( Iorio et al., J. Pharmacol. Exp. Ther. 226, 462). Because SKF 75670, the 7-OH analogue of SCH 23390, is a partial D-1 agonist, we conclude that the 7-Cl substituent of SCH 23390 contributes to its D-1 antagonist activity. Because SKF 83509, the desmethyl analogue of SCH 23390, is a selective D-1 antagonist, we conclude that the N-methyl substituent of SCH 23390 is not essential for its D-1 antagonist activity.