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TRANSCRIPT
GABA and Sleep
.
Jaime M. Monti l S. R. Pandi-Perumal l
Hanns MohlerEditors
GABA and Sleep
Molecular, Functional and Clinical Aspects
EditorsProf. Jaime M. MontiClinics Hospital MontevideoSchool of MedicineDept. Pharmacology & TherapeuticsZudanez Street 2833/602/60211300 [email protected]
Prof. Dr. Hanns MohlerInstitute of PharmacologyUniversity of Zurich and Department ofChemistry and Applied BiosciencesSwiss Federal Institute of Technology(ETH) ZurichWinterthurerstr. 1908057 [email protected]
Dr. S.R. Pandi-PerumalSomnogen Inc1261 College StreetToronto, ON M6H [email protected]
ISBN 978-3-0346-0225-9 e-ISBN 978-3-0346-0226-6DOI 10.1007/978-3-0346-0226-6
Library of Congress Control Number: 2010935596
# Springer Basel AG 2010This work is subject to copyright. All rights are reserved, whether the whole or part of the material isconcerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcast-ing, 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
.
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 sleep-
promoting agents. It is interesting that the hypnotic properties of both the barbitu-
rates 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 Mohler 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 Mohler team; we know today that their hypnotic action is
mediated principally by the a1GABAA receptor, which is one of the several
receptor subtypes.
Does the unabated popularity of the benzodiazepine receptor agonists imply
that they come close to the ideal sleeping pill? This is not the case, since their
untoward actions limit their use. These include abuse, tolerance, rebound
insomnia, memory impairment, ataxia, and daytime impairment of performance.
Also the sleep EEG does not show the typical features of physiological sleep.
There is no doubt that the introduction of benzodiazepines and their analogs
represented major progress in the treatment of insomnia, since the agents used
previously had a less propitious profile. However, the advances in the last
decades were mainly due to the development of agents with more favorable
vii
pharmacokinetic properties and to their increasingly judicious and circumspect
application in therapy.
The ideal hypnotic would be a compound promoting physiological sleep. Is there
an endogenous sleep promoting substance? The search for such an agent was
initiated at the beginning of the last century by Henri Pieron in France and Kuniomi
Ishimori in Japan. They reported sleep-inducing effects after infusing cerebrospinal
fluid or brain extracts from sleep-deprived dogs into naıve animals. In the mean-
time, a large number of endogenous compounds with sleep-promoting properties
has been identified. They include hormones, prostaglandins, cytokines, and purine
nucleosides. However, none of these agents were shown to play a central role in
physiological sleep regulation. Moreover, a translation from the experimental level
to the clinical level has not occurred.
The approach focusing on neurotransmitters and neuromediators appears to be
more promising. Antagonists at receptors of the serotonin, histamine, and orexine
system and agonists at receptors of the melatonin and GABAA system were shown
in clinical trials to have hypnotic properties. Moreover, some of these drugs
affected the EEG in ways resembling physiological sleep intensification. However,
despite these interesting developments, the predominant position of benzodiazepine
receptor agonists is unlikely to be soon challenged.
In addition to their hypnotic properties, benzodiazepines also have anxiolytic,
anticonvulsant, and central muscle relaxant effects. Moreover, some agents are
used as intravenously administered short-acting anesthetics. This wide range of
actions may hamper their therapeutic use as hypnotics. One way to enhance the
selectivity is to develop agents targeting specific subtypes of the GABAA receptor.
This strategy may lead to advances by allowing an ever more subtle modulation of
the GABA system. In view of such developments, it is most welcome that the
present volume is devoted to the molecular, functional, and clinical aspects of
GABA and sleep. The editors, renowned experts in their field, have compiled an
impressive series of authoritative overviews from experienced basic and clinical
scientists. By providing a bridge between basic physiology and pharmacology,
sleep science, and therapeutics, the volume will be useful to experts and students
from a wide variety of disciplines.
University of Zurich Alexander Borbely
viii Foreword
Preface
The increase in our knowledge of the GABA (g-aminobutyric acid) system in recent
years has led to major advances in our understanding of sleep physiology, sleep
disorders and clinical sleep medicine. The goal of this first edition is to review the
major achievements made in characterizing the role of GABA in the physiology and
pathology of sleep regulation and in identifying GABAergic subsystems which
show potential for novel pharmacological treatments of sleep disorders.
