GABA and Sleep Molecular, Functional and Clinical Aspects
GABA (gamma-aminobutyric acid) is the main neurotransmitter regulating sleep. The majority of drugs presently in use for the treatment of sleep disorders act by enhancing GABAergic neuronal inhibition. This book brings together many of the world’s leading
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Jaime M. Monti Hanns Mo¨hler
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S. R. Pandi-Perumal
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Editors
GABA and Sleep Molecular, Functional and Clinical Aspects
Editors Prof. Jaime M. Monti Clinics Hospital Montevideo School of Medicine Dept. Pharmacology & Therapeutics Zudanez Street 2833/602/602 11300 Montevideo Uruguay [email protected]
Dr. S.R. Pandi-Perumal Somnogen Inc 1261 College Street Toronto, ON M6H 1C5 Canada [email protected]
Prof. Dr. Hanns Mo¨hler Institute of Pharmacology University of Zurich and Department of Chemistry and Applied Biosciences Swiss Federal Institute of Technology (ETH) Zurich Winterthurerstr. 190 8057 Zu¨rich Switzerland [email protected]
ISBN 978-3-0346-0225-9 e-ISBN 978-3-0346-0226-6 DOI 10.1007/978-3-0346-0226-6 Library of Congress Control Number: 2010935596 # Springer Basel AG 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. For any kind of use, permission of the copyright owner must be obtained. Cover Illustration: Distribution of a1 GABAA receptors shown immunohistochemically in mouse brain. Courtesy of Jean-Marc Fritschy, Institute of Pharmacology, University of Zurich Cover design: deblik, Berlin Printed on acid-free paper Springer Basel AG is part of Springer Science þ Business Media (www.springer.com)
Dedicated to our wives and families
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Foreword
Insomnia has plagued mankind since time immemorial. For a long time, plant remedies were the only pharmacological means of obtaining some relief. The situation changed with the discovery of synthetic hypnotics. The barbiturates were introduced at the beginning of the twentieth century and remained the most popular compounds for 50 years. Their era came to a close with the discovery of the sleep-promoting properties of the benzodiazepines. Currently, we look back on another 50-year period dominated by this class of hypnotics. Benzodiazepines and their analogs have still not relinquished their status as the most widely used sleeppromoting agents. It is interesting that the hypnotic properties of both the barbiturates and the benzodiazepines were discovered by chance and that their mechanism of action remained obscure for a long time. Today we know that they act via the promotion of GABA, the principal inhibitory neurotransmitter in the brain. While the functions of GABA became increasingly clear after the discovery of its role in the central nervous system in the early 1950s, its implication in sleep regulation remained unknown. A major milestone was the identification of the binding site of benzodiazepines by Mo¨hler and Okada in 1977. It soon became obvious that benzodiazepines exert their action by promoting the synaptic release of GABA indirectly by binding to an allosteric site of the receptor complex. Thanks to the recent work of the Mo¨hler team; we know today that their hypnotic action
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