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Page 1: Neuroactive Steroids in Brain Function, Behavior and … · 2013-07-19 · Foreword Over the past few decades the involvement of neurosteroids in brain function and mental health

Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders

Page 2: Neuroactive Steroids in Brain Function, Behavior and … · 2013-07-19 · Foreword Over the past few decades the involvement of neurosteroids in brain function and mental health

Michael S. Ritsner • Abraham WeizmanEditors

Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders

Novel Strategies for Research and Treatment

Page 3: Neuroactive Steroids in Brain Function, Behavior and … · 2013-07-19 · Foreword Over the past few decades the involvement of neurosteroids in brain function and mental health

Editors:Michael S. Ritsner, M.D., Ph.D.Associate Professor of Psychiatry and

Head of Cognitive & Psychobiology Research Laboratory

The Rappaport Faculty of Medicine Technion - Israel Institute of Technology Haifa and Director Acute Department Sha’ar Menashe Mental Health Center Hadera, Israel

Abraham Weizman, M.D.Professor of Psychiatry Director of Felsenstein Medical

Research Center Sackler Faculty of Medicine Tel Aviv University, and Director of

Research Unit Geha Mental Health Center Petah Tikva, Israel

ISBN 978-1-4020-6853-9 e-ISBN 978-1-4020-6854-6

Library of Congress Control Number: 2008920052

© 2008 Springer Science + Business Media, B.V.No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work.

Printed on acid-free paper

9 8 7 6 5 4 3 2 1

springer.com

Page 4: Neuroactive Steroids in Brain Function, Behavior and … · 2013-07-19 · Foreword Over the past few decades the involvement of neurosteroids in brain function and mental health

Foreword

Over the past few decades the involvement of neurosteroids in brain function and mental health has attracted much interest, not only from a neuroscience perspective, but also from clinical and therapeutic aspects. In recent years, much of the research has focused on the multifunctional position of neurosteroids in the nervous system. The areas that have been explored, in particular, are the cellular and molecular mechanisms involved in the activity of neurosteroids in the brain, the role of neurosteroids in brain development, neurodegeneration and neuroplasticity, and their pharmacological properties. The large increase in the number of publications highlights this amplified interest in neurosteroids. Over the last 7 years at least 400 papers have been published describing the putative role of neurosteroids in the modulation of basic brain function and in the etiology and treatment of psychiatric and neurological disorders.

Contributors to this book are amongst the most active basic researchers and cli-nicians in the field and provide new perspectives not only clarifying some of the ongoing controversies, but also proposing diverse aspects and new insights. The book is organized in two major sections: “Neuroactive steroids and brain function’, and ‘Neuroactive steroids and neuropsychiatric disorders”. Though the selection of topics has been influenced by the current state of the art and the issues that require further elaboration, one should not assume that these are the only significant issues at this time. As often happens in publications composed of contributions by multi-ple authors from diverse orientations and academic backgrounds, differences in approaches and opinions are inevitable, as is some overlap. Indeed we consider such diversity to be one of this book’s strengths. We also believe this book to be the first of its kind to go beyond the neuropsychiatric disorders and delve into the neurobiological basis for clinical symptomatology, psychopathology, emotional regulation, cognitive functioning, and novel pharmacological strategies.

We sincerely hope that this book will broaden the knowledge and deepen the understanding of the complex role of neurosteroids in the regulation of brain func-tions and in the pathophysiology and pharmacotherapy of neuropsychiatric disorders, and that it will be of interest to a broad spectrum of readers including clinicians, researchers and students, in the fields of neuroscience and mental health.

2007 Michael S. RitsnerAbraham Weizman

v

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Contents

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

Part I Neuroactive Steroids and Brain Functions

Chapter 1 Neurosteroid: Molecular Mechanisms of Action on the GABAA Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Ming-De Wang, Mozibur Rahman, Jessica Strömberg, Per Lundgren, David Haage, Inga-Maj Johansson, and Torbjörn Bäckström

Chapter 2 Steroid Metabolism in Glial Cells. . . . . . . . . . . . . . . . . . . . . . 43 Roberto C. Melcangi and Luis M. Garcia-Segura

Chapter 3 Involvement of Neuroactive Steroids in Hippocampal Disorders: Lessons from Animal Models. . . . . . . . . . . . . . . . 61

Alejandro F. De Nicola, Luciana Pietranera, Juan Beauquis, Françoise Homo-Delarche, and Flavia E. Saravia

Chapter 4 Estrogen Modulation of Visceral Nociception . . . . . . . . . . . . 89 Victor V. Chaban

Chapter 5 Neuroactive Steroids: Effects on Cognitive Functions . . . . . 103 Torbjörn Bäckström, Vita Birzniece, Guillén Fernández,

Inga-Maj Johansson, Kristiina Kask, Charlotte Lindblad, Per Lundgren, Sigrid Nyberg, Gianna Ragagnin, Inger Sundström-Poromaa, Jessica Strömberg, Sahruh Turkmen, Ming-De Wang, Frank van Broekhoven, and Guido van Wingen

Chapter 6 Estrogen, Cholinergic System and Cognition . . . . . . . . . . . . 123 Sonsoles de Lacalle, Bryan Hyler, and Thomas Borowski

vii

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Chapter 7 Local Production of Estrogen and its Rapid Modulatory Action on Synaptic Plasticity . . . . . . . . . . . . . . . . . . . . . . . . 143

Suguru Kawato, Yasushi Hojo, Hideo Mukai, Gen Murakami, Mari Ogiue-Ikeda, Hirotaka Ishii, and Tetsuya Kimoto

Chapter 8 Effects of Estradiol and DHEA on Morphological Synaptic Plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

Tibor Hajszan, Zsofi a Hoyk, Luis Miguel Garcia-Segura, and Arpad Parducz

Chapter 9 Pregnane Steroids and Short-Term Neural Plasticity . . . . 187 Yuri B. Saalmann and Mike B. Calford

