Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons
File(s)11171.full.pdf (5.41 MB) Uygun et al.2016.J Neurosci (in press).pdf (3.94 MB)
Published version
Accepted version
Author(s)
Type
Journal Article
Abstract
Zolpidem, a GABAA 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 α2 and/or α3 subunit-containing receptors. Compared with natural NREM sleep, zolpidem also decreases the EEG power, an effect that depends on α1 subunit-containing receptors, and which may make zolpidem-induced 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 GABAA receptor γ2 subunit gene are zolpidem-insensitive. Using these mice, GABAA receptors in the frontal motor neocortex and hypothalamic (tuberomammillary nucleus) histaminergic-neurons of γ2I77 mice were made selectively sensitive to zolpidem by genetically swapping the γ2I77 subunits with γ2F77 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 GABAA 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.
Date Issued
2016-11-02
Online Publication Date
2016-11-02
Date Acceptance
2016-08-17
ISSN
0270-6474
Publisher
Society for Neuroscience
Start Page
11171
End Page
11184
Journal / Book Title
Journal of Neuroscience
Volume
36
Issue
44
Copyright Statement
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0).
Source Database
manual-entry
Sponsor
Medical Research Council (MRC)
Biotechnology and Biological Sciences Research Council (BBSRC)
Wellcome Trust
Grant Number
G0901892
BB/K018159/1
107841/Z/15/Z
Subjects
GABA-A receptor
histamine
insomnia
sleep
tuberomammillary nucleus
zolpidem
Neurology & Neurosurgery
Medical And Health Sciences
Psychology And Cognitive Sciences
Publication Status
Published