UNIVERSITY OF MALTA

LIFE SCIENCE RESEARCH SEMINARS

Web: http://www.um.edu.mt/events/scisem/ Email: scisem@um.edu.mt

Abstract form

Title: 5-HT2C receptors in the pathophysiology of CNS disease Presenter: Prof Giuseppe Di Giovanni

Contact address: Department of Physiology and Biochemistry, Tel: +356 23402776

Fax: +356 21310577 Email: giuseppe.digiovanni@um.edu.mt

Presentation date: 4 April 2011

Abstract Approximately 200-250 words. Please email to scisem@um.edu.mt.

Several studies have focused on the role of serotonergic 5-HT2C receptors in the

regulation of forebrain dopamine (DA) function and have highlighted their potential

as a target for improved treatments of neuropsychiatric disorders related to central

DA-ergic neuron dysfunction. I’ll summarize our and other works that have

extensively explored the role of 5-HT2C receptors in the control of DA systems both

in basal and drug-induced conditions, using in vivo electrophysiological and

microdialytic techniques. It is well established that this receptor subtype exerts both

tonic and phasic modulation of central DA-ergic function. This evidence has led to

the suggestion that drugs acting on 5-HT2C receptors have potential as novel

antipsychotic (APD) and antidepressant agents and may also be used in the

treatment of other neuropsychiatric disorders such as Parkinson’s disease and

psychoactive substance abuse. The physiology, pharmacology and anatomical

distribution of the 5-HT2C receptors in the central nervous system (CNS) will first be

introduced. Moreover, experimental data regarding the effect of 5-HT2C selective

agents on the neuronal activity of DA neurons of the ventral tegmental area (VTA)

and substantia nigra pars compacta (SNc), as well as the changes of basal DA

release in the striatum, nucleus accumbens and cerebral cortex, are discussed.

Finally, I will also discuss the potential use of 5-HT2C agents in the treatment of

depression, schizophrenia, Parkinson's disease and drug abuse.

Giuseppe Di GiovanniEditor-in-Chief Ennio EspositoVincenzo Di MatteoAssistent Editors

5-HT2C

Receptors in the Pathophysiology of CNS Disease SPRINGER

EditorsEditor-in-ChiefProf. Giuseppe Di GiovanniUniversity of Malta Department of Physiology and BiochemistryMsida, Maltagiuseppe.digiovanni@um.edu.mt

Assistant EditorDr Ennio EspositoConsorzio Mario Negri Sud Centro di RicercheFarmacologiche e BiomedicheChieti, Italyesposito@negrisud.it

Assistant EditorDr Vincenzo Di MatteoConsorzio Mario Negri Sud Centro di RicercheFarmacologiche e BiomedicheChieti, Italyvdimatteo@negrisud.it

ISBN 978-1-60761-940-6 e-ISBN 978-1-60761-941-3DOI 10.1007/978-1-60761-941-3Springer New York Dordrecht Heidelberg London

© Springer Science+Business Media, LLC 2011All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden.The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.

Printed on acid-free paper

Humana Press is part of Springer Science+Business Media (www.springer.com)

To my wife Samantha,For her abundant support, for her patience and understanding, and for her love

G. Di Giovanni

vii

Preface

Accepting the challenge of editing the first book on a subject is a risky business, particularly if you attempt to produce an overview in the research of 5-HT

2C recep-

tors, an area now going back over 25 years with so productive results. Nevertheless, I have embarked on this unique editorial enterprise with the aim of giving pleasure to the readers and researchers and not least to myself, confident that it will be instrumental in future research in 5-HT

2C pathophysiology. A few years ago Bryan

Roth edited, for the same series “The Receptors,” a very fine volume on serotonin receptors. The present volume is a further development of this and is a thorough examination of the 5-HT

2C receptor subclass, needed to cover the extraordinary

amount of research into nearly every aspect of 5-HT2C

receptor function that has recently emerged. This is not surprising, considering that the 5-HT

2C receptor is a

prominent central serotonin receptor subtype, widely expressed within the central and the peripheral nervous system and is thought to play a major role in the regula-tion of a plethora of behaviors. Therefore, it has been shown by experimental and clinical observation that it may represent a possible therapeutic target for the devel-opment of drugs for a range of CNS disorders such as schizophrenia, depression, drug abuse, eating disorders, Parkinson’s disease, and epilepsy, to cite but a few. The book, a result of the efforts of an international group of authors, has the aim of providing an update of the functional status of the 5-HT

2C receptor, covering

molecular, cellular, anatomical, biochemical, and behavioral aspects, to highlight its distinctive regulatory properties, the emerging functional significance of consti-tutive activity and RNA-editing in vivo, and the therapeutic potentiality in different diseases that are singled-out in different chapters.

While covering the latest research, for obvious reasons, this volume cannot be exhaustive and it has been impossible to include a number of authors of obvious merit. I hope that more volumes on the subject will be possible in the future.

I want to thank all the authors who have responded very willingly and contrib-uted their time and expertise in preparing their individual contribution to a consis-tently high standard. My thanks go to Vincenzo Di Matteo and Ennio Esposito who have contributed to the realization of this book. I am indebted to Philippe De Deurwaerdère, who has unselfishly dedicated his time and expertise to insightful and helpful reading of this text and Dr Clare Austen for reviewing the English style of these manuscripts.

viii Preface

Finally, I would like to express my sincere appreciation to Kime Neve, series editor, and Matthew Giampoala, Springer publishing editor, for their help in driving the book’s development and eventual publication.

I hope that the contents of this volume will further inspire and stimulate discus-sions and new interdisciplinary research on the 5-HT

2C receptor.

May 2010 Prof. Giuseppe Di Giovanni University of Malta

Msida, Malta

ix

Contents

1 The Making of the 5-HT2C Receptor ....................................................... 1Jose M. Palacios, Angel Pazos, and Daniel Hoyer

2 Serotonin 5-HT2C Receptors: Chemical Neuronatomy in the Mammalian Brain .......................................................................... 17Guadalupe Mengod

3 The Medicinal Chemistry of 5-HT2C Receptor Ligands ......................... 29Marcello Leopoldo, Enza Lacivita, Paola De Giorgio, Francesco Berardi, and Roberto Perrone

4 Insights into 5-HT2C Receptor Function Gained from Transgenic Mouse Models ............................................................... 51Stephen J. Bonasera

5 Serotonin 5-HT2C Receptor Signal Transduction ................................... 75Maria N. Garnovskaya and John R. Raymond

6 Homology Modeling of 5-HT2C Receptors .............................................. 97Nicolas Renault, Amaury Farce, and Philippe Chavatte

7 5-HT2C Receptor Dimerization ................................................................. 129Katharine Herrick-Davis and Dinah T. Farrington

8 RNA Editing of 5-HT2C Receptor and Neuropsychiatric Diseases ................................................................ 157Kazuya Iwamoto, Miki Bundo, and Tadafumi Kato

9 Serotonergic Control of Adult Neurogenesis: Focus on 5-HT2C Receptors ...................................................................... 169Annie Daszuta

x Contents

10 The Constitutive Activity of 5-HT2C Receptors as an Additional Modality of Interaction of the Serotonergic System ..................................................................... 187Sylvia Navailles and Philippe De Deurwaerdère

11 The 5-HT2C Receptor Subtype Controls Central Dopaminergic Systems: Evidence from Electrophysiological and Neurochemical Studies ................................ 215Giuseppe Di Giovanni, Ennio Esposito, and Vincenzo Di Matteo

12 The Role of 5-HT2C Receptors in the Pathophysiology and Treatment of Depression ......................... 249Eliyahu Dremencov, Joost H.A. Folgering, Sandra Hogg, Laurence Tecott, and Thomas I.F.H. Cremers

13 5-HT2C Receptors and Suicidal Behavior .............................................. 261Fabio Panariello, Naima Javaid, and Vincenzo De Luca

14 The 5-HT2C Receptor as a Target for Schizophrenia ........................... 275Herbert Y. Meltzer, Liwen Sun, and Hitoshi Hashimoto

15 Serotonin and Reward-Related Behavior: Focus on 5-HT2C Receptors .................................................................... 293Paul J. Fletcher and Guy A. Higgins

16 Tat-3L4F: A Novel Peptide for Treating Drug Addiction by Disrupting Interaction Between PTEN and 5-HT2C Receptor ................................................................... 325Amy Hu, Lintao Jia, Jean-Christian Maillet, and Xia Zhang

17 The Role of Serotonin in Eating Behavior: Focus on 5-HT2C Receptors .................................................................... 339Jason C.G. Halford

18 Physiological and Pathophysiological Aspects of 5-HT2c Receptors in Basal Ganglia .................................................... 351Philippe De Deurwaerdère, Laurence Mignon, and Marie-Françoise Chesselet

19 Modeling Tardive Dyskinesia: Predictive 5-HT2C Receptor Antagonist Treatment................................................ 383Richard M. Kostrzewa

xiContents

20 The Role of 5-HT2A/2C Receptors in Sleep and Waking ........................ 393Jaime M. Monti and Héctor Jantos

21 Role of Alternative Splicing of the 5-HT2C Receptor in the Prader–Willi Syndrome .............................................. 413Shivendra Kishore and Stefan Stamm

22 The Role of 5-HT2C Receptor in Epilepsy ............................................. 429Rita Jakus and Gyorgy Bagdy

23 The Role of Serotonin on Attentional Processes and Executive Functioning: Focus on 5-HT2C Receptors .................... 445Eleftheria Tsaltas and Vasileios Boulougouris

24 5-HT2C Receptors in Learning ............................................................... 461López-Vázquez Miguel Ángel, Gutiérrez-Guzmán Blanca Érika, Cervantes Miguel, and Olvera-Cortés María Esther

25 The Role of 5-HT2C Polymorphisms in Behavioral and Psychological Symptoms of Alzheimer Disease ............................ 509Antonia Pritchard

26 Ocular Hypotension: Involvement of Serotonergic 5-HT2 Receptors ..... 523Najam A. Sharif

Index ................................................................................................................. 545