Chapter 10 Steroidogenesis and Neuroplasticity in the Songbird Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

Colin J. Saldanha and Barney A. Schlinger

Chapter 11 Dehydroepiandrosterone, as Endogenous Inhibitor of Neuronal Cell Apoptosis: Potential Therapeutic Implications in Neurodegenerative Diseases . . . . . . . . . . . . 217

Ioannis Charalampopoulos, Christos Tsatsanis, Andrew N. Margioris, Elias Castanas, and Achille Gravanis

Chapter 12 DHEA and DHEA-S, and their Functions in the Brain and Adrenal Medulla . . . . . . . . . . . . . . . . . . . . 227

Alexander W. Krug, Christian G. Ziegler, and Stefan R. Bornstein

Chapter 13 Neurosteroids in the Aging Brain . . . . . . . . . . . . . . . . . . . . . 241 Rael D. Strous

Part II Neuroactive Steroids and Neuropsychiatric Disorders

Chapter 14 Dehydroepiandrosterone and Pregnenolone Alterations in Schizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . 251

Michael S. Ritsner, Anatoly Gibel, Yael Ratner, and Abraham Weizman

Chapter 15 Neurosteroids in Cortical Development and the Etiology of Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

Samantha S. Gizerian

viii Contents

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Chapter 16 Neurosteroid Perturbation and Neuropsychiatric Symptoms in Schizophrenia: From the Mechanisms to the Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325

Flavia di Michele, Carlo Caltagirone, and Gianfranco Spalletta

Chapter 17 Dehydroepiandrosterone Administration in Treating Medical and Neuropsychiatric Disorders: High Hopes, Disappointing Results, and Topics for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337

Michael S. Ritsner

Chapter 18 Allopregnanolone and Pregnenolone Alterations Following Pharmacological Agents in Rodents and Clinical Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369

Victoria M. Payne, Jason D. Kilts, Jennifer C. Naylor, Jennifer L. Strauss, Patrick S. Calhoun, Roger D. Madison, and Christine E. Marx

Chapter 19 Reconsidering Classifi cations of Depression Syndromes: Lessons from Neuroactive Steroids and Evolutionary Sciences . . . . . . . . . . . . . . . . . . . . . . . . . . 385

Bernardo Dubrovsky

Chapter 20 Neuroactive Steroids in Brain and Relevance to Mood . . . 423 Torbjörn Bäckström, Lotta Andréen, Marie Bixo, Inger Björn,

Guillén Fernández, Inga-Maj Johansson, Per Lundgren, Magnus Löfgren, Sigrid Nyberg, Gianna Ragagnin, Inger Poromaa-Sundström, Jessica Strömberg, Frank van Broekhoven, Guido van Wingen, and Ming-De Wang

Chapter 21 The Role of Neuroactive Steroids in Anxiety Disorders . . . 435 Erin M. MacKenzie, Glen B. Baker,

and Jean-Michel Le Mellédo

Chapter 22 The Role of Midbrain 3a,5a-THP in Mediating Exploration, Anxiety, Social, and Reproductive Behavior . 449

Cheryl A. Frye and Madeline E. Rhodes

Chapter 23 The Role of Progesterone and its Metabolites in Premenstrual Disorders of Affect . . . . . . . . . . . . . . . . . . 483

Akiko Dohi, Glenn H. Dillon, and Meharvan Singh

Contents ix

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Chapter 24 Neurosteroid Derangement in Women Diagnosed with Eating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493

Daniel Stein, Rachel Maayan, Ron Loewenthal, and Abraham Weizman

Chapter 25 Neurosteroids in Alcohol and Substance Use . . . . . . . . . . . 509 Brett C. Ginsburg, Lisa R. Gerak, Lance R. McMahon,

and John D. Roache

Chapter 26 The Role of Neurosteroids in Development of Pediatric Psychopathology . . . . . . . . . . . . . . . . . . . . . . . . 539

Pavel Golubchik and Abraham Weizman

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555

x Contents

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Contributors

Lotta Andréen, M.D., Ph.D.Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Sweden, [email protected]

Torbjörn Bäckström, M.D., Ph.D.Professor, Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

Glen B. Baker, Ph.D., D.Sc.Professor, Department of Psychiatry, Mackenzie Centre, University of Alberta, Edmonton, Alberta, Canada, [email protected]

Juan BeauquisLaboratory of Neuroendocrine Biochemistry,Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina, and Department of Biochemistry, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina, [email protected]

Vita Birzniece, M.D., Ph.D.Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

Marie Bixo, M.D., Ph.D.Associate professor, Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

Inger Björn, M.D., Ph.D.Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

xi

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Stefan R. Bornstein, M.D., Ph.D.Professor of Medicine, Director and Chair, Department of Medicine III, University of Dresden, Dresden, Germany, [email protected]

Thomas Borowski, Ph.D.Assistant Professor, Department of Psychology & Neuroscience, Claremont, California, USA, [email protected]

Frank van Broekhoven, M.D., Ph.D.sDepartment of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands, [email protected].

Mike B. Calford, Ph.D.Professor, Pro Vice-Chancellor, Health, University of Newcastle, New South Wales 2308, Australia, [email protected]

Patrick S. Calhoun, Ph.D. Director, Health Services Research Core, VA Mid-Atlantic Mental Illness Research, Education & Clinical Center (MIRECC), Director, Psychology Post-Doctoral Training, Durham VA Medical Center, Assistant Clinical Professor, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA, [email protected]

Carlo Caltagirone, M.D. IRCCS Santa Lucia Foundation, Department of Clinical and Behavioural Neurology, Rome, and Department of Neuroscience, Tor Vergata University, Rome, Italy, [email protected]

Victor V. Chaban, Ph.D.Assistant Professor, Department of Biomedical Sciences, Charles Drew University of Medicine and Science, David Geffen School of Medicine at UCLA, Los Angeles, California, USA, [email protected]

Ioannis Charalampopoulos, Ph.D.Research Fellow, Department of Pharmacology, School of Medicine, University of Crete, [email protected]

