Effects of three Benzodiazepines (Nitrazepam, Flunitrazepam and Bromazepam) on Sleep of Normal Subjects, Studied with an Automatic Sleep Scoring System

Gaillard, J.-M.; Schulz, Pierre; Tissot, R

doi:10.1055/s-0028-1094383

Cited by 76 publications

(34 citation statements)

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“…The 12-h values of NBA after Veh were the same in both genotypes and are in the range of those reported previously in mice (18)(19)(20)(21)(22). The discrepancy between the increase of sleep continuity and the reduction of power in the lower EEG frequencies is consistent with the findings in humans, where an acute dose of a BZ such as flunitrazepam and midazolam or the BZ-site ligands zopiclone and zolpidem suppressed SWA (9,10,13,15,24,25) with a concomitant reduction in movement activity (9,24,26). Under conditions of enhanced physiological sleep pressure sleep fragmentation is low, and in the rat the SWA increase in NREM sleep is negatively correlated with NBA (27).…”

Section: Discussionsupporting

confidence: 76%

Diazepam-induced changes in sleep: Role of the α1 GABA_Areceptor subtype

Tobler

Kopp

Deboer

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

216

132

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Ligands acting at the benzodiazepine (BZ) site of ␥-aminobutyric acid type A (GABAA) receptors currently are the most widely used hypnotics. BZs such as diazepam (Dz) potentiate GABAA receptor activation. To determine the GABAA receptor subtypes that mediate the hypnotic action of Dz wild-type mice and mice that harbor Dz-insensitive ␣1 GABAA receptors [␣1 (H101R) mice] were compared. Sleep latency and the amount of sleep after Dz treatment were not affected by the point mutation. An initial reduction of rapid eye movement (REM) sleep also occurred equally in both genotypes. Furthermore, the Dz-induced changes in the sleep and waking electroencephalogram (EEG) spectra, the increase in power density above 21 Hz in non-REM sleep and waking, and the suppression of slow-wave activity (SWA; EEG power in the 0.75-to 4.0-Hz band) in non-REM sleep were present in both genotypes. Surprisingly, these effects were even more pronounced in ␣1(H101R) mice and sleep continuity was enhanced by Dz only in the mutants. Interestingly, Dz did not affect the initial surge of SWA at the transitions to sleep, indicating that the SWA-generating mechanisms are not impaired by the BZ. We conclude that the REM sleep inhibiting action of Dz and its effect on the EEG spectra in sleep and waking are mediated by GABAA receptors other than ␣1, i.e., ␣2, ␣3, or ␣5 GABAA receptors. Because ␣1 GABAA receptors mediate the sedative action of Dz, our results provide evidence that the hypnotic effect of Dz and its EEG ''fingerprint'' can be dissociated from its sedative action.F ast synaptic inhibition in the mammalian central nervous system is largely mediated by activation of ␥-aminobutyric acid type A (GABA A ) receptors. GABA A receptors are heteromeric membrane proteins that operate as GABA-gated ion channels. Most GABA A receptors are composed of ␣, ␤, and ␥ 2 subunits with a pentameric stoichiometry (1). GABA A receptor function can be enhanced by allosteric modulators, e.g., benzodiazepines (BZ), barbiturates, and neurosteroids. This enhancement of neuronal inhibition by GABA is one of the most powerful therapeutic strategies for treatment of central nervous system diseases such as sleep disturbances, anxiety disorders, muscle spasms, and seizure disorders (2). Classical BZ like diazepam (Dz) bind to GABA A receptors that contain the ␣ subunits ␣1, ␣2, ␣3 or ␣5, hereafter called ␣1, ␣2, ␣3, or ␣5 GABA A receptors, respectively (3). GABA A receptors containing the ␣4 or ␣6 subunits are insensitive to Dz. The ␣ subunits show distinct patterns of distribution in the brain (4).The ␣1 GABA A receptors represent Ϸ60% of all Dz-sensitive GABA A receptors in the brain and are found mainly in the cerebral and cerebellar cortex, thalamus, and pallidum (4). To assess the functions of this most prevalent receptor subtype in the pharmacological spectrum of Dz, a point-mutated knock-in mouse line, [␣1(H101R)], in which the ␣1 GABA A receptors are insensitive to Dz, has been developed (5, 6). These mice represent a useful tool to distinguish between Dz acti...

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Section: Discussionsupporting

confidence: 76%

Diazepam-induced changes in sleep: Role of the α1 GABA_Areceptor subtype

Tobler

Kopp

Deboer

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

216

132

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“…pueden interactuar directamente con los receptores a benzodiacepinas, los cuales ejercen sus efectos a través de la modulación GABAérgica. [21][22][23][24][25] Esto sugiere que la interacción de la melatonina con el sistema GABAérgico podría estar relacionado con la activación de los mecanismos neurofisiológicos de instalación del sueño.…”

