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Understanding Nicotine and Tobacco Addiction: Novartis Foundation Symposium 275, Volume 275. Edited by Gregory Bock and Jamie Goode Copyright  Novartis Foundation 2006. ISBN: 0-470-01657-4 UNDERSTANDING NICOTINE AND TOBACCO ADDICTION The Novartis Foundation is an international scientific and educational charity (UK Registered Charity No.313574).Known until September 1997 as the Ciba Foundation,it was established in 1947 by the CIBA company of Basle,which merged with Sandoz in 1996,to form Novartis.The Foundation operates independently in London under English trust law.It was formally opened on 22 June 1949. The Foundation promotes the study and general knowledge of science and in particular encourages international co-operation in scientific research.To this end,it organizes internationally acclaimed meetings (typically eight symposia and allied open meetings and 15–20 discussion meetings each year) and publishes eight books per year featuring the presented papers and discussions from the symposia.Although primarily an operational rather than a grant-making foundation,it awards bursaries to young scientists to attend the symposia and afterwards work with one of the other participants. The Foundation’s headquarters at 41 Portland Place,London W1B 1BN, provide library facilities,open to graduates in science and allied disciplines. Media relations are fostered by regular press conferences and by articles prepared by the Foundation’s Science Writer in Residence.The Foundation offers accommodation and meeting facilities to visiting scientists and their societies. Information on all Foundation activities can be found at http://www.novartisfound.org.uk Novartis Foundation Symposium 275 UNDERSTANDING NICOTINE AND TOBACCO ADDICTION 2006 Copyright © Novartis Foundation 2006 Published in 2006 by John Wiley & Sons Ltd, The Atrium,Southern Gate, Chichester PO19 8SQ,UK National 01243 779777 International (+44) 1243 779777 e-mail (for orders and customer service enquires):[email protected] Visit our Home Page on http://eu.wiley.com All Rights Reserved.No part of this book may be reproduced,stored in a retrieval system or transmitted in any form or by any means,electronic,mechanical,photocopying,recording,scanning or otherwise,except under the terms of the Copyright,Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd,90 Tottenham Court Road,London W1T 4LP,UK,without permission in writing of the Publisher.Requests to the Publisher should be addressed to the Permissions Department,John Wiley & Sons Ltd,The Atrium,Southern Gate, Chichester,West Sussex PO19 8SQ,England,or emailed to [email protected],or faxed to (+44) 1243 770620. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered.It is sold on the understanding that the Publisher is not engaged in rendering professional services.If professional advice or other expert assistance is required, the services of a competent professional should be sought. Other Wiley Editorial Offices John Wiley & Sons Inc.,111 River Street,Hoboken,NJ 07030,USA Jossey-Bass,989 Market Street,San Francisco,CA 94103-1741,USA Wiley-VCH Verlag GmbH,Boschstr.12,D-69469 Weinheim,Germany John Wiley & Sons Australia Ltd,33 Park Road,Milton,Queensland 4064,Australia John Wiley & Sons (Asia) Pte Ltd,2 Clementi Loop #02-01,Jin Xing Distripark,Singapore 129809 John Wiley & Sons Canada Ltd,22 Worcester Road,Etobicoke,Ontario,Canada M9W 1L1 Wiley also publishes its books in a variety of electronic formats.Some content that appears in print may not be available in electronic books. Novartis Foundation Symposium 275 viii +276 pages,27 figures,11 tables British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN-13 978-0-470-01657-2 ISBN-10 0-470-01657-4 Typeset in 101/on 121/pt Garamond by SNP Best-set Typesetter Ltd.,Hong Kong 2 2 Printed and bound in Great Britain by T.J.International Ltd,Padstow,Cornwall. This book is printed on acid-free paper responsibly manufactured from sustainable forestry, in which at least two trees are planted for each one used for paper production. Contents Symposium on Understanding nicotine and tobacco addiction, held at the Novartis Foundation, London, 17–19 May 2005 Editors: Gregory Bock (Organizer) and Jamie Goode This symposium is based on a proposal made by Robert West and Gino van Heeke William A.Corrigall Chair’s introduction 1 Richard Petoand Richard Doll The hazards of smoking and the benefits of stopping 3 Discussion 15 Ian Stolerman Animal models for nicotine dependence 17 Discussion 28 Robert West Defining and assessing nicotine dependence in humans 36 Discussion 52 General discussion I 59 Uwe Maskos,Sylvie Granon,Philippe Faureand Jean-Pierre Changeux Nicotinic acetylcholine receptor functions in the CNS investigated with a novel method of stereotaxic gene re-expression in knockout mice 64 Discussion 79 Marina R.Picciotto Nicotine-mediated activation of signal transduction pathways 83 Discussion 90 David Balfour Complementary roles for the accumbal shell and core in nicotine dependence 96 Discussion 105 v vi CONTENTS Christian Heidbreder The dopamine D system:new opportunities for 3 dopamine-based reward 116 Discussion 123 Athina Markou Pathways and systems involved in nicotine dependence 132 Discussion 145 Arthur L.Brody Localizing tobacco dependence pathways with functional brain imaging 153 Discussion 166 Caryn Lerman Pharmacogenetic approach to nicotine dependence treatment 171 Discussion 178 Robert Walton Pharmacogenomics and smoking cessation 184 Discussion 194 General discussion II Power in studies 197 Receptor desensitization 199 Peter Hajek What limits the efficacy of current nicotine replacement therapies? 