Elias Castanas, M.D., Ph.D.Professor, Department of Experimental Endocrinology, School of Medicine, University of Crete, [email protected]

xii Contributors

Page 11: Neuroactive Steroids in Brain Function, Behavior and … · 2013-07-19 · Foreword Over the past few decades the involvement of neurosteroids in brain function and mental health

Glenn H. Dillon, Ph.D.Professor and Vice President for Research, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, USA

Akiko DohiGraduate Student, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA

Bernardo DubrovskyResearch Scientist, McGill University, Montreal, QC, Canada, [email protected]

Guillen Fernández, M.D., Ph.D.Professor, F.C. Donders Centre for Cognitive Neuroimaging, Radboud University Nijmegen, The Netherlands, [email protected]

Cheryl A. Frye, Ph.D.Professor, Department of Psychology, The University at Albany-SUNY, Albany, New York, USA, [email protected]

Luis Miguel Garcia-SeguraInstituto Cajal, C.S.I.C., Spain, [email protected]

Lisa R. GerakAssistant Professor, Department of Pharmacology, The University of Texas Health Science Center at San Antonio, Texas, USA

Anatoly Gibel, M.D.Senior Psychiatrists, Acute Department, Sha’ar Menashe Mental Health Center, Israel, [email protected]

Brett C. GinsburgAssistant Professor, Division of Alcohol and Drug Addiction, Department of Psychiatry, The University of Texas Health Science Center at San Antonio, Texas, USA, [email protected]

Samantha S. Gizerian, Ph.D.Assistant Professor, Department of Biomedical Sciences, Charles R. Drew University of Medicine and Science, Los Angeles, California, USA, [email protected]

Contributors xiii

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Pavel Golubchik, M.D.Child and Adolescent Outpatient Clinic, Geha Mental Health Center, Petah Tiqva, Israel, [email protected]

Achille Gravanis, Pharm.D., Ph.D.Professor, Department of Pharmacology, School of Medicine, University of Crete, [email protected]

David Haage, Ph.D.Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

Tibor Hajszan, M.D., Ph.D.Institute of Biophysics, Biological Research Center, Szeged, Hungary, [email protected]

Yasushi HojoDepartment of Biophysics and Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Japan

Françoise Homo-DelarcheCNRS UMR 7059, Université Paris, Diderot, Paris, France, [email protected]

Zsofia Hoyk, Ph.D.Institute of Biophysics, Biological Research Center, Szeged, Hungary, [email protected]

Bryan HylerThe Charles Drew University School of Medicine, Los Angeles, California, USA, [email protected]

Hirotaka IshiiDepartment of Biophysics and Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Japan

Inga-Maj Johansson, Ph.D.Associate professor, Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

Kristiina Kask, M.D, Ph.D.sDepartment of Women’s and Children’s Health, Academic Hospital, Uppsala, Sweden, [email protected]

xiv Contributors

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Suguru KawatoProfessor, Department of Biophysics and Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Japan, [email protected]

Erin M. MacKenzie, B.Sc.Department of Psychiatry, Mackenzie Centre, University of Alberta, Edmonton, Alberta, Canada, [email protected]

Jason D. Kilts, Ph.D.Senior Research Associate, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham VA Medical Center, Durham, North Carolina, USA, [email protected]

Tetsuya KimotoDepartment of Biophysics and Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Japan

Alexander W. Krug, M.D.Research scientist, Medizinische Klinik III, Medizinische Fakultät Carl Gustav Carus Universität Dresden, Germany, [email protected]

Sonsoles de Lacalle, M.D., Ph.D.Associate Professor and Chair, Department of Biomedical Sciences, The Charles Drew University, Los Angeles, California, USA, [email protected]

Charlotte Lindblad, Ph.D.s,Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

Ron Loewenthal, M.D. Tissue-Typing Laboratory and Bone Marrow Registry, The Safra Children’s Hospital, The Chaim Sheba Medical Center, Tel Hashomer, The Sackler Faculty of Medicine, Tel Aviv University, Israel

Magnus Löfgren, Ph.D.sUmeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

Per Lundgren, Ph.D.Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

Contributors xv

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Rachel Maayan, Ph.D.Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Israel

Lance R. McMahonAssistant Professor, Department of Pharmacology, The University of Texas Health Science Center at San Antonio, Texas, USA

Roger D. Madison, Ph.D.Associate Research Professor, Department of Experimental Surgery, Associate Medical Research Professor, Department of Neurobiology, Duke University Medical Center, Research Career Scientist, Durham VA Medical Center, Durham, North Carolina, USA, [email protected]

Andrew N. Margioris, M.D.Professor, Department of Clinical Chemistry, School of Medicine, University of Crete, [email protected]

Christine E. Marx’s, M.D., M,A.Associate Professor, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Director, Clinical Interventions Core; Director, Psychiatry Fellowship Program, VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC), Durham VA Medical Center, Durham, North Carolina, USA, [email protected]

Roberto C. Melcangi, Ph.D.Professor, Department of Endocrinology, Laboratory of Neuroendocrinology, University of Milan, Italy, [email protected]

Jean-Michel Le Melledo, M.D.Professor, Department of Psychiatry, Mackenzie Centre, University of Alberta, Edmonton, Alberta, Canada, [email protected]

Flavia di Michele, M.D., Ph.D.Mental Health Service and Department of Neuroscience, Tor Vergata University, Rome, Italy

Hideo MukaiDepartment of Biophysics and Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Japan

Gen MurakamiDepartment of Biophysics and Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Japan

xvi Contributors

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Jennifer C. Naylor, Ph.D.Research Associate, Duke University Medical Center, Durham VA Medical Center, North Carolina, USA, [email protected]

Alejandro F. De NicolaDirector, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina, [email protected]

Sigrid Nyberg, Ph.D.Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

Mari Ogiue-IkedaDepartment of Biophysics and Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Japan

