The Receptors Bruno P. Guiard Giuseppe Di Giovanni Editors 5-HT2A Receptors in the Central Nervous System The Receptors Volume 32 Series Editor Giuseppe Di Giovanni Department of Physiology & Biochemistry Faculty of Medicine and Surgery University of Malta Msida, Malta The Receptors book Series, founded in the 1980’s, is a broad-based and well- respected series on all aspects of receptor neurophysiology. The series presents published volumes that comprehensively review neural receptors for a specific hormone or neurotransmitter by invited leading specialists. Particular attention is paid to in-depth studies of receptors’ role in health and neuropathological processes. Recent volumes in the series cover chemical, physical, modeling, biological, pharmacological, anatomical aspects and drug discovery regarding different receptors. All books in this series have, with a rigorous editing, a strong reference value and provide essential up-to-date resources for neuroscience researchers, lecturers, students and pharmaceutical research. More information about this series at http://www.springer.com/series/7668 Bruno P. Guiard • Giuseppe Di Giovanni Editors 5-HT2A Receptors in the Central Nervous System Editors Bruno P. Guiard Giuseppe Di Giovanni Faculté de Pharmacie Department of Physiology Université Paris Sud and Biochemistry Université Paris-Saclay University of Malta Chatenay-Malabry, France Msida MSD, Malta Centre de Recherches sur la Cognition Animale (CRCA) Centre de Biologie Intégrative (CBI) Université de Toulouse; CNRS, UPS Toulouse, France The Receptors ISBN 978-3-319-70472-2 ISBN 978-3-319-70474-6 (eBook) https://doi.org/10.1007/978-3-319-70474-6 Library of Congress Control Number: 2017964095 © Springer International Publishing AG 2018 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Printed on acid-free paper This Humana Press imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Preface It was a great honour and pleasure for us to prepare this book entitled 5-HT2A Receptors in the Central Nervous System. The serotonin 5-HT2A receptor, cloned in 1994, is principally coupled to Gq/11 protein and it is expressed in different brain regions involved in cognition, perception, sensorimotor gating and mood. A major flaw in the study of the 5-HT2A receptor has relied on the lack of selective tools for mapping its distribution in the brain and examining its specific contribution to phys- iological and pathological processes. Nevertheless, by combining pharmacological approaches with 5-HT2 receptor ligands or antibodies with genetic tools (e.g., con- stitutive or tissue-specific 5-HT2A receptor knockout mice), it has been possible to unveil a complex and fascinating organization of this receptor at both cellular and subcellular levels. Interestingly, in the last few years, our knowledge on the 5-HT2A receptor has undergone a revolution owing to the discovery of many peculiar phar- macological properties. For example, the 5-HT2A receptors have been shown to interact with various G protein coupled receptors to form stable homo- or hetero- meric complexes, such as D2, mGlu2 and CB1 receptors likely responsible for changes in binding and coupling properties. There is another mechanism by which 5-HT2A receptor can regulate its signalling. Although it is well documented that agonist stimulation leads to internalization of the 5-HT2A receptors through a βarrestins2-dependent mechanism, recent evidence suggests that βarrestins can also facilitate G protein-independent signalling by functioning as adaptor proteins, nota- bly with the 5-HT2A receptors. The first chapters of this book are therefore aimed at reviewing the recent discovery of the pharmacological properties of the 5-HT2A receptors since their better understanding may open avenues for the design of new therapeutic compounds and thereby to improve the treatment of a number of psychi- atric and neurological disorders. The next section of chapters reviews our under- standing of the role(s) of the 5-HT2A receptors in several brain functions including sleep, memory, emotion and food intake. This compelling evidence reviewed here