Brain states such as sleep or waking are governed by distinct synchronized
oscillatory neuronal networks which give rise to changing EEG patterns. It has
increasingly been recognized that the sculpting of neuronal rhythms, the control of
neuronal firing and the selection of temporary assemblies of neurons are controlled
by a rich diversity of GABAergic interneurons. In addition, mutual inhibition
between the brain nuclei which promote sleep and the arousal systems is known
to result in switching properties that define waking and sleep states. In this process,
which is driven by homeostatic and circadian influences, GABA neurons play also a
significant role. The evidence reviewed in this volume clearly demonstrates that
GABAergic regulatory control is at the center of sleep physiology, pathophysiology
and therapeutics.
To accommodate the diverse temporal dynamics of GABAergic signaling, a
corresponding diversity of GABA receptors is required on the target cells. Besides
the metabotropic GABAB receptor, the fast-responding ionotropic GABAA recep-
tors are of special relevance in as much as they represent the exclusive target of
benzodiazepine (BZD) drugs. More recently, the discovery of GABAA receptor
subtypes, largely characterized by distinct a subunits, has opened up new opportu-
nities for drug development. For instance, sedation, a common denominator of
GABAA receptor-related hypnotics, is mediated by a1 receptors, while a2 receptors
selectively mediate the anxiolytic action of BZD.
Additionally, our understanding of the pharmacokinetic determinants (absorp-
tion rate, elimination half-life, dosage) of hypnotic drug action has progressed in
parallel with the development and clinical use of a series of BDZ and non-BDZ
hypnotic drugs.
ix
The BDZ derivatives reduce sleep latency, the number of nocturnal awakenings,
and wake time after sleep onset. Increases in total sleep time are related to greater
amounts of stage 2 (intermediate sleep). By contrast, stage 3 and 4 sleep (deep
sleep) and REM sleep (dream sleep) are decreased in patients with chronic primary
insomnia and comorbid insomnia. On the other hand, the non-BZD derivatives
zolpidem, zopiclone, eszopiclone and indiplon, which primarily act selectively at
a1 GABAA receptors, increase total sleep time without reducing slow wave sleep
and REM sleep. Interestingely, the selective extrasynaptic GABA-receptor agonist
gaboxadol increases slowwave sleep, that is, it mimics the effect of sleep deprivation.
The intricate nature of sleep regulation via the GABA system is particularly
apparent in nuclei of the arousal system such as the dorsal raphe nucleus (DRN), the
locus coeruleus and the pontine cholinergic system. In the DRN, local administra-
tion of the GABAA receptor agonist muscimol increases REM sleep, whereas the
local microinjection of serotonin 5-HT1B, 5-HT2A/C, and 5-HT7 receptor agonists
induces the opposite effect. This result has been ascribed to the inhibition of
GABAergic interneurons and the activation of long-projection GABAergic cells,
respectively. GABA also plays a critical neuromodulatory role in the interaction
between pontine noradrenergic and cholinergic systems. Cholinergic mechanisms
are important for REM sleep induction in the pontis oralis and sublaterodorsal
nuclei, and GABAergic modulation of these sites can inhibit or prevent the occur-
rence of REM sleep.
Organization of the First Edition
This volume is divided into three major parts. Part I: Basic Physiology and
Pharmacology; Part II: Sleep Science and Circuitry; and finally, Part III. Hypnotics.
The volume consists of 20 chapters and covers a broad range of topics related to
the basic, pharmacological, and clinical aspects of GABA and sleep.
Part I consists of an overview of the basic pharmacology of the GABAergic
system. The topics covered include the most recent understanding concerning the
pharmacology and physiology of the GABAergic system and its receptor subtypes,
the development of subtype-selective GABAA receptor compounds for the treatment
of insomnia, anxiety and epilepsy, distribution of GABAA receptor subtypes in the
human brain, and finally, the pharmacokinetic determinants of the clinical effects of
benzodiazepine agonists.
Part II is the largest section in this volume and addresses the topic of sleep
circuitries. These include sleep and its modulation by drugs that affect the
GABAA receptor function, subcortical neuromodulation of feedforward and feed-
back inhibitory microcircuits by the reticular activating system, and circadian
regulation of sleep. This section also addresses the role of melatonin in sleep and
the possible involvement of GABAergic mechanisms.
Part III addresses the pathophysiology of sleep disorders, differential diagnosis
of insomnia, and safety and efficacy profiles of various GABAergic drugs, includ-
ing zolpiclone, zolpidem, eszopiclone, zaleplon, and Indiplon.
This volume is intended for pharmacologists, CNS drug discovery scientists,
basic and clinical researchers, psychiatrists, and other general practitioners who
x Preface
seek an overall grasp of the physiology and clinical pharmacology of sleep. It will
be helpful for medical students and graduate students of biomedical and sleep
medicine specialties.