Arpad Parducz, Ph.D., D.Sc.Institute of Biophysics, Biological Research Center, Szeged, Hungary, [email protected]

Victoria M. Payne, M.D., M.S.Psychiatry Research Fellow, VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC), Durham VA Medical Center, Durham, North Carolina, USA, [email protected]

Luciana PietraneraLaboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina, and Department of Biochemistry, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina, [email protected]

Gianna Ragagnin, Ph.D.Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

Mozibur Rahman, M.D., Ph.D.Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

Yael Ratner, M.D.Senior Psychiatrists, Acute Department, Sha’ar Menashe Mental Health Center, Israel, [email protected]

Contributors xvii

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Madeline E. RhodesPsychology Department, Smith College, Northampton, Massachusetts, USA, [email protected]

Michael S. Ritsner, M.D., Ph.D.Associate Professor of psychiatry, and Head, Cognitive and Psychobiology Research Laboratory, The Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa Director, Acute Department, Sha’ar Menashe Mental Health Center, Hadera, Israel, [email protected]; [email protected]

John D. RoacheProfessor, Division of Alcohol and Drug Addiction Department of Psychiatry, The University of Texas Health Science Center, San Antonio, Texas, USA

Yuri B. Saalmann, Ph.D.Research Scientist, Cognitive Neuroscience Laboratory, Department of Psychology, Royal Holloway, University of London, [email protected]

Colin J. Saldanha Ph.D.Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania, USA, [email protected]

Flavia E. SaraviaLaboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental, Buenos Aires, and Department of Biochemistry, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina, [email protected]

Barney A. SchlingerProfessor and Vice-Chair, Department of Physiological Science, UCLA, Los Angeles, California, USA, [email protected]

Meharvan Singh, Ph.D.Associate Professor, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, USA, [email protected]

Gianfranco Spalletta, M.D., Ph.D.IRCCS Santa Lucia Foundation, Department of Clinical and Behavioural Neurology, Rome, and Department of Neuroscience, Tor Vergata University, Rome, Italy, [email protected]

xviii Contributors

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Daniel Stein, M.D.Pediatric Psychosomatic Department, Safra Children’s Hospital, The Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel, [email protected]

Jessica Strömberg, Ph.D.Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, Jessica, [email protected]

Inger Sundström-Poromaa, M.D., Ph.D.Professor, Department Women’s and Children’s Health, Academic Hospital, Uppsala, Sweden, [email protected]

Jennifer L. Strauss, Ph.D.Assistant Professor, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Health Scientist, Durham VA Medical Center, Durham, North Carolina, USA, [email protected]

Rael D. Strous, M.D.Beer Yaakov Mental Health Center, Sackler Faculty of Medicine, Tel Aviv University, Israel, [email protected]

Erika Timby, M.D., Ph.D.Student, Umeå neurosteroid Research Center, Department of Clinical Sciences, Umeå University, Sweden, [email protected]

Christos Tsatsanis, Ph.D.Assistant Professor, Department of Clinical Chemistry, School of Medicine, University of Crete, [email protected]

Sahruh Turkmen, M.D., Ph.D.Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

Ming-De Wang, M.D., Ph.D.Associate Professor, Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Norrlands University Hospital, Sweden, [email protected]

Contributors xix

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Abraham Weizman, M.D.Professor of Psychiatry and Director of Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University and Director of Research Unit, Geha Mental Health Center, Petah Tikva, Israel, [email protected]

Guido van Wingen, Ph.D., F.C.Donders Centre for Cognitive Neuroimaging, Radboud University Nijmegen, The Netherlands, [email protected]

Christian G. Ziegler, Ph.D.Research Scientist, Medizinische Klinik III, Medizinische Fakultät Carl Gustav Carus, Universität Dresden, Dresden, Germany

xx Contributors

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Part INeuroactive Steroids and Brain Functions

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Chapter 1Neurosteroid: Molecular Mechanisms of Action on the GABAA Receptor

Ming-De Wang*, †, Mozibur Rahman†, Jessica Strömberg, Per Lundgren, David Haage, Inga-Maj Johansson, and Torbjörn Bäckström

Abstract Neurosteroids represent a class of endogenous steroids that are synthesized in the brain, the adrenals and the gonads and have potent and selective effects on the gamma-aminobutyric acid type A (GABA

A receptor). 3α-Hydroxy A-ring-reduced

metabolites of progesterone, deoxycorticosterone and testosterone enhance the the Cl– flux through GABA

A receptor conductance at nanomolar concentrations in

a non-genomic (rapid and direct) manner. Studies on the GABAA receptors have

shown that allopregnanolone (3α-OH-5α-pregnan-20-one), 5α-androstane-3α,17α-diol (Adiol) and (3 5 3, 21-dihydroxypregnan-20-one (3α5αTHDOC) enhance the GABA mediated Cl– currents acting on a site (or sites) distinct from the GABA, benzodiazepine, barbiturate and picrotoxin binding sites. This modulation site (or sites) has a well-defined structure–activity relationship with a 3α-hydroxy and a 20-ketone configuration in the pregnane molecule required for agonist action. However, the neurosteroid pregnenolone sulfate (PS) is a non-competitive GABA

A

receptor antagonist and inhibits GABA-activated Cl– currents in an activation-dependent manner. 3β-hydroxy A-ring reduced pregnane steroids are pregnenolone sulfate-like GABA

A receptors antagonists and inhibit the GABA

A receptor’s function

and its potentiation induced by their 3α-diasteromers in a non-competitive manner. The specificity of neurosteroid action on the GABA

A receptor results from a variety

of molecular mechanisms, including receptor subunit composition, receptor activation–deactivation, and steroid concentration. Here, we will review the GABA-modulatory actions of the neurosteroids. The molecular mechanisms underpinning the non-genomic effect of agonist and antagonist neurosteroids will be discussed with particular emphasis being given to the role of GABA

A receptor isoforms.