Section: Discussionunclassified

Efectos de la melatonina sobre la macro-arquitectura del sueño en pacientes con demencia tipo Alzheimer

et al. 2013

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SUMMARYThe objective of the present study was to evaluate the 5 mg. melatonin effects on the sleep macro-architecture in eight patients with middle to moderate Alzheimer´s disease (DTA). Using the polysomnographic technique (PSG), we made a simple-blind, non-randomized, controlled with placebo study. The PSG was carried out according to the following order: night 1: placebo administration; night 2 and 3: continues melatonin administration. In the first night with melatonin treatment, the sleep latency to the first episode of Stage 2, Delta and REM sleep, was significantly diminished as compared with placebo (≤.05). No significant difference in total time of each sleep stage and sleep efficiency was observed. Nevertheless, a tendency to diminish the total time of nocturnal wake and increase of the total sleep time in the second night with melatonin treatment was observed. We conclude that melatonin can improve sleep in patients with middle to moderate DTA.Key words: Alzheimer, sleep, melatonin. RESUMENEl objetivo del presente estudio fue determinar los efectos de 5 mg. de melatonina de liberación inmediata sobre la macro-arquitectura del sueño en ocho pacientes con diagnóstico de Demencia Tipo Alzheimer (DTA) de media a moderada. Utilizando la técnica polisomnográfica (PSG) se realizó un estudio simple ciego, no aleatorio, controlado con placebo. Los registros PSG se llevaron a cabo de la siguiente manera: Noche 1: administración de placebo; noche 2 y 3: administración continua de melatonina (5 mg). Observamos que el tratamiento con melatonina durante la primera noche de administración disminuyó significativamente la latencia de la fase 2, del sueño de ondas delta y el sueño de MOR al ser comparadas con el placebo (P ≤.05). No se observaron diferencias significativas en el tiempo total de cada fase de sueño; tampoco se observaron diferencias en la eficiencia del sueño en presencia de la melatonina. Sin embargo se observó una tendencia a la disminución del tiempo total de vigilia y un aumento del tiempo total de sueño, principalmente durante la segunda noche de tratamiento. Concluimos que la melatonina puede mejorar el sueño en pacientes con DTA de media a moderada.Palabras clave: Alzheimer, sueño, melatonina. INTRODUCCIÓNLa demencia tipo Alzheimer (DTA) es el principal tipo de demencia que se presenta en personas de la tercera edad. En México afecta al 35% de la población de 65 años de edad y es la cuarta causa principal de muerte en el país, después de las enfermedades del corazón, del cáncer y de la diabetes. 1 Este tipo de demencia inicia aproximadamente a partir de los 55 años de edad, con una pérdida progresiva de la memoria, cambios en la personalidad y comportamiento desinhibido. Asimismo se alteran funciones cognitivas como el lenguaje, el pensamiento abstracto, así como el reconocimiento de personas y lugares.2 En cuanto a las funciones fisiológicas básicas, se ha observado que el sueño se ve afectado en este tipo de demencia. En pacientes con DTA se ha observado disminución o ausencia del sueño Delta, ...

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“…Flunitrazepam (Ro 5-4200) is a new and potent benzodiazepine hypnotic which seems to be similar to nitrazepam in its effects on sleep (Gaillard, Shulz & Tissot, 1973;Kales & Scharf, 1973;Oswald, Lewis, Tagney, Firth & Haider, 1973). As part of its general assessment, the residual effects of this compound were studied in the present experiment: two doses were compared to a placebo on a battery of physiological and psychological tests.…”

Section: Introduction Methodsmentioning

confidence: 99%

Residual effects of flunitrazepam.

Bond¹,

Lader²

1975

Brit J Clinical Pharma

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1Twelve normal subjects were tested on a large battery of tests after a hypnotic dose of flunitrazepam (1 or 2 mg) and a placebo. Psychological tests were given 12 h after the drug and physiological tests 1 2, 15 and 18 h after the drug. 2 The tests included self-ratings of hypnotic effects and mood, the electroencephalogram, the auditory electroencephalographic evoked response, skin conductance, tapping, cardsorting and the symbol copying test. 3 Both doses of flunitrazepam were effective hypnotics according to the ratings, with an anxiolytic effect the following day. The EEG was significantly altered up to 18 h after the drug and the behavioural tests showed a motor impairment 12 h after drug administration. 4 Nearly all changes displayed linear dose-related trends.

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Effects of three Benzodiazepines (Nitrazepam, Flunitrazepam and Bromazepam) on Sleep of Normal Subjects, Studied with an Automatic Sleep Scoring System

Cited by 76 publications

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Diazepam-induced changes in sleep: Role of the α1 GABA_Areceptor subtype

Diazepam-induced changes in sleep: Role of the α1 GABA_Areceptor subtype

Efectos de la melatonina sobre la macro-arquitectura del sueño en pacientes con demencia tipo Alzheimer

Residual effects of flunitrazepam.

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Effects of three Benzodiazepines (Nitrazepam, Flunitrazepam and Bromazepam) on Sleep of Normal Subjects, Studied with an Automatic Sleep Scoring System

Cited by 76 publications

References 0 publications

Diazepam-induced changes in sleep: Role of the α1 GABAAreceptor subtype

Diazepam-induced changes in sleep: Role of the α1 GABAAreceptor subtype

Efectos de la melatonina sobre la macro-arquitectura del sueño en pacientes con demencia tipo Alzheimer

Residual effects of flunitrazepam.

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Product

Resources

About

Diazepam-induced changes in sleep: Role of the α1 GABA_Areceptor subtype

Diazepam-induced changes in sleep: Role of the α1 GABA_Areceptor subtype