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Modulation of GABA-A receptor function and sleep

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Brickley et al.Curr Opin Physiol revised.Dec 2017.pdfAccepted version3.99 MBAdobe PDFView/Open
Title: Modulation of GABA-A receptor function and sleep
Authors: Brickley, SG
Wisden, W
Franks, NP
Item Type: Journal Article
Abstract: The intravenous general anaesthetics (propofol & etomidate), the barbiturates, steroids (e.g. alphaxalone, allopregnanalone), the benzodiazepines and the widely prescribed ‘sleeping pill’, the imidazopyridine zolpidem, are all positive allosteric modulators (PAMs) of GABAA receptors. PAMs enhance ongoing GABAergic communication between neurons. For treating primary insomnia, zolpidem remains a gold-standard medication — it reduces the latency to NREM sleep with a rapid onset and short half-life, leading to relatively few hangover effects. In this review, we discuss the role of the different GABAA receptor subtypes in the action of sleep-promoting drugs. Certain neuronal hub areas exert disproportionate effects on the brain's vigilance states. For example, injecting GABAA agonists and PAMs into the mesopontine tegmental anaesthesia area (MPTA) induces an anaesthetic-like state. Similarly, by selectively increasing the GABA drive onto arousal-promoting nuclei, such as the histaminergic neurons in the tuberomammillary nucleus, a more natural NREM-like sleep emerges. Some patients suffering from idiopathic hypersomnia have an unidentified GABAA receptor PAM in their cerebral spinal fluid. Treating these patients with benzodiazepine PAM site antagonists improves their symptoms. More knowledge of endogenous GABAA receptor PAMs could provide insight into sleep physiology.
Issue Date: 1-Apr-2018
Date of Acceptance: 21-Dec-2017
URI: http://hdl.handle.net/10044/1/55616
DOI: https://dx.doi.org/10.1016/j.cophys.2017.12.011
ISSN: 2468-8673
Publisher: Elsevier
Start Page: 51
End Page: 57
Journal / Book Title: Current Opinion in Physiology
Volume: 2
Copyright Statement: © 2018 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor/Funder: British Journal of Anaesthesia
Wellcome Trust
Wellcome Trust
Wellcome Trust
Netherlands Organisation for Scientific Research
Funder's Grant Number: BJA/RCoA funding from the 2009
107839/Z/15/Z
107841/Z/15/Z
107841/Z/15/Z
019.161LW.010
Publication Status: Published
Online Publication Date: 2018-01-05
Appears in Collections:Faculty of Natural Sciences