Keywords Neurosteroid, GABA, allopregnanolone, pregnenolone sulfate, agonist, antagonist

* Umeå Neurosteroid Research Center, Department of Clinical Science, Section of Obstetric & Gynecology, Umeå University, 901 85 Umeå, Sweden

† Ming-De Wang and Mozibur Rahman contributed equally in this work.

M.S. Ritsner and A. Weizman (eds.), Neuroactive Steroids in Brain Function, 3Behavior and Neuropsychiatric Disorders© Springer 2008

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4 M. Wang et al.

Abbreviations CNS central nervous system; GABA γ-amino butyric acid; NMDA N-methyl-d-aspartate; PMDD premenstrual dystrophic disorder; PKC protein kinase C; TBPS t-butyl bicyclophosphorothionate; P450scc P-450 side chain cleavage; P450

21 steroid 21 hydroxylase; 3α-HSD 3α-hydroxysteroid dehydrogenase; 3β-

HSD 3β-hydroxysteroid dehydrogenase; StAR steroidogenic acute-regulatory; 3α-OH 3α-hydroxyl; 3β-OH 3β-hydroxyl; 3α5αp 3α-OH-5α-pregnan-20-one, allo-pregnanolone; 3α5βP 3α-OH-5β-pregnan-20-one, pregnanolone; 3α5αTHDOC 3α, 5α-tetrahydrodeoxy-corticosterone; 3α5βTHDOC 3α, 5β-tetrahydrode-oxy-corticosterone; PS pregnenolone sulfate; DHEAS dehydroepiandrosterone sulfate; 3β5αP 3β-OH-5α -pregnan-20-one, isoallopregnanolone; 3β5βP 3β-OH-5β -pregnan-20-one, epipregnanolone; 3β5βTHDOC 5β-pregnan-3β, 21-diol-20-one; 3α-adiol/3α5αADL 5α-androstane-3α,17β-diol; DOC deoxycorticosterone; sIPSC spontaneous inhibitory post-synaptic current; DGC dentate gyrus granule cells; CGC cerebellar granule cells; MPN medial preoptic nucleus; EC

50 concentration of

drug that produces 50% of maximum response

1.1 The Metabolites of Sex and Stress Hormones are Neuroactive

The sex hormones, estrogen, progesterone and testosterone, influence a variety of behaviors in vertebrates in addition to their functional roles in the reproductive sys-tem.1 In adult women, estradiol is mainly produced in the granulose cell from the developing follicle and the corpus luteum in the ovary. Progesterone is synthesized mainly in the granulose cells of corpus luteum, the placenta and the adrenal glands.2 Sex hormones act through genomic mechanisms through the intracellular receptors that are located in the nucleus or cytoplasm.3 They act as ligand-activated transcrip-tion factors in the regulation of gene expression (Fig. 1.1). However, metabolites of progesterone and several stress hormones act on the membrane bound receptor via a fast non-genomic mechanism. The receptor binding to DNA and RNA synthesis is thus not required (Fig. 1.1).1–3 While the genomic action of sex hormones requires a time period from minutes to hours and limited by the rate of protein biosynthesis,4 the modulatory effect on the membrane receptor is fast occurring event and requires only milliseconds to seconds.4 Today it is known that metabolites of sex and stress hormones act non-genomically in the CNS and alter neuronal excitability.5–7 The term “neurosteroid” was introduced to describe these steroid metabolites that mod-ulate neuronal activity.6 The 3αOH A-ring reduced metabolites of progesterone and deoxycorticosterone, allopregnanolone (3α5αP) and 3α, 5α-tetrahydrodeoxy-corticosterone (3α5αTHDOC) were first shown to modulate neuronal excitability by interaction with the GABA

A receptor.5 Several other neurotransmitters like the

NMDA,8 the nicotinic,9 the muscarinic,10 the serotonergic11 and the adrenergic system12 are also targets for neurosteroids (Fig. 1.1). The functional modulation of

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1 Neurosteroid: Molecular Mechanisms of Action on the GABAA Receptor 5

Fig. 1.1 The genomic and non-genomic site of action of steroid hormones and their metabolites. At the left the non genomic mechanism is presented. Neuroactive steroids are exemplified as well as different membrane receptors which they target. The reaction time for neurosteroids are fast which is indicated by the time line. An example is when the GABA

A-receptor agonist steroid

3α5αP (Allopregnanolone) binds to the receptor enhancing the GABA effect which results in an increase in the chloride ion influx into the cell. The increase in intracellular chloride ions leads to a hyperpolarization. Such action can be as fast as in the millisecond interval

The genomic mechanism and an example of steroid hormones are presented at the right side. Classical steroid hormones penetrate the cell membrane. In the cytosol steroids bind to their specific receptors estrogen receptor (ER) and progesterone receptors (PR), respectively. The steroid–receptor complex translocates into the nucleus and binds to specific response elements of the DNA. This activates the transcription of mRNA which later can be translated into pro-teins. The action of the estrogen receptor can be regulated by phosphorylation by protein kinase A. The activation or inactivation of protein kinase A is in this example regulated by a stimulat-ing G-protein coupled to the adrenergic (α2) receptor or by an inactivating G-protein coupled to the dopamine (D1-like) receptor. That occurs when dopamine or noradrenalin binds to their receptors. The genomic action is slow and long lasting

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6 M. Wang et al.

the GABAA receptor by neurosteroids at low concentrations is believed to induce

moderate to severe adverse mood changes in up to 20% of female individuals.13, 14 The clinical complex of premenstrual dystrophic disorders (PMDD),15, 16 petit mal epilepsy,17, 18 and catamenial epilepsy19 are among the disorders that may involve neurosteroid action. At higher doses, neurosteroids may affect learning,20 act as anxiolytic, anti-aggressive, sedative/anesthetic, and anti-epileptic agents in both animals and humans.6, 21–23

