Sleep-Stabilizing Effects of E-6199, Compared to Zopiclone, Zolpidem and THIP in Mice

Alexandre, C; Dordal, Alberto; Aixendri, Ramon; Guzmán, Antonio; Hamon, Michel; Adrien, Joëlle

doi:10.1093/sleep/31.2.259

Cited by 33 publications

(38 citation statements)

References 35 publications

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“…Examples of the primary EEG/EMG recordings for saline-and zolpidem-injected C57BL/6 (␥2F77) and ␥2I77 lox mice are shown in Figure 2. In agreement with previous studies (Kopp et al, 2004;Alexandre et al, 2008), we found that the power of "NREM sleep" produced by zolpidem in C57BL/6J mice was lower than that found in natural NREM sleep. Zolpidem reduced power during NREM sleep (Fig.…”

Section: Zolpidem Does Not Induce Sleep In ␥2i77supporting

confidence: 93%

“…The effect persisted until at least 90 min after injection. These data, reduced sleep latency and prolonged sleep time, are consistent with previous reports on zolpidem's action in C57BL/6J mice (Kopp et al, 2004;Alexandre et al, 2008). By contrast, there was no change in the sleep time above baseline in zolpidem-injected ␥2I77 lox mice (n ϭ 6 paired t test, t (5) ϭ 0.18, p ϭ 0.86; Fig.…”

Section: Zolpidem Does Not Induce Sleep In ␥2i77supporting

confidence: 92%

“…By these measures, zolpidem's key clinical action, reduction of sleep latency, is mimicked by increasing inhibition onto histaminergic neurons. However, the NREM sleep induced by zolpidem in humans and wild-type rodents does not entirely resemble natural sleep because "zolpidem sleep" has diminished power in the EEG compared with natural NREM sleep for frequencies Ͼ5 Hz in rodents (Kopp et al, 2004;Alexandre et al, 2008), and most frequencies in humans (Landolt et al, 2000). It is not clear whether this diminished EEG power is a good or bad feature of zolpidem-induced sleep.…”

Section: Discussionmentioning

confidence: 99%

“…In the United States alone, there were 53.4 million prescriptions for zolpidem in 2010 (Greenblatt and Roth, 2012). The drug decreases sleep latency, the time to the onset of NREM sleep (Arbilla et al, 1985;Gottesmann et al, 1998;Alexandre et al, 2008;Anaclet et al, 2012;Xu et al, 2014). After taking a 10 mg tablet of zolpidem, the average person goes to sleep after ϳ12 min (Greenblatt and Roth, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…After taking a 10 mg tablet of zolpidem, the average person goes to sleep after ϳ12 min (Greenblatt and Roth, 2012). Compared with natural (drug-free) NREM sleep, however, the NREM sleep induced by zolpidem has reduced power in most EEG frequencies (Landolt et al, 2000;Kopp et al, 2004;Alexandre et al, 2008). This reduced power may indicate that zolpidem-induced sleep is suboptimal compared with natural NREM sleep.…”

Section: Introductionmentioning

confidence: 99%

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Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons

Uygun¹,

Z²,

Zecharia³

et al. 2016

J. Neurosci.

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Zolpidem, a GABA A receptor-positive modulator, is the gold-standard drug for treating insomnia. Zolpidem prolongs IPSCs to decrease sleep latency and increase sleep time, effects that depend on ␣2 and/or ␣3 subunit-containing receptors. Compared with natural NREM sleep, zolpidem also decreases the EEG power, an effect that depends on ␣1 subunit-containing receptors, and which may make zolpideminduced sleep less optimal. In this paper, we investigate whether zolpidem needs to potentiate only particular GABAergic pathways to induce sleep without reducing EEG power. Mice with a knock-in F77I mutation in the GABA A receptor ␥2 subunit gene are zolpideminsensitive. Using these mice, GABA A receptors in the frontal motor neocortex and hypothalamic (tuberomammillary nucleus) histaminergic-neurons of ␥2I77 mice were made selectively sensitive to zolpidem by genetically swapping the ␥2I77 subunits with ␥2F77 subunits. When histamine neurons were made selectively zolpidem-sensitive, systemic administration of zolpidem shortened sleep latency and increased sleep time. But in contrast to the effect of zolpidem on wild-type mice, the power in the EEG spectra of NREM sleep was not decreased, suggesting that these EEG power-reducing effects of zolpidem do not depend on reduced histamine release. Selective potentiation of GABA A receptors in the frontal cortex by systemic zolpidem administration also reduced sleep latency, but less so than for histamine neurons. These results could help with the design of new sedatives that induce a more natural sleep.