The information presented is based on the most recent sleep literature and
stresses the relevance to clinical medicine and therapeutics. Information about
specific drugs is occasionally repeated in several chapters throughout this volume
by various authors. It is the editors’ hope that this redundancy will be construed as a
benefit.
We welcome communication from our readers concerning this volume and its
organization, and especially concerning any inaccuracies or omissions that remain.
We take full responsibility for any such inaccuracies, and we appreciate having
them drawn to our attention.
In summary, it is our hope that this volume will enable interested scientific and
medical researchers to develop a better understanding of the science and practice of
sleep medicine. We also hope that this volume will generate new ideas that lead to
improvements in the care of patients who suffer from sleep disorders.
Uruguay Jaime M. Monti
Canada S.R. Pandi-Perumal
Switzerland Hanns Mohler
September 2010
Preface xi
.
About the Editors
Jaime M. Monti MD has won many awards for his research, including the Claude
Bernard Award (Clinical Sleep Research) from the Government of France and
the Schering Award for Basic Sleep Research in Germany. He is a member of
the International College of Neuropsychopharmacology, Sleep Research Society
(USA), European Sleep Research Society, and the Argentinian Society of Sleep
Medicine.
S.R. Pandi-Perumal MSc is the President and CEO of Somnogen Inc, a New
York Corporation. An internationally recognized sleep researcher, his interest
focuses on sleep and biological rhythms research.
Hanns Mohler is Emeritus Professor of Pharmacology and former director of the
Swiss National Center of Neuroscience Research and director of the Institute of
Pharmacology of the University and Swiss Federal Institute of Technology (ETH)
Zurich. He is amember of the EuropeanAcademy of Sciences and the SwissAcademy
of Medical Sciences. His research is dedicated to the therapeutic neuroscience
in neurology and psychiatry and includes the discovery of the benzodiazepine receptor
and the functional identification of GABAA receptor subtypes.
xiii
.
Credits and Acknowledgements
This volume owes its final shape and form to the assistance and hard work of many
talented people. Creating a book, which surveys a broadly interdisciplinary field
such as sleep medicine, involves the collaborative scholarship of many individuals.
We express our profound gratitude to the many people who have helped in this
endeavor.
Our sincere appreciation goes to Professor Borbely, who graciously agreed to
write the foreword. The editors also wish to express their sincere appreciation
and owe endless gratitude to all our distinguished contributors for their schol-
arly contribution that facilitated the development of this volume. Our largest
debt obviously goes to our outstanding authors who, regardless of how busy
they were, managed to find time for this project. They, in a most diligent and
thoughtful way, have brought a wide range of interests and disciplines to this
volume.
It is of course a pleasure to thank our many colleagues who commented on
individual chapters and have provided invaluable suggestions: we are indebted to
them all.
We would like to thank the secretarial and administrative staffs of our respective
institutions, for helping us to stay on task and for their attention to detail.
We acknowledge with gratitude the work of the editorial department of
Birkhauser-Verlag. We are especially indebted to Dr. Beatrice Menz, Senior Com-
missioning Editor – Medicine, who was an enthusiastic and instrumental supporter
from the start. We also thank the Birkhauser-Verlag production department collea-
gues for their meticulous work.
A very special debt of gratitude and appreciation is owed to the several
reviewers who made numerous helpful suggestions during the conception of
this project.
Last, but certainly not the least, we are most grateful to our wives and families,
who provided invaluable support.
xv
To all the people who contributed to this volume, we express our sincere
gratitude.