1.2 Biosynthesis of Neurosteroids

Neurosteroids are formed de novo in neurons and glia, or generated by metabolism of circulating precursors that originate in peripheral steroidogenic organs.24 Neurosteroids are commonly referred to as A-ring reduced metabolites of proges-terone, deoxycorticosterone and testosterone.24 The brain synthesis of neurosteroids is controlled by an endogenous peptide-diazepam binding inhibitor, a ligand for the “peripheral” benzodiazepine binding site (Fig. 1.1).25 Astrocytes and neurons expresses cytochrome P450scc that convert cholesterol to pregnenolone, is required for the steroid synthesis (Fig. 1.2).26, 27 3β-HSD converts pregnenolone to proges-terone. 5α-reductase and 3α-HSD involve the synthesis of allopregnanolone from progesterone, whereas its 5β-isomer pregnanolone is produced by the enzymatic activity of 5β-reductase and 3α-HSD (Fig. 1.2). Because the activity of the 3α-HSD is stronger than that of the 5α-reductase, the latter enzyme is required in the rate-limiting step of the neurosteroid synthesis.28, 29 Allopregnanolone and pregne-nolone are potent agonists on the GABA

A receptor.5, 6, 30 Allopregnanolone can

accumulate in the brain after adrenalectomy and gonadectomy.31–33 This indicates that allopregnanolone can be synthesized in the brain via A-ring reduction of progesterone.

Pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS) are naturally occurring neurosteroids that inhibit the GABA

A receptor function.6 PS

is synthesized from pregnenolone by the enzyme sulfotransferase (Fig. 1.2). Conversion from DHEA to DHEAS is also mediated by sulfotransferase. DHEA is metabolized from pregnenolone by cytochrome P450

C17.34 On the other hand,

3β-HSD is essential for the synthesis of 3β-OH steroids, i.e., epipregnanolone and isoallopregnanolone35(Fig. 1.3). PS, DHEAS and 3β-OH steroids act as GABA

A receptor antagonists36, 37 and can be measured from human blood

samples.38

Stress hormones, 3α5α-THDOC and 3α5βTHDOC are also potent modula-tors of the GABA

A receptor.5, 39–41 Both 3α5αTHDOC and 3α5βTHDOC have

significant sedative effects in vivo. 3α5αTHDOC is a metabolite of the min-eralocorticoid DOC and is responsible for the sedative and anti-seizure activ-ity of DOC in animal models.42 DOC can be metabolized from progesterone and this conversion is mediated by P450

21.43 The conversion of deoxycorticos-

terone into 3α5αTHDOC occurs both in peripheral tissues and in the brain.44

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1 Neurosteroid: Molecular Mechanisms of Action on the GABAA Receptor 7

Fig. 1.2 Bio-synthesis of allopregnanolone and pregnenolone sulfate (PS) from cholesterol within the neuron or glial cell. Enzymes involved are P450 side-chain cleavage (P450scc), 3α-hydroxysteroid dehydrogenase (3α-HSD), 3β-hydroxysteroid dehydrogenase (3β-HSD). Transport of cholesterol across the mitochondrial membrane is enhanced by the steroidogenic acute-regulatory (StAR) protein and the mitochondrial benzodiazepine receptor (MBR). 5α-DHP represents 5α-dihydroprogesterone

The A-ring reduced metabolites of testosterone, 3α5α-adiol, acts as a GABAA

receptor agonist.45 The synthesis of 3α5α-THDOC and 3α5α-adiol is shown in Figs. 1.4 and 1.5.

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8 M. Wang et al.

O O

OO

H

5α−reductase 3β-HSD

Progesterone 5α-DHP

HHO

3β5αP (Isoallopregnanolone)

O

Fig. 1.3 Synthesis of 3β-OH steroids isoallopregnanolone. Enzymes involved are indicated at the arrows

O

OH

OH

OH

H

OH

OH

3α-HDS

RoDH1

5α-reductase

Testosterone Dihydrotestosterone 5α-Androstane-3α,17β-diol

Fig. 1.4 Synthesis of 5α-androstane 3α,17β-diol. RoDH1 represents the rat retinol dehydroge-nase 1 enzyme.287 Enzymes involved are indicated at the arrows

O

OH

O

O O

OH

O

O

OH

HO

O

HH

P45021

5α−reductase 3α-HSD

Progesterone 5α-DHDOCDeoxycorticosterone 3α5αTHDOC

Fig. 1.5 Synthesis of 3α5αTHDOC. Enzymes involved are indicated at the arrows

1.2.1 Neurosteriod Concentration in Human

The physiological concentration of the neurosteriods depends on the type of sampled tissue, stress, and fluctuation of precursor hormones in the body. Table 1.1 shows the normal range of neurosteriods in the human plasma and/brain tissue.

1.3 The GABAA Receptor

GABA mediates most of the inhibitory neurotransmission in the mammalian brain. GABA is synthesized by two isoforms of glutamic acid decarboxylase (GAD).46–48 GABA-mediated inhibition is crucially in both short-term and long-term regulation of

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1 Neurosteroid: Molecular Mechanisms of Action on the GABAA Receptor 9

neuronal excitability. It has been estimated that approximately 33% of the synapses in the mammalian cerebral cortex are GABAergic.49 Three different types of receptors, GABA

A, GABA

B and GABA

C receptors can be identified in the CNS.50 GABA

A recep-

tors are members of the ligand gated ion channel superfamily51 which is coupled to the Cl– channel. The metabotropic GABA

B receptor is coupled to certain K+ and Ca2+ chan-

nels via a GTP binding protein (G-protein) and/or other messengers.52 The GABAA

receptor is bicuculline sensitive and the GABAB receptor is baclofen sensitive. The third

type of GABA receptor, insensitive to both bicuculline and baclofen, is designated as the GABA

C receptor.53 The GABA

C responses are also of the fast type associated with

the opening of an Cl– channel; they are unaffected by typical modulators of GABAA

receptor such as benzodiazepines and barbiturates.50, 54

To date, 16 isoforms of the GABAA receptor have been identified.55 These comprise