raises the possibility that the 5-HT2A receptor might be a relevant and promising target for the treatment of pathologies such as schizophrenia, mood and eating dis- orders, pain, epilepsy or Parkinson’s disease. The final section of chapters further supports this evidence by illustrating how the 5-HT2A receptor directly or indirectly v vi Preface controls neuronal excitability and brain plasticity through its interactions with monoaminergic, GABAergic and glutamatergic neurons but also with neurotrophic factors. The scope of the book is vast, going from the 5-HT2A receptor genome to its therapeutic applications based on clinical and preclinical observations. We have embarked on this unique editorial enterprise with the aim of providing the most recent achievements, a result of the efforts of an international group of scholars. We have also prepared this book for a wide audience (students, researchers, practitio- ners and caregivers) offering them a valuable and integrated insight into the mecha- nisms of action of the 5-HT2A receptors. We hope that the contents of this book will further inspire and stimulate discussions and new interdisciplinary research on the 5-HT2A receptor. We would like to thank all the authors for their contribution and outstanding review manuscripts in their area of expertise. A particular acknowledgement should be given to Springer editors, Ms. Portia Wong, the Developmental Editor, who helped us to manage this project and Ms. Simina Calin, the Neuroscience Editor, for coordinating the entire project. Msida, Malta Bruno Guiard Toulouse, France Giuseppe Di Giovanni September, 2017 Contents Part I Properties and Distribution of the 5-HT2AR Pharmacological Analysis in Favour of a Physiological Role for the Constitutive Activity of 5-HT2A Receptors in Learning .......... 3 Philippe De Deurwaerdère, Guillaume Drutel, and Giuseppe Di Giovanni βArrestins: Ligand-Directed Regulators of 5-HT2A Receptor Trafficking and Signaling Events ................................. 31 Cullen L. Schmid and Laura M. Bohn 5-HT2A Receptor Heterodimerization .............................. 57 Sylwia Łukasiewicz, Ewa Błasiak, and Marta Dziedzicka-Wasylewska Brain Distribution .............................................. 67 Cristiano Bombardi PET Imaging of the 5-HT2A Receptor System: A Tool to Study the Receptor’s In Vivo Brain Function ....................... 85 Matthias M. Herth and Gitte M. Knudsen Part II 5-HT2AR Related Brain Functions Serotonergic Receptor 5-HT2A in the Cardiosympathovagal System ..... 137 M. Kermorgant, A. Pavy-Le Traon, J.M. Senard, and D.N. Arvanitis Crosstalk Between 5-HT2A and mGlu2 Receptors: Implications in Schizophrenia and Its Treatment ............................... 147 José L. Moreno and Javier González-Maeso Schizophrenia ................................................. 191 Anna Castañé and Albert Adell vii viii Contents Role of Serotonin-2A Receptors in Pathophysiology and Treatment of Depression ..................................... 205 Lucia Moravčíková, Kristína Csatlósová, Barbora Ďurišová, Katarína Ondáčová, Michaela Pavlovičová, Ľubica Lacinová, and Eliyahu Dremencov Brain Circuits Regulated by the 5-HT2A Receptor: Behavioural Consequences on Anxiety and Fear Memory ........................ 231 L. Moulédous, P. Roullet, and Bruno P. Guiard 5-HT2A/2B/2C Receptors, Memory and Therapeutic Targets ............. 259 Alfredo Meneses, Rossana Nieto-Vera, and Rosa María Anaya-Jiménez 5-HT2A Receptors in the Basal Ganglia ............................. 273 Cristina Miguelez, Teresa Morera-Herreras, and Philippe De Deurwaerdère The Involvement of 5-HT2A Receptor in the Regulation of Sleep and Wakefulness, and the Potential Therapeutic Use of Selective 5-HT2A Receptor Antagonists and Inverse Agonists for the Treatment of an Insomnia Disorder ................. 311 Jaime M. Monti, Seithikurippu R. Pandi Perumal, D. Warren Spence, and Pablo Torterolo 5-HT2A Receptors and Pain ...................................... 339 Christine Courteix, Amandine Dupuis, Pierre-Yves Martin, and Benoit Sion 5-HT2A Receptors in Eating Disorders ............................