Uruguay Jaime M. Monti
Canada S.R. Pandi-Perumal
Switzerland Hanns Mohler
xvi Credits and Acknowledgements
Contents
Part I Basic Physiology and Pharmacology
Physiology and Pharmacology of the GABA System: Focus on GABA
Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Hanns Mohler
Development of Subtype-Selective GABAA Receptor Compounds
for the Treatment of Anxiety, Sleep Disorders and Epilepsy . . . . . . . . . . . . . . 25
John R. Atack
Distribution of GABAA Receptor Subunits in the Human Brain . . . . . . . . . 73
H.J Waldvogel, K. Baer, and R.L.M. Faull
Pharmacokinetic Determinants of the Clinical Effects
of Benzodiazepine Agonist Hypnotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
David J. Greenblatt
Part II Sleep Science and Circuitry
Sleep and Its Modulation by Substances That Affect GABAA
Receptor Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Axel Steiger
Subcortical Neuromodulation of Feedforward and Feedback
Inhibitory Microcircuits by the Reticular Activating System . . . . . . . . . . . . 147
J. Josh Lawrence
Function of GABAB and r-Containing GABAA Receptors
(GABAC Receptors) in the Regulation of Basic and Higher
Integrated Sleep-Waking Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Claude Gottesmann
xvii
Interactions Between GABAergic and Serotonergic Processes
in the Dorsal Raphe Nucleus in the Control of REM Sleep
and Wakefulness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Jaime M. Monti
GABA-ergic Modulation of Pontine Cholinergic and Noradrenergic
Neurons for REM Sleep Generation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Dinesh Pal and Birendra Nath Mallick
Involvement of GABAergic Mechanisms in the Laterodorsal and
Pedunculopontine Tegmental Nuclei (LDT–PPT) in the Promotion
of REM Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Pablo Torterolo and Giancarlo Vanini
GABAergic Mechanisms in the Ventral Oral Pontine Tegmentum:
The REM Sleep-Induction Site – in the Modulation
of Sleep–Wake States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Fernando Reinoso-Suarez, Carmen de la Roza, Margarita L. Rodrigo-Angulo,
Isabel de Andres, Angel Nunez, and Miguel Garzon
The Role of GABAergic Modulation of Mesopontine Cholinergic
Neurotransmission in Rapid Eye Movement (REM) Sleep . . . . . . . . . . . . . . . 253
Gerald A. Marks and Christopher M. Sinton
Melatonin and Sleep: Possible Involvement of GABAergic
Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
Daniel P. Cardinali, S.R. Pandi-Perumal, Lennard P. Niles,
and Gregory M. Brown
GABA Involvement in the Circadian Regulation of Sleep . . . . . . . . . . . . . . . . 303
J. Christopher Ehlen, Daniel L. Hummer, Ketema N. Paul,
and H. Elliott Albers
Part III Hypnotics
Pathophysiology of Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Thomas C. Wetter, Pierre A. Beitinger, Marie E. Beitinger,
and Bastian Wollweber
Insomnia: Differential Diagnosis and Current Treatment Approach . . . . 363
J.F. Pagel and Gerald Kram
xviii Contents
Zolpidem in the Treatment of Adult and Elderly Primary
Insomnia Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
Luc Staner, Francoise Cornette, Sarah Otmani, Jean-Francois Nedelec,
and Philippe Danjou
Efficacy and Safety of Zopiclone and Eszopiclone in the Treatment
of Primary and Comorbid Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Jadwiga S. Najib
Indiplon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
David N. Neubauer
Polysomnographic and Clinical Assessment of Zaleplon
for the Treatment of Primary Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Joseph Barbera and Colin Shapiro
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
Contents xix
.
List of Contributors
H. Elliott Albers Center for Behavioral Neuroscience (CBN), Regents Professor,
Neuroscience Institute, Georgia State University, P.O. Box 5030, Atlanta, GA
30302-5030, USA, [email protected]
John R. Atack Department of Neuroscience, Johnson & Johnson Pharmaceutical
Research and Development, Building 020, Room 1A6, Turnhoutseweg 30, 2340
Beerse, Belgium, [email protected]
Kristin Baer Molecular Neuroscience, School of Medicine, Institute of Life
Science, Swansea University, Singleton Park, Swansea SA2 8PP, UK, k.baer@
swansea.ac.uk
Joseph Barbera The Youthdale Child and Adolescent Sleep Centre, Department
of Psychiatry, University of Toronto, Toronto, ON, Canada, joseph.barbera@
utoronto.ca
Marie E. Beitinger Clinical Sleep Research, Max Planck Institute of Psychiatry,
Kraepelinstrasse 10, 80804 Munich, Germany, [email protected]
Pierre A. Beitinger Clinical Scientist, Clinical Sleep Research, Max Planck
Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany, beitinger@
mpipsykl.mpg.de
Gregory M. Brown Professor Emeritus, Dept of Psychiatry, Faculty of Medicine,
University of Toronto, Mailing: 422-100 Bronte Road, L6L 6L5 Oakville, Toronto,
ON, Canada, [email protected]
Daniel P. Cardinali Department of Teaching and Research, Faculty of Medical
Sciences, Pontificia Universidad Catolica Argentina, Av. Alicia Moreau de
Justo 1500, 4o piso, 1107 Buenos Aires, Argentina, [email protected];
Francoise Cornette Forenap Pharma, 27 rue du 4eme R.S.M., 68250 Rouffach,
France
Philippe Danjou Forenap Pharma, 27 rue du 4eme R.S.M., 68250 Rouffach,
France
xxi
J. Christopher Ehlen Circadian Rhythms and Sleep Disorders Program, Assistant
Professor, Neuroscience Institute, Morehouse School of Medicine, 720 Westview
Drive, SW MRC F14, Atlanta, GA 30310-1495, USA, [email protected]
Isabel de Andres Departamento de Anatomıa Histologıa y Neurociencia. Facultad
de Medicina, Universidad Autonoma de Madrid, Arzobispo Morcillo 4, Madrid
28029, Spain, [email protected]
Carmen de la Roza Departamento de Anatomıa Histologıa y Neurociencia.