α1–6, β1–3, γ1–3, δ, ε, π and θ. The GABAA receptor is pentameric proteins56 of five

different subunits containing 2α/2β/1γ or δ/ε/π/θ subunit variants (Fig. 1.6).57–59 Immunological, pharmacological, and functional analysis give the evidence that the

Fig. 1.6 Presentation of the GABAA receptor with putative binding sites for neuroactive steroids,

barbiturates, benzodiazepines, and picrotoxin. At the right, the transmembrane domains of five subunits are shown. Note that the second transmembrane domain of each subunit forms the chlo-ride ion channel lining

Table 1.1 Neurosteroid concentration in human plasma and brain (mean ± SEM)

Plasma (nM) Brain (nM)

Steroids Follicular Luteal Postmenopausal Luteal

Progesterone 5.0 ± 0.50 288 34.7 ± 2.40 65 289 137 289

3a-OH-5b-pregnan-20-one 0.6 ± 0.00 290 1.1 ± 0.50 – 114 289

3a-OH-5a-pregnan-20-one 0.53 ± 0.19 291 2.14 ± 0.37 47 289 66 289

3b-OH-5a-pregnan-20-one 0.29 ± 0.14 291 1.23 ± 0.28 – –3b-OH-5b-pregnan-20-one 0.09 ± 0.08 291 0.26 ± 0.13 – –Pregnenolone sulfate 11.2 ± 0.6 288 15.2 ± 0.8289 – 100 292

Pregnenolone *2.19 293 – – –3a5a-Androstane-3a,17b-diol *0.475 293 – – –Superscript numerals denote references* Concentration in adult men

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10 M. Wang et al.

α1β2γ2 combination represents the largest population of GABAA receptor (∼60%)

followed by α2β3γ2 (∼15–20%) and α3βnγ2 (∼10–15%, n = 1,2 or 3; Fig. 1.7).60–63 Receptors containing the α4-, α5-, and α6-subnit, as well as the β1-, γ1–3, δ-, π- and θ-subunit, form a minor receptor population. The α4βnδ, α4βnγ and the α6β2/3γ2 receptor – each of these is less than 5% of all the GABA

A receptor quantity (Fig. 1.7).

α6βnδ has a small population in the cerebellum and α6β2/3γ2 receptors are located exclusively in the cerebellum. Another GABA

A receptor subunit namely, ρ-subunits are

expressed primarily in the retina, forming GABAC receptor.64 Structurally, the GABA

C

receptor differs from classical GABAA receptors in that the Cl– channel comprises

a homopentamer of ρ-subunit rather than heteropentamers.64

The expression of GABAA receptor subtypes in the adult brain exhibits a

remarkable regional and neuronal specificity which suggests that individual subtypes are present in distinct neuronal circuits. The α1β2γ2 receptor is present in most brain areas and it is localized to interneurons in the hippocampus and cortex (layer I–IV), and cerebral Purkinje cells.65 The α2β3γ2 receptor is present in cerebral cortex (layer I–IV), hippocampal formation, amygdale, striatum, olfactory bulb, hypothalamus, superior colliculi, and motor nuclei.62 The α3βnγ2, α3γ2 and α3θ receptors are abundant in the cerebral cortex (layers V–VI), amygdala, olfac-tory bulb, thalamic reticular and intralaminar nuclei, superior colliculus, brainstem, spinal cord, and locus coeruleus. The α4βnδ (n = 1, 2 or 3) receptor is presented in the dentate gyrus and thalamus. The α5β3γ2 receptor is localized in hippocampal pyramidal cells, deep cortical layers, amygdala, olfactory bulb, hypothalamus, superior colliculus, superior olivary nucleus, spinal trigeminal nucleus and spinal cord. The α6β2/3γ2, α6β2/3δ and α6β2/3γ2 receptors are found mainly in the cer-ebellum and dorsal cochlear nucleus.62

Fig. 1.7 The proportions of different GABAA receptors in the central nervous system (CNS)

(based on the report by Mohler et al.61 and Fritschy et al.62)

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1 Neurosteroid: Molecular Mechanisms of Action on the GABAA Receptor 11

1.3.1 Pharmacological Properties of the GABAA Receptors

The GABAA receptor can be modulated by a number of therapeutic agents, including

benzodiazepines,66, 67 barbiturates,68 anaesthetics, ethanol,69 zinc70 and neuroster-oids.71, 72 Pharmacological analysis of GABA

A receptors revealed that the α-subunit

determine the GABA affinity,73 α- and γ-subunit regulate benzodiazepine site phar-macology.73–76 In fact, the binding pocket of benzodiazepines is located between the α- and γ-subunits.77 The α1-, α2-, α3-, and α5-containing GABA

A receptors are

diazepam-sensitive receptors, whereas the α4- and α6-subunit containing GABAA

receptors are insensitive to diazepam.78, 79 The α1-, α2-, α3-, and α5-subunits are distinguished further by their affinity to zolpidem (α1 > α2 = α3 > > α5) and various β-carbolines (α1 > α2 = α3).80, 81 Neurosteroids are allosteric modulators of recom-binant and native GABA

A receptors.82 Neurochemical, electrophysiological, and

behavioral evidence accumulated over the last two decades suggest that the GABAA

receptor also mediate certain acute and chronic actions of ethanol.83–85 Ethanol exhibits an array of central depressant actions, including anxiolytic, anticonvulsant, sedative-hypnotic, muscle relaxant, and general anesthetic effects, in a dose-dependent manner.83, 86 However, some recent attempts have failed to reproduce these effect by ethanol.87, 88

Bicuculline, Zn2+, TBPS, picrotoxin and pregnenolone sulfate (PS) are the antagonists of GABA

A receptor. Bicuculline is the competitive blocker of GABA-

site.89, 90 Picrotoxin, Zn2+ and PS inhibit the GABAA receptor through direct and

indirect block of the Cl– channel.37, 90, 91 Experimental convulsants like pentylene-tetrazol and the cage convulsant TBPS act as Cl– channel blockers on the GABA

A

receptor.92

1.3.2 Pharmacological Properties of the GABAA Receptor

Depends on the Subunit Composition

There is evidence that many subunits are related to several behavioral effects. Transgenic mouse models enable exciting new perspectives for the development of the pharmacology of modulating agents of GABA

A receptors and their effect on

different subunits. Benzodiazepines have dual properties on the GABAA function-

sedative and anxiolytic. A histidine residue at α1, α2, α3, and α5 subunits is crucial for benzodiazepines binding. The sedative effect of benzodiazepines is mediated via the α1 subunit containing GABA

A receptors.93 In mice, replacing histidine by

arginine at position 101 at α1 subunit leads to abolition of the motor component of sedation, amnesic and anticonvulsant effects whereas anxiolytic and muscle relax-ant effects of diazepam are retained.93, 94 In contrast, the α2 subunit appears to be a major determinant for the anxiolytic and muscle relaxant effects of benzodi-azepines.95, 96 Agonistic activity at the α3 subunit also mediate the anxiolytic activ-ity of benzodiazepines, although it occurred only at high receptor occupancy.97 Recently, it has been shown that the α5 subunit is important for sedative tolerance

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12 M. Wang et al.

development to benzodiazepines and for acquisition and expression of associative memory and spatial learning.98–101 In addition, the α4 subunit is also implicated in the regulation of anxiety.102 A concentration-dependent decrease of the α4 subunit is seen after 4-day application of allopregnanolone to developing neuronal cells,103 whereas in the hippocampus and cerebellum, an increase in this subunit can be detected after withdrawal from chronic progesterone (or allopregnanolone) expo-sure and after short-term treatment.102, 104–106 The α6 subunit is highly sensitive to pentobarbital effects107 and neuroactive steroids.108 In recent years, there has been an accumulating amount of evidence for the involvement of GABA

A receptors in

the action of anesthetics. In vitro studied on recombinant receptors, the intravenous anesthetic etomidate shows GABA

A subtype selectivity for β2- and β3-containing

receptors.109 A recent study shows that β3-containing receptors are the primary mediators of the anesthetic effects whereas β2, probably in combination with α1, and γ subunits mediates the sedating effects of etomidate.110 The γ-subunit is thought to confer sensitivity of the receptor to benzodiazepines.111, 112 The γ1- and γ3-containing receptors have a 10–30-fold lower affinity for flunitrazepam than do receptors containing γ2-subunit.112–115 On the other hand, absence of γ subunit is essential for zinc sensitivity.91 The γ2-subunit is also involved in anxiety regulation, and it is changed during hormone treatment and pregnancy.104, 116–119 The γ2-subunit is essential for clustering of GABA

A receptors and gephyrin and synaptic localiza-

tion.117, 120 62, 121 The δ-subunit is responsible for tonic conductance and important for neuroactive steroid modulation on GABA

A receptor.122 Receptor knockout studies

have revealed that the absence of the δ-subunit decreases the sensitivity to neuroac-tive steroids such as pregnanolone and alphaxalone, thereby influencing the dura-tion of anesthesia and the anxiolytic effect of those steroids.123 The ε-subunit reduces neuroactive steroid and anesthetic modulation.108, 124, 125

Functionally, distinct subunit-specific properties have been identified in both recombinant and native receptors, supporting the concept that GABA

A receptor

heterogeneity is a major facet determining the functional properties of GABAergic inhibitory circuits.126, 127 In particular, the type of α-subunit determines the kinetics of receptor deactivation,128–130 and the presence of the δ-subunit results in markedly increased agonist affinity and apparent lack of desensitization.131–133

1.3.3 Synaptic and Extrasynaptic GABAA Receptors

The GABAA receptor, like other receptors in the brain can be synaptic or extrasyn-

aptic. Receptors located at the synaptic junctions are known as “synaptic” whereas the receptors over the neuronal surface outside the synaptic cleft are known as the “extra-synaptic”.134 The synaptic receptors contain γ-subunits and can be rapidly expressed on the neuronal membrane. It is sensitive to both benzodiazepines and neurosteroids. On the other hand, the extrasynaptic receptors contain δ-subunits instead of γ-subunits and are usually difficult to express on the neuronal membrane. δ-subunits are highly sensitive to GABA and neorsteroids but not to benzodi-

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1 Neurosteroid: Molecular Mechanisms of Action on the GABAA Receptor 13

azepines. The expression of α1β2/3γ2, α2β2/3γ2 and α3β2/3γ2 receptors are the predominant synaptic receptors.135 Receptors that contain α4-, α5- or α6-subunits, α6βnδ, α4βnδ and α5βnγ2 receptors, are predominantly or exclusively extrasynaptic (Fig. 1.8).62, 136 In the synapse, each vesicle is thought to release several thousands of GABA molecules into the synaptic cleft and leading to a high concentration of GABA (0.3–1.0 mM) in a time span of 10–100 ms.137, 138 There are only a few number of receptors, from ten to a few hundreds, clustered opposite the release site.139–141 Synaptically released GABA acting on postsynaptic GABA

A receptors

producing “phasic” inhibition, whereas “tonic” inhibition results from the continu-ous activation of extrasynaptic receptors by ambient GABA.135 The main feature of

Fig. 1.8 Neuroactive steroids’ effect on the synaptic and extrasynaptic GABAA receptors and

type of inhibition produced by them (adapted from Belelli and Lambert153). On the left: Phasic inhibition exerted by stimulation of synaptic GABA

A receptors. The receptors are in densely

expressed and react upon a brief, high concentration of GABA released from the presynaptic terminal

On the right: Tonic inhibition which occurs upon activation of extrasynaptic GABAA receptors

localized elsewhere in the post synaptic cell membrane than in the synapse. These receptors are less densely expressed than the synaptic type and react on persistent and low concentrations of GABA

This figure shows also that there is a synthesis of allopregnanolone in the neuron as well as in the glial cell. Allopregnanolone interacts with synaptic and extrasynaptic GABA

A receptors