204 Discussion 213 Saul Shiffman,Stuart Fergusonand Deborah Scharf Exploring behavioural mechanisms of nicotine replacement therapy for smoking cessation 219 Discussion 231 Rachel F.Tyndaleand Edward M.Sellers Modifying the metabolism of nicotine as a therapeutic strategy 235 Discussion 244 William A.Corrigall Challenges in discovery and development of pharmacotherapies for tobacco addiction 249 Discussion 259 Final discussion Nicotine comorbidity 262 Animal models 264 Index of contributors 266 Subject index 268 Participants David Balfour Section of Psychiatry, Division of Pathology & Neuroscience, Ninewells Hospital & Medical School,Dundee DD1 9SY,UK Daniel Bertrand Department of Neurosciences, Faculty of Medicine, Univer- sity of Geneva,CH-1211 Geneva 4,Switzerland Arthur L. Brody UCLA Department of Psychiatry, 300 UCLA Medical Plaza, Ste 2200,Los Angeles,CA 90095,USA Lisiane Bizarro (Novartis Foundation Bursar)Instituto de Psicologia,Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600, RS-90035-003, Brazil Anthony Caggiula Department of Psychology, University of Pittsburgh, 3131 Sennott Square,210 Bouquet Street,Pittsburgh,PA 15260,USA Jean-Pierre Changeux Receptors and Cognition Laboratory,Institut Pasteur,25 Rue du Dr Roux,F-75724 Paris 15,France Cristiano Chiamulera Section in Pharmacology, Department of Medicine and Public Health, University of Verona, P.le L. Scuro, 10, I-37100 Verona, Italy Paul B.S.Clarke Department of Pharmacology and Therapeutics,McGill Uni- versity, 3655 Promenade Sir-William-Osler, Room 1325, Montreal, QC H3G 1Y6,Canada William A. Corrigall (Chair) Corrigall Consulting, 48 Highland Park Blvd., Thornhill, ON L3T 1B3, Canada, and Minneapolis Medical Research Founda- tion,914 South Eighth Street Minneapolis,MN 55404,USA Fabrizio Gasparini Neuroscience Research, Novartis Institute for BioMedical Research Basel,WSJ-386.715,Postfach,CH-4002 Basel,Switzerland Peter Hajek Tobacco Dependence Research Centre, Barts and The London, Queen Mary’s School of Medicine and Dentistry, Turner Street, Whitechapel, London E1 2AD,UK vii viii PARTICIPANTS Christian Heidbreder Centre of Excellence for Drug Discovery in Psychiatry, GlaxoSmithKline Pharmaceuticals,I-37135 Verona,Italy Martin J. Jarvis Department of Epidemiology and Public Health, University College London,Gower Street,London WC1E 6BT,UK Caryn Lerman Transdisciplinary Tobacco Use Research Center, University of Pennsylvania,3535 Market Street,Suite 4100,Philadelphia,PA 19104,USA Athina Markou Molecular and Integrative Neurosciences Department, SP2400 The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037,USA Kenneth Perkins WPIC University of Pittsburgh, 3811 O’Hara St, Pittsburgh, PA 15213,USA Richard Peto Clinical Trial Service Unit and Epidemiological Studies Unit, Radcliffe Infirmary,Oxford OX2 6HE,UK Marina R.Picciotto Yale University,Department of Psychiatry,34 Park Street, CMHC 3 Fl,New Haven,CT 06520,USA Jane Powell Room 309 Whitehead Building, Psychology Department, Gold- smiths College,University of London,New Cross,SE14 6NW Saul Shiffman Department of Psychology, University of Pittsburgh, Sennott Square, 3rd Floor, 210 S. Bouquet Street (corner of Forbes), Pittsburgh, PA 15260,USA Ian Stolerman Section of Behavioural Pharmacology, Institute of Psychiatry PO49,King’s College London,De Crespigny Park,London SE5 8AF,UK Rachel F. Tyndale Centre for Addiction and Mental Health, Department of Pharmacology, Room 4326, Medical Sciences Building, 1 King’s College Circle, University of Toronto,Toronto,Ontario M5S 1A8,Canada Gino Van Heeke Novartis Institute for Biochemical Research, Wimblehurst Road,Horsham,West Sussex RH12 5AB,UK Robert Walton Department of Clinical Pharmacology, University of Oxford, Radcliffe Infirmary,Woodstock Road,Oxford,OX2 6HE,UK Robert West Cancer Research UK Health Behaviour Unit,Department of Epi- demiology and Public Health, University College London, Brook House, 2–16 Torrington Place,London WC1E 6BT,UK Understanding Nicotine and Tobacco Addiction: Novartis Foundation Symposium 275, Volume 275. Edited by Gregory Bock and Jamie Goode Copyright  Novartis Foundation 2006. ISBN: 0-470-01657-4 Chair’s introduction William A.Corrigall Corrigall Consulting, