Effects of biperiden on sleep at baseline and after 72 h of REM sleep deprivation in the cat

We examined the effects of the muscarinic M1 antagonist biperiden in cats. In the first experiment a dose-response analysis was performed with intraventricular injection (IV ventricle) of biperiden. In the second experiment after REM sleep deprivation cats were injected with either biperiden (0.1 mg/kg) or saline. Biperiden produced a reduction in REM sleep percentage and an increase in REM sleep latency with these high doses. The 0.1 mg/kg biperiden dose, which did not suppress REM sleep at baseline, did reduce the REM sleep rebound. The present study suggests a modulatory role of biperiden on REM sleep regulatory processes. The fact that an effect of biperiden is noted only at the high doses suggests that at these doses the drug is influencing non-M1 receptors. Changes in the sensitivity of these receptors as a result of REM sleep deprivation might explain why a dose of biperiden will reduce REM sleep rebound, while being ineffective in suppressing REM sleep at baseline.     

Effects of nicotine on perceptual speed

Two experiments investigating the effects of nicotine on performance in the inspection time (IT) procedure are reported. Experiment 1 compared ITs in smoking (0.8 mg nicotine cigarette), sham-smoking, and no-smoking conditions. IT was significantly shorter in the smoking condition as compared to both the no-smoking or sham-smoking conditions, suggesting that nicotine enhances early information processing. This result is of particular interest because of the correlation between IT and IQ reported in previous experiments. The nicotine related decrease in IT raises the possibility that nicotine enhances at least a subset of the physiological processes underlying intellectual performance. Experiment 2 examined the persistence of this nicotine related enhancement in IT, and investigated the effects of nicotine across 480 IT trials. Results suggested that ITs derived from the last third of the 480 trials were significantly shorter in the 0.8 mg cigarette condition than in no-smoking condition. The results from these two experiments, taken together with recent work examining the effects of nicotine on the string length measure of AEP waveform complexity and Hick decision time (DT), and studies investigating cognitive functioning and cholinergic system dysfunction in dementia, suggest a role of the cholinergic system in intellectual performance.     

Changes in sleep after acute and repeated administration of nicotine in the rat

Rationale: Acetylcholine clearly plays a role in regulating sleep. This influence may involve nicotinic systems because several studies have demonstrated that nicotine treatment alters sleep. However, the literature that suggests an effect of nicotine treatment on sleep is contradictory, perhaps because different doses and routes of administration were used. Objective: The studies reported here evaluated the effects of several doses of nicotine on REM sleep in the rat. Methods: Male Wistar rats were prepared with a set of sleep recording electrodes and, following habituation to the test chamber, were used in one of three studies: a) a dose-response analysis of an acute dose of nicotine on REM sleep measured during the first 4 h after injection; b) a chronic treatment experiment; or c) a mecamylamine blockade experiment. Results: Acute nicotine administration decreased REM sleep in a dose-dependent fashion; significant effects were observed following injection with the 0.5 and 1.0 mg/kg doses. A decrease in slow wave sleep and an increase in wakefulness were also observed. Mecamylamine by itself did not affect REM sleep, but it blocked the effects on sleep produced by nicotine when given 30 min before a 1 mg/kg dose of nicotine. Rats that had been injected once daily with a 0.1 mg/kg dose of nicotine showed an increase in REM sleep after the third injection, whereas rats that had been chronically treated with a higher dose (0.5 mg/kg) displayed a reduction in REM and total sleep time. Conclusion: These findings argue that the effects of both acute and chronic nicotine treatment on sleep are influenced by the dose of nicotine used. Received: 7 July 1998 / Final version: 9 March 1999     

Subjective and polysomnographic effects of milnacipran on sleep in depressed patients

The effects of milnacipran (50 mg bid) on sleep patterns of eight depressed inpatients, treated for 4 weeks, were studied during the initial (days 1-3) and terminal (days 26-28) treatment periods and compared with those obtained from three sleep recordings performed just prior to the initiation of the treatment. The clinical evolution of patients was evaluated weekly using the MADRS depression scale and the Spiegel and Norris sleep scales. Clinical improvement, shown by a mean reduction of 58% in MADRS scale scores, was accompanied by an improvement of disturbed sleep parameters. From the beginning of treatment, there was an increase in the total duration of sleep and stage II sleep, a decrease in sleep latency and an increase in sleep efficiency. Total REM sleep was not modified although, since there was an increase in total sleep time, the percent REM sleep was significantly reduced. REM latency was increased early in the study, an effect classically associated with antidepressant treatment. This study suggests that milnacipran improves disturbed sleep parameters in depressed patients without any additional disturbance at the onset of treatment.     

Effects of nicotine on head-shakes and tryptophan metabolites

RATIONALE: Nicotine appears to ameliorate the tics of Tourette syndrome. There is evidence that plasma concentrations of the tryptophan metabolite kynurenine may be elevated in this condition. Rodent head-shakes have been proposed as a putative model of Tourette syndrome and are potentiated by kynurenine. OBJECTIVES: To determine the effects of acute and chronic nicotine on mouse head-shakes, and to study whether nicotine influences brain and plasma levels of kynurenine and certain of its further metabolites in this species. METHODS: Behavioural and biochemical studies. RESULTS: Acute (-10 min) administration of (-)-nicotine, or the nicotinic agonist (+)-epibatidine, dose dependently attenuated head-shakes induced by the 5-HT2A/2C receptor agonist +/-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). This attenuation was inhibited by the nicotinic receptor antagonist mecamylamine. Acute nicotine did not affect either spontaneous head-shakes or plasma and brain kynurenine. Fifteen hours after the last of twice daily injections of nicotine (1.6 mg/kg for 7 days), the frequency of spontaneous and DOI-induced head-shakes was significantly potentiated and there was a significant elevation of both plasma and brain kynurenine, although no differences were detected in plasma concentrations of tryptophan, kynurenic acid, 3-hydroxykynurenine or 3-hydroxyanthranilic acid. Brain levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid were also unaffected. In contrast, all these measures were unchanged 15 h after a single nicotine dose (1.6 mg/kg). CONCLUSIONS: The acute studies indicate that head-shakes induced by DOI are indeed inhibited by nicotinic receptor agonists and suggest that this is not a consequence of an increase in kynurenine. While a role for kynurenine or its metabolites in increasing the head-shake rate after chronic nicotine cannot be excluded, alternative explanations included alterations in the expression or functional status of nicotinic receptor components and further work will be required to characterise this effect.     

Effects of rapid tryptophan depletion on mood and urge to drink in patients with co-morbid major depression and alcohol dependence

Rationale Rapid tryptophan depletion (RTD) has been used to study central serotonin function and may therefore be useful in understanding co-morbid alcohol dependence (AD) and major depressive disorder (MDD).Objectives To examine (1) the effect of RTD on mood and urge to drink among patients with AD and MDD and (2) the association of RTD effects with alleles of a functional polymorphism in the gene encoding the serotonin transporter protein.Methods Double-blind, placebo-controlled study, in which 14 treatment responders recruited from one of two placebo-controlled trials of serotonergic antidepressants were enrolled. Patients underwent two day-long sessions, which were either a tryptophan depletion session or a sham session. During each session, mood and urge for alcohol were measured at regular intervals.Results Five hours after RTD, plasma TRP concentrations decreased by 73.1%. There was a significant effect of session on both mood and the urge to drink. Genotype moderated the effect of session on mood, such that, during RTD, individuals homozygous for the long allele reported greater depression than did subjects with one or two copies of the S allele.Conclusions This study provides support for the role of serotonergic neurotransmission in modulating mood and alcohol urges, and underscores the utility of these effects as a phenotype for genetic analysis. These findings may also help to identify alcoholics who are at greatest risk for MDD.     

Enhancement of cocaine-seeking behavior by repeated nicotine exposure in rats

RATIONALE: Drugs with addictive liability have a high probability of co-abuse in many addicts. For example, cocaine users are several times more likely to smoke cigarettes than non-cocaine users, and smoking increases during cocaine use. Previous work has provided evidence that nicotine and cocaine have interactive neurochemical effects, particularly with regard to dopamine (DA) transmission. OBJECTIVES: The present study examined the impact of nicotine treatment on the reinforcement efficacy of self-administered cocaine and non-reinforced responding for cocaine in rats. METHODS: Rats were trained to self-administer cocaine (i.v.) on a progressive ratio (PR) schedule of reinforcement. Self-administration training continued until stable responding was obtained. Acute nicotine pretreatment consisted of a subcutaneous injection (0.15, 0.3 and 0.6 mg/kg) 3 min prior to cocaine access. In the repeated treatment condition, a separate group of animals was given nicotine (0.6 mg/kg, s.c.) 3 min prior to cocaine access for 14 consecutive days. During extinction trials, these animals were injected with nicotine (0.6 mg/kg, s.c.) after 45 min of non-reinforced responding. RESULTS: Acute nicotine treatment produced an inverted U-shaped dose-response function with lower doses increasing and the highest dose decreasing the number of cocaine infusions obtained during a session. Animals treated repeatedly with the highest dose of nicotine showed a significant increase in the number of cocaine infusions by day 8 of nicotine treatment. During extinction sessions when cocaine was not available, injections of nicotine in these animals caused a reinstatement of the previously rewarded lever-press behavior. CONCLUSIONS: These findings indicate that nicotine can facilitate cocaine reinforcement, may contribute to the transition from moderate drug-taking to an escalation of drug intake which is characteristic of addiction, and may trigger relapse.     

Effects on sleep of acetylcholine perfusion of the locus coeruleus of cats

The loci coeruleus of freely moving cats were perfused bilaterally with acetylcholine at a dose of 0.001 μg/μl per min, while the animals were recorded polygraphically. The controls consisted of experiments in which no perfusions were done, and experiments in which the loci coeruleus were perfused bilaterally with saline, 1 μl/min. The acetylcholine produced a sharp inhibition of rapid eye movement (REM) sleep, prolonged the sleep cycle and the REM interval and decreased the number of REM periods and the mean duration of the REM episodes. Total sleep time was increased. This was entirely due to a specific elevation by acetylcholine of deep slow-wave sleep; light slow-wave sleep was not affected. The data support the Hobson-McCarley hypothesis of how the brain controls the REM state, and also suggest that cholinergic stimulation of the locus coeruleus may be important for the shift from REM sleep into slow-wave sleep.     

Effect of clonidine on sleep patterns in man

Summary Clonidine (300 µg orally) increased in man the total duration of sleep and strikingly reduced the duration of REM sleep. Yohimbine (10 mg per os) did not alter the sleep patterns in man but antagonized the effects of clonidine. These results provide evidence that an sympathomimetic mechanism could suppress REM sleep and increased the total duration of sleep.     

Amphetamine effects on recovery sleep following total sleep deprivation

Normal, healthy adult males participated in a sleep deprivation study during which periodic assessments of mood, alertness, cognitive performance, and vital signs were made. After 48 hours of continuous wakefulness, placebo or d-amphetamine (5, 10, 20 mg) was administered orally in a double-blind fashion. Assessments continued for an additional 14 hours at which time the subjects were allowed to sleep. A significant difference in total sleep time was observed with the highest amphetamine group (20 mg) averaging 7·0 hours vs. 8·1 hours for the placebo group. The decrease in total sleep time was due largely to a significant decrease in REM time. The number of REM episodes was not affected by drug. Latency to the first REM episode was decreased by the 5 and 10 mg dose but unchanged by the 20 mg dose of amphetamine. Amphetamine's significant effects on total sleep time and other parameters more than 15 hours after administration indicate a prolonged drug effect.     

莫达非尼对72h快速眼动睡眠剥夺大鼠海马基质金属蛋白酶9和认知功能的影响

目的研究莫达非尼对72 h快速眼动(REM)睡眠剥夺大鼠海马基质金属蛋白酶9(MMP-9)和认知功能的影响。方法将成年雄性SD大鼠随机分为五组(n=6):正常对照组(CC)、环境对照+空间训练组(TC)、空间训练+REM睡眠剥夺组(SD)、SD+莫达非尼200 mg·kg^(-1)·d(-1)·d^(-1)×3 d组(MD)、SD+安慰剂对照组(CMC)。大鼠的空间训练采用Y型迷宫。用改良多平台睡眠剥夺法建立REM睡眠剥夺模型。应用免疫印迹方法测定MMP-9的蛋白质水平。RT-PCR检测MMP-9 mRNA的相对含量。结果TC组比CC组错误反应次数(EN)显著减少(P<0.05),SD组比TC组EN显著增多(P<0.01),CMC组与SD组无显著差别(P>0.05),MD组比CMC组EN显著减少(P<0.01)。TC组比CC组MMP-9蛋白含量显著增高(P<0.01);经72 h睡眠剥夺后,SD组比TC组MMP-9蛋白含量显著增高(P<0.01),而与CMC组比较无显著差异(P>0.05);给予莫达非尼72 h后,MD组比CMC组MMP-9蛋白含量显著降低(P<0.01)。经RT-PCR检测MMP-9 mRNA表达的结果在上述各组中与免疫印迹检测的结果相一致。结论莫达非尼显著提高72 h REM睡眠剥夺大鼠认知功能,可能与其调节MMP-9 mRNA表达有关。     

Effects of vincamine on EEG sleep patterns in man: A pilot study

Summary

Nightly EEG recordings were performed in 8 healthy volunteers after intramuscular injections of placebo and 30?mg vincamine, under double-blind conditions, according to a crossover design. The single dose of vincamine induced a significant decrease in sleep Stage 4. a decrease in REM stages which approached statistical significance, and finally an increase in REM latency only in subjects showing low baseline values of this parameter. The above data confirm the awakening and antidepressant action of vincamine observed in previous studies in both animals and man.     

在猫取消睡眠后莫达非尼和安非他明对睡眠觉醒周期的作用(英文)

目的:对猫正常条件下和取消睡眠后莫达非尼和安非他明对睡眠觉醒周期以及脑皮质电波的作用进行测定。方法:应用水池平台技术取消猫的睡眠。在取消睡眠前或取消睡眠后分别给于猫口服莫达非尼5mg·kg~(-1)、安非他明1mg·kg~(-1)。结果:莫达非尼在取消睡眠前或取消睡眠后引起的觉醒作用相同(8-9h),并且不增加后续睡眠的反弹。相反安非他明在取消睡眠后的觉醒作用持续时间(8h)少于正常条件下引起的觉醒时间(10-12h),引起慢波睡眠和异相睡眠的明显反弹。结论:上述结果提示莫达非尼有效地拮抗嗜睡状态和过度睡眠症状而不引起后续睡眠时间的增加。     

Effects of thienodiazepine derivatives on human sleep as compared to those of benzodiazepine derivatives

The effects of new thienodiazepine derivatives, such as clotiazepam and Y-7131, on normal human sleep were investigated on 5 subjects and compared to those of benzodiazepine derivatives, such as diazepam and nitrazepam. REM sleep was significantly decreased only with 2 mg of Y-7131 and rebound elevation of REM sleep did not follow in recovery 1 and 2 nights. By using partial differential REM deprivation which was designed by us, there was also no rebound elevation of REM sleep noted in recovery 2 night following 2 mg of Y-7131 medication. REM sleep was not suppressed with 15 mg of clotiazepam, 6 mg of diazepam and 10 mg of nitrazepam when compared to the baseline night. With regard to NREM sleep, stage 2 was significantly increased with 15 mg of clotiazepam and 10 mg of nitrazepam, but stage SWS was significantly decreased with 10 mg of nitrazepam.     

Effects of single and multiple doses of dexnafenodone,imipramine and placebo on sleep of young healthy volunteers

The effects on polygraphically recorded sleep of single and repeated doses of dexnafenodone (20 mg daily) were determined in 12 young, healthy subjects, and compared to those of imipramine (75 mg daily: six subjects) and placebo (six subjects). After two adaptation nights, sleep was recorded at baseline (night 0), and after the first (night 1) and last (night 5) evening administration of the study drugs. REM sleep was substantially inhibited in both nights under the two active treatments, whereby the effect appeared immediately. With the exception of slow wave sleep (SWS), which was more reduced in night 1 under imipramine than under dexnafenodone, the other sleep stages were essentially unchanged. Time awake during bed rest increased under both active treatments, with a more rapid increase under dexnafenodone. Dexnafenodone, a potent inhibitor of noradrenaline, and to a lesser degree of serotonin reuptake, induced changes in the pattern of sleep which are comparable to those of non-sedating tricyclic antidepressants. The mode of action as well as the pharmacodynamic profile of dexnafenodone led to the expectation that this new substance will show antidepressive activity on a clinical level.     

Effects of the acute administration of ethanol on the sleep of the rat: a dose-response study.

Seven-hr sleep recordings were performed on rats following intraperitoneal injection of saline or one of four doses of ethanol (1.1, 1.5, 2.0 or 2.5 g/kg). Total minutes of REM sleep and percentage REM sleep were decreased in a dose-dependent manner. Percentage nonREM sleep increased with progressively higher doses. The decrease in REM sleep appeared to be related to a decrease in the number of REM sleep episodes and an increase in the length of the REM-nonREM cycle. Other variables such as mean length of REM sleep episodes and REM sleep efficiency were unchanged. An analysis of the first and second 3.5 hr of the recording showed that ethanol continued to have marked effects on REM and nonREM sleep during the second 3.5 hr, when blood levels were declining. Ethanol produced decreases in sleep latency, but total sleep time was unchanged.     

Effects of veniafaxine in the sleep architecture of rats

 Different venlafaxine doses (1, 5, and 10 mg/kg) and saline solution were administered to ten male Wistar rats (Latin-Square design). Compared with saline, venlafaxine produced a dose-related supression of REM sleep and an increase in wake time while slow wave sleep was reduced. This effect is similar to the one that has been reported with some tricyclic antidepressants. Received: 31 July 1996 / Final version: 5 November 1996     

Studies on the time course and the effect of cholinergic and adrenergic receptor blockers on the stimulus effect of nicotine

This study investigated the stimulus property of nicotine in the rat. The primary objectives of the study were 1. to determine the time course of the nicotine stimulus and its relationship to brain levels of the drug and 2. to determine whether the nicotine stimulus is dependent upon the integrity of specific neurotransmitter systems. A lever choice discrimination was used. After injection of nicotine, depression of one lever in an operant test chamber resulted in food reinforcement according to a variable interval schedule of 15 sec. When saline was administered, the opposite lever was reinforced. A high degree of discriminated responding was observed when either 400 g/kg or 200 g/kg of nicotine was used as a discriminative stimulus. The degree of discrimination decreased as the length of the time period between the injection of nicotine and the test of discrimination was increased. This decline in discrimination was similar to the decline in brain levels of nicotine suggesting that nicotine discrimination is directly related to the concentration of nicotine in the brain. Atropine, mecamylamine, dibenamine, propranolol and -methyl-para-tyrosine (AMPT) were all tested, in a range of doses, for effects upon nicotine discrimination. Of these, only mecamylamine antagonized the nicotine stimulus. These results indicate that the stimulus effect of nicotine is mediated specifically through nicotinic-cholinergic receptors and not muscarinic-cholinergic or adrenergic receptors.A preliminary report of this investigation appeared in the Pharmacologist 15, 452 (1973).     

Effect of temazepam and temazepam-ethanol on sleep

Summary The effects of temazepam 20 mg and temazepam 20 mg plus whisky 100 ml on sleep and performance were investigated in 5 healthy volunteers in comparison with placebo. In the sleep laboratory, after temazepam there was a trend for reduction of sleep latency, stage wake and stage 1 sleep, and for an increase in REM sleep. The addition of alcohol to the regimen reduced the sleep latency still further, and diminished REM sleep. In subjective assessments, temazepam received the highest score for quality of sleep and the temazepam/alcohol combination that for ease of falling asleep. None of the observed changes reached statistical significance. No morning hangover, as measured by effects on wakefulness, performance or affective state, was seen after the combined treatment. Its effect on blood pressure was negligible. It is concluded that the combined administration of temazepam and alcohol in the doses used here does not result in excessive additive, but in moderate pharmacological effects.     

The relationship between changes in REM sleep and clinical improvement in depressed patients treated with amitriptyline

EEG sleep recordings were obtained on consecutive nights from six hospitalized depressed patients before, during, and after treatment with amitriptyline for a total of 370 nights of data, about 85% of all nights of the study. Amitriptyline significantly reduced time spent in rapid eye movement (REM) sleep and prolonged the REM latency throughout the treatment period. Three patients who improved during treatment showed a REM rebound when amitriptyline was discontinued, whereas three patients who did not improve showed no REM rebound.