Facultad de Medicina, Universidad Autonoma de Madrid, Arzobispo Morcillo 4,
Madrid, 28029, Spain, [email protected]
Richard L.M. Faull Department of Anatomy with Radiology and Centre for Brain
Research, Faculty of Medical and Health Sciences, University of Auckland, Private
Bag 92019, Auckland 1023, New Zealand, [email protected]
Miguel Garzon Departamento de Anatomıa Histologıa y Neurociencia. Facultad
de Medicina, Universidad Autonoma de Madrid, Arzobispo Morcillo 4, Madrid
28029, Spain, [email protected]
Claude Gottesmann Department de Biologie, Faculte des Sciences, Universite de
Nice-Sophia Antipolis, Mail: Cl. Gottesmann, 22 parc Lubonis, 06000 Nice,
France, [email protected]
David J. Greenblatt Department of Pharmacology and Experimental Therapeu-
tics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA
02111, USA, [email protected]
Daniel L. Hummer Assistant Professor, Department of Psychology, Morehouse
College, Atlanta, GA, USA, [email protected]
Jerrold A. Kram 985 Atlantic Ave, Suite 250, Alameda, CA 94501, USA,
J. Josh Lawrence COBRE Center for Structural and Functional Neuroscience,
Department of Biomedical and Pharmaceutical Sciences, The University of
Montana, 32 Campus Drive, Skaggs Building 385/391, Missoula, MT 59812-
1552, USA, [email protected]
Birendra Nath Mallick School of Life Sciences, Jawaharlal Nehru University,
New Delhi 110067, India, [email protected]
Gerald A. Marks Veterans Affairs Medical Center, MC# 151, 4500 South
Lancaster Road, Dallas, TX 75216, USA; Department of Veterans Affairs, North
Texas Health Care System and Departments of Psychiatry, The University of Texas
Southwestern Medical Center, Dallas, TX, USA, [email protected]
Hanns Mohler Institute of Pharmacology, University of Zurich and Department of
Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH)
Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland, [email protected]
xxii List of Contributors
JaimeM.Monti Department of Pharmacology and Therapeutics, Clinics Hospital,
School of Medicine, 2833/602 Zudanez Street, Montevideo 11300, Uruguay,
Jadwiga Najib Professor of Pharmacy Practice, Arnold and Marie Schwartz
College of Pharmacy, Division of Pharmacy Practice, Long Island University, 5th
Floor, 75 DeKalb Avenue, Brooklyn, New York 11201, [email protected]
Jean-Francois Nedelec Forenap R&D, 27 rue du 4eme R.S.M, 68250, Rouffach,
France
David N. Neubauer Johns Hopkins Bayview Medical Center, 4940 Eastern
Avenue, Box 151, Baltimore, MD 21224, USA, [email protected]
Lennard P. Niles Faculty of Health Sciences, Department of Psychiatry and
Behavioural Neurosciences, McMaster University, Hamilton, ON L8N 3Z5,
Canada, [email protected]
Angel Nunez Departamento de Anatomıa Histologıa y Neurociencia. Facultad de
Medicina, Universidad Autonoma de Madrid, Arzobispo Morcillo 4, Madrid
28029, Spain, [email protected]
Sarah Otmani Forenap R&D, 27 rue du 4eme R.S.M, 68250, Rouffach, France
James F. Pagel Rocky Mountain Sleep Disorders Center, Pueblo CO 81003, USA,
Dinesh Pal Department of Anesthesiology, University of Michigan, 1150 West
Medical Center Drive, 7433 Medical Sciences Building 1, Ann Arbor, MI 48109-
0615, USA, [email protected]
S.R. Pandi-Perumal President and Chief Executive Officer, Somnogen Inc, Tor-
onto, ON M6K 2V9, Canada, [email protected]
Ketema N. Paul Circadian Rhythms and Sleep Disorders Program, Neuroscience
Institute, Morehouse School of Medicine, Atlanta, GA, USA, [email protected]
Fernando Reinoso-Suarez Departamento de Anatomıa Histologıa y Neurociencia.
Facultad de Medicina, Universidad Autonoma de Madrid, Arzobispo Morcillo 4,
Madrid 28029, Spain, [email protected]
Margarita Lucia Rodrigo-Angulo Departamento de Anatomıa Histologıa y
Neurociencia. Facultad de Medicina, Universidad Autonoma de Madrid, Arzobispo
Morcillo 4, Madrid 28029, Spain, [email protected]
Colin M. Shapiro University Health Network, Department of Psychiatry and
Ophthalomology, University of Toronto, Toronto, ON, Canada, susanne Suzanne.