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Section: Zolpidem Does Not Induce Sleep In ␥2i77supporting

confidence: 93%

Section: Zolpidem Does Not Induce Sleep In ␥2i77supporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons

Uygun¹,

Z²,

Zecharia³

et al. 2016

J. Neurosci.

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A Novel Potent Sleep‐Promoting Effect of Turmeric: Turmeric Increases Non‐Rapid Eye Movement Sleep in Mice Via Histamine H₁Receptor Blockade

Yoon

Lee

et al. 2021

Molecular Nutrition Food Res

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Scope: Turmeric has a broad spectrum of biological properties; however, the sleep-promoting effects of turmeric have not yet been reported. Thus, this study aims to investigate the effect of turmeric on sleep and the molecular mechanism underlying this effect. Methods and Results: Pentobarbital-induce sleep test and sleep-wake profile assessment using recorded electroencephalography are used to evaluate the hypnotic effects of the turmeric extract (TE) compared to diazepam on sleep in mice. Additionally, the molecular mechanism of TE's sleep effect is investigated using ex vivo electrophysiological recordings from brain slices in histamine H 1 receptor (H 1 R) knockout mice. Oral administration of TE and diazepam significantly reduce sleep latency and increase non-rapid eye movement sleep (NREMS) duration without delta activity in mice. Like doxepin, TE inhibits the H 1 R agonist (2-pyridylethylamine dihydrochloride)-induced increase in action potentials in the hypothalamic neurons. In animal tests using neurotransmitter agonists or antagonists, TE effect mimick H 1 R antagonistic effect of doxepin. Additionally, both reduce sleep latency and increase NREMS in wild-type mice, although these effects are not observed in H 1 R knockout mice. Conclusion: TE has a sleep-promoting effect owing to reduction in sleep latency and enhancement of NREMS via H 1 R blockade; therefore, it could be useful in insomnia.

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GABA Receptors and the Pharmacology of Sleep

Wisden

Franks

2017

Handbook of Experimental Pharmacology

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Current GABAergic sleep-promoting medications were developed pragmatically, without making use of the immense diversity of GABA receptors. Pharmacogenetic experiments are leading to an understanding of the circuit mechanisms in the hypothalamus by which zolpidem and similar compounds induce sleep at α2βγ2-type GABA receptors. Drugs acting at more selective receptor types, for example, at receptors containing the α2 and/or α3 subunits expressed in hypothalamic and brain stem areas, could in principle be useful as hypnotics/anxiolytics. A highly promising sleep-promoting drug, gaboxadol, which activates αβδ-type receptors failed in clinical trials. Thus, for the time being, drugs such as zolpidem, which work as positive allosteric modulators at GABA receptors, continue to be some of the most effective compounds to treat primary insomnia.

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Sleep-Stabilizing Effects of E-6199, Compared to Zopiclone, Zolpidem and THIP in Mice

Abstract: Our findings demonstrate that E-6199 may be an effective hypnotic compound that promotes and improves NREMS, without producing EEG side effects, tolerance or withdrawal phenomena, when administered under chronic conditions.

Cited by 33 publications

References 35 publications

Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons

Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons

A Novel Potent Sleep‐Promoting Effect of Turmeric: Turmeric Increases Non‐Rapid Eye Movement Sleep in Mice Via Histamine H₁Receptor Blockade

GABA Receptors and the Pharmacology of Sleep

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Sleep-Stabilizing Effects of E-6199, Compared to Zopiclone, Zolpidem and THIP in Mice

Abstract: Our findings demonstrate that E-6199 may be an effective hypnotic compound that promotes and improves NREMS, without producing EEG side effects, tolerance or withdrawal phenomena, when administered under chronic conditions.

Cited by 33 publications

References 35 publications

Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons

Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons

A Novel Potent Sleep‐Promoting Effect of Turmeric: Turmeric Increases Non‐Rapid Eye Movement Sleep in Mice Via Histamine H1Receptor Blockade

GABA Receptors and the Pharmacology of Sleep

Contact Info

Product

Resources

About

A Novel Potent Sleep‐Promoting Effect of Turmeric: Turmeric Increases Non‐Rapid Eye Movement Sleep in Mice Via Histamine H₁Receptor Blockade