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Sleep and sedative states induced by targeting the histamine and noradrenergic systems

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Title: Sleep and sedative states induced by targeting the histamine and noradrenergic systems
Authors: Yu, X
Franks, N
Wisden, W
Item Type: Journal Article
Abstract: Sedatives target just a handful of receptors and ion channels. But we have no satisfying explanation for how activating these receptors produces sedation. In particular, do sedatives act at restricted brain locations and circuitries or more widely? Two prominent sedative drugs in clinical use are zolpidem, a GABAA receptor positive allosteric modulator, and dexmedetomidine (DEX), a selective α2 adrenergic receptor agonist. By targeting hypothalamic neuromodulatory systems both drugs induce a sleep-like state, but in different ways: zolpidem primarily reduces the latency to NREM sleep, and is a controlled substance taken by many people to help them sleep; DEX produces prominent slow wave activity in the electroencephalogram (EEG) resembling stage 2 NREM sleep, but with complications of hypothermia and lowered blood pressure—it is used for long term sedation in hospital intensive care units—under DEX-induced sedation patients are arousable and responsive, and this drug reduces the risk of delirium. DEX, and another α2 adrenergic agonist xylazine, are also widely used in veterinary clinics to sedate animals. Here we review how these two different classes of sedatives, zolpidem and dexmedetomideine, can selectively interact with some nodal points of the circuitry that promote wakefulness allowing the transition to NREM sleep. Zolpidem enhances GABAergic transmission onto histamine neurons in the hypothalamic tuberomammillary nucleus (TMN) to hasten the transition to NREM sleep, and DEX interacts with neurons in the preoptic hypothalamic area that induce sleep and body cooling. This knowledge may aid the design of more precise acting sedatives, and at the same time, reveal more about the natural sleep-wake circuitry.
Issue Date: 26-Jan-2018
Date of Acceptance: 11-Jan-2018
URI: http://hdl.handle.net/10044/1/55867
DOI: https://dx.doi.org/10.3389/fncir.2018.00004
ISSN: 1662-5110
Publisher: Frontiers Media
Journal / Book Title: Frontiers in Neural Circuits
Volume: 12
Copyright Statement: © 2018 Yu, Franks and Wisden. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Sponsor/Funder: Wellcome Trust
Biotechnology and Biological Sciences Research Council (BBSRC)
Wellcome Trust
Wellcome Trust
Wellcome Trust
UK DRI Ltd
Funder's Grant Number: 094211/Z/10/Z
BB/K018159/1
107839/Z/15/Z
107841/Z/15/Z
107841/Z/15/Z
N/A
Keywords: Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
sedation
NREM sleep
zolpidem
GABA(A) receptor
histamine
alpha 2 adrenergic agonists
dexmedetomidine
xylazine
LOCUS-COERULEUS NEURONS
VENTROLATERAL PREOPTIC NEURONS
SUBUNIT MESSENGER-RNAS
INTENSIVE-CARE UNIT
KNOCK-OUT MICE
BASAL FOREBRAIN
HISTIDINE-DECARBOXYLASE
GENERAL-ANESTHESIA
TUBEROMAMMILLARY NUCLEUS
RAT-BRAIN
GABAA receptor
α2 adrenergic agonists
Publication Status: Published
Article Number: 4
Appears in Collections:Faculty of Natural Sciences



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