List of Contributors xxiii
Christopher M. Sinton Department of Internal Medicine, The University of
Texas Southwestern Medical Center, Dallas, TX USA, christopher.sinton@
utsouthwestern.edu
Luc Staner Unite d’Exploration des Rythmes Veille-Sommeil, Centre Hospitalier
de Rouffach, France and Head of Scientific Information and Communication,
Forenap FRP, 27 rue du 4eme RSM, B.P. 27, 68250 Rouffach, France, luc.
Axel Steiger Department of Psychiatry, Max Planck Institute of Psychiatry,
Kraepelinstrasse 2-10, 80804 Munich, Germany [email protected]
Pablo Torterolo Department of Physiology, School of Medicine, Universidad de
la Republica, General Flores 2125, 11800 Montevideo, Uruguay, ptortero@fmed.
edu.uy
Giancarlo Vanini Department of Anesthesiology, School of Medicine, University
of Michigan, 48109 Ann Arbor, MI USA, [email protected]
H.J. Waldvogel Department of Anatomy with Radiology and Centre for Brain
Research, Faculty of Medical and Health Sciences, University of Auckland, Private
Bag 92019, Auckland 1023, New Zealand, [email protected]
Thomas C. Wetter Department of Sleep Medicine, Clinic of Affective Disorders
and General Psychiatry, Psychiatric University Hospital Zurich, Lenggstrasse 31,
CH 8032 Zurich, Switzerland, [email protected]
Bastian Wollweber Clinical Sleep Research, Max Planck Institute of Psychiatry,
Kraepelinstrasse 10, 80804 Munich, Germany, [email protected]
xxiv List of Contributors
Part IBasic Physiology and Pharmacology
Physiology and Pharmacology of the GABA
System: Focus on GABA Receptors
Hanns Mohler
Abstract Wake and sleep states have long been known to be implemented
by distinct synchronized neural oscillations. Changes in the pattern of neural
oscillations have recently been recognized to be largely due to the impact of
GABAergic regulation. Inhibitory interneurons are the main players in sculpting
neuronal rhythms, controlling spike timing, selecting network assemblies and
implementing brain states. A rich diversity of GABAergic interneurons imprints
its activity, mediated through a comparably rich diversity of GABAA receptors.
Pharmacologically, there is a clear division of labor among GABAA receptor
subtypes. Sedation, a common denominator of GABAA receptor-related hypnotics,
is mediated via a1GABAA receptors. However, the hypnotic EEG finger print of
diazepam is largely linked to a2GABAA receptors, pointing to two distinct receptor
systems for sleep regulation. Anxiety is a major impairment of sleep, which can be
selectively controlled by a2 GABAA receptor modulators. Chronic pain, another
frequent sleep impediment can be alleviated by a2/GABAA receptor modulators.
Chronic pain, another frequent sleep impediment can be alleviated by a2/a3GABAA
receptor modulators. Finally, cognitive deficits can be pharmacologically addressed
by partial inverse agonists of a5GABAA receptors. Thus, in the future, it is
conceivable that disease-specific hypnotics could be developed by combining the
modulation of suitable GABAA receptor subtypes. GABAB receptors play a phar-
macological role as target of g-hydroxybutyrate, which is frequently used in the
treatment of narcolepsy. Thus, as our understanding of GABAergic deficits in sleep
disturbances increases, the strategic targeting of GABA receptor subtypes may
represent a new approach for the personalized pharmacological management of
sleep disorders.
H. Mohler
Institute of Pharmacology, University of Zurich and Department of Chemistry and Applied
Biosciences Swiss Federal Institute of Technology (ETH), Zurich, Winterthurerstr. 190,
CH-8057 Z€urich, Switzerlande-mail: [email protected]
J.M. Monti et al. (eds.), GABA and Sleep,DOI 10.1007/978-3-0346-0226-6_1, # Springer Basel AG 2010
3
1 Neural Oscillations and GABA
Over the past several decades, GABAergic inhibition has been recognized to play a
central role in the brain circuitries that regulate the daily cycles of sleep and
wakefulness [1]. Mutual inhibition between the arousal and sleep-promoting cir-
cuitry results in switching properties that define wake and sleep states. This process
is under homeostatic influence (“need to sleep”) and circadian drive [2]. The
present review focuses on the physiology and pharmacology of GABA receptors
and their ligands in the promotion of sleep.
Sleep promotion through the ventrolateral preoptic area (VLPO) of the anterior
hypothalamus is effectuated by neurons that produce GABA and the inhibitory
neuropeptide galanin. They project to the aminergic ascending arousal system of the
brain stem (coeruleus and raphe) and the histaminergic wake-promoting tuberomam-
millary nucleus (TMN) of the hypothalamus. VLPO neurons also receive afferents
from each of the major monoaminergic systems. Thus, the VLPO can be inhibited by
the very arousal systems that it inhibits during sleep. These circuits contain mutually
inhibitory elements and contribute to the “flip–flop switch” between wake and sleep
under the influence of yet unidentified homeostatic factors (somnogens) [1, 3, 4].
Different brain states are associated with distinct synchronized oscillatory neural
activities, which give rise to distinct EEG patterns. Alpha waves are prominent
when the eyes are closed and subjects are in a relaxed state (“cortical idling”). Sleep
and the transition between different stages of sleep are characterized by different
EEG patterns [4], which reflect the ability of cortical neurons to oscillate synchro-
nously in various frequency bands such as b, d, or theta-waves or spindles. The
computational advantage of synchronized neural oscillations is that it orchestrates
the spike firing of neurons in discrete time windows. The assumption is that an
activity that is synchronized with millisecond precision summates more effectively
than a nonsynchronized activity and thereby favors processing of the selected
responses or brain states.
In the distributive architecture of the brain, functionally related areas require a
mechanism to communicate. Synchronized oscillations are thought to be the major
mechanism to coordinate interactions of large numbers of neurons that are
distributed within or across different specialized brain areas. The best studied
example of a transient synchronization of neural discharges is the gamma frequency
band (30–80 Hz), which is thought to be a neuronal correlate of a cognitive content
(e.g., in sensory perception) or an executive program (e.g., motor response), in
which the synchronization is presumed to link the neural networks involved.
Complex brains have developed special mechanisms for the grouping of princi-
pal cells into temporal coalitions of local or distant networks. It largely consists of
the inhibitory neuron “clocking” network [5] i.e. GABAergic interneurons, which
temporally regulate pyramidal cell activity (Fig. 1). In cortical circuits, the inhibi-
tory neurons control spike timing of principal cells, sculpt neuronal rhythms, select
cell assemblies, and implement brain states. To achieve this regulatory control of
the relatively uniform pyramidal cells, GABA interneurons display a rich diversity,
4 H. Mohler
which imprints a GABAergic conductance matrix on pyramidal cells. The inter-
neurons innervate discrete subcellular domains of pyramidal cells such as the soma,
the axon initial segment, or dendrites, and act in discrete time windows to achieve
the computational sophistication [6]. Since cortical interneurons receive not only
local input but are also under modulatory control from subcortical areas such as
brain stem nuclei and hypothalamus, the wake-sleep regulation areas can impinge
on the oscillatory patterns by modulating GABAergic control.
2 Role of GABA Receptors
The dynamics of GABAergic control in different frequencies require GABA
receptors, which are able to faithfully transmit the temporal dynamics of transmitter
signaling. GABA receptors are differentially expressed to suit the particular neural
circuit and are structurally diverse to accommodate the temporal demands. There
are two major types of GABA receptors, ionotropic GABAA receptors and metabo-
tropic GABAB receptors. GABAA receptors are pentameric ligand-gated chloride
ion channels, which mediate the major inhibitory responses and act prominently in
oscillation control (7–9). GABAB receptors are dimeric G-protein-coupled
Fig. 1 Spatiotemporal interaction between pyramidal cells and several classes of interneurons
during network oscillations, shown as a schematic summary of the main synaptic connections of
pyramidal (P, blue), PV-expressing basket (green), axo-axonic (red), bistratified (brown), O-LM(violet), and three classes of CCK-expressing interneurons (yellow). The firing probability histo-
grams (right part) show that interneurons innervating different domains of pyramidal cells fire
with distinct temporal patterns during theta and ripple oscillations, and their spike timing is
coupled to field gamma oscillations to differing degrees. The same somatic and dendritic domains
receive differentially timed input from several types of GABAergic interneuron Ach, acetylcho-
line. The figure is taken from [6]
Physiology and Pharmacology of the GABA System 5
receptors, which largely affect excitatory and inhibitory neurotransmitter release.
Both receptors, but GABAA receptors in particular, have been recognized to be
crucial for an understanding of the physiology and pathology of major brain
systems and for the development of drugs for a host of neurological and psychiatric
diseases [7–9]. The present review focuses on the role of the GABA receptors in the
regulation of sleep and in the pharmacotherapy of sleep disorders.
3 GABAA Receptors and their Multiplicity
Based on the presence of seven subunit families comprising at least 18 subunits in
the CNS (a1-6, b1-3, g1-3, d, e, y, r1-3,), the GABAA-receptors display an extraordi-
nary structural heterogeneity (Fig. 2). Nevertheless, all subunits exhibit a similar
topology with a large extracellular N-terminal domain (�200 amino acids), four
a-helical transmembrane segments (M1–M4), a large intracellular loop connecting
transmembrane segments 3 and 4, and a short extracellularly located C-terminal
SubunitSubunitrepertoirerepertoire
a 1-61-6
b 1-31-3g 1-31-3
d 1
r 1-31-3
e 1q 1
GABAGABAA -ReceptorReceptor
Benzodiazepine siteBenzodiazepine siteClCl–
GephyrinGephyrin
TubulinTubulin
b
GABA
GABA-Transporter
a g2
Fig. 2 Scheme of GABAergic synapse depicting major elements of signal transduction. The
GABAA receptors represent GABA-gated chloride channels and are heteromeric membrane
proteins, which are linked (directly or indirectly) to the synaptic anchoring protein gephyrin and
the cytoskeleton (Tubulin). The sequence of subunits corresponds to a modeling proposal [10].
The binding sites for GABA and benzodiazepines are located at the interface of a/b and a/g2 subunits, respectively. Synaptic GABAA receptors mediate phasic inhibition providing a
rapid point-to-point communication for synaptic integration and control of rhythmic network
activities. Extrasynaptic GABAA receptors (not shown) are activated from synaptic spillover or
nonvesicular release of GABA. They mediate tonic inhibition and provide a maintenance level of
control of neuronal excitability [11, 12]
6 H. Mohler
sequence. Within the extracellular N-terminal domain, all subunits contain a 15
amino acid long disulfide-linked loop, which is characteristic for all members of the
Cys-loop superfamily, which also includes the glycine-, the nicotinic acetylcholine-,
and the 5HT3-receptor as oligomeric ligand-gated ion channels.
With few exceptions, GABAA receptors are heteropentamers composed of iso-
forms of three types of subunits, a, b, and g (Fig. 2) [13–15]. The structural diver-
sity of GABAA receptors means that they have a range of differences in their
channel kinetics, affinity for GABA, rate of desensitization, ability for transient
chemical modification such as phosphorylation, cell-type-specific expression, and –
in the case of multiple receptors in a neuron – a domain-specific location. This
confers to each receptor considerable adaptive flexibility to meet the requirements
of the interneuron-associated circuits [11].
4 Benzodiazepine-Sensitive GABAA Receptors
Receptors containing the a1, a2, a3, or a5 subunits in combination with the b2 or b3subunit and the g2 subunit are most prevalent in the brain. These receptors are
sensitive to modulation by classical benzodiazepines, such as diazepam, which
continue to represent a major class of hypnotics and anxiolytics. The most prevalent
GABAA receptor subtype is composed of a1b2g2 subunits with only a few brain
regions lacking this receptor (e.g., granule cell layer of the olfactory bulb, reticular
nucleus of the thalamus, spinal cord motoneurons) [8].
Receptors containing the a2 or a3 subunit are considerably less abundant and arehighly expressed in brain areas where the a1 subunit is absent or present at low
levels. The a2 receptors are particularly prominent on the axon initial segment of
pyramidal cells in the cortex and hippocampus and also represent the major
GABAA receptor in the central nucleus of the amygdala. The a3 GABAA receptors
are the main subtypes expressed in monoaminergic and basal forebrain cholinergic
cells [43], and are, in addition, located in the thalamic reticular nucleus, and thus
strategically positioned for modulating thalamic oscillations [44]. Receptors con-
taining the a5 subunit are less widely distributed in the brain but are expressed to a
significant extent extrasynaptically on pyramidal cells of the hippocampus,
where they are predominately coassembled with the b3 and g2 subunits. Receptorscontaining the d-subunit are exclusively extrasynaptic, supporting tonic inhibition.
The molecular factors regulating GABAA receptor assembly, domain-specific
insertion, and recycling are increasingly being recognized [45].
It should be kept in mind that complex benzodiazepine actions, such as the
development of tolerance, can implicate more than a single receptor subtype. For
instance, while the sedative action of diazepam is mediated by a1 GABAA receptors
(see below), the development of tolerance to this action under chronic diazepam
treatment requires the interaction with both a1 GABAA receptors and a5 GABAA
receptors [46]. In general, classical benzodiazepine drugs, such as diazepam don’t
distinguish GABAA receptor subtypes by affinity of intrinsic activity [40].
Physiology and Pharmacology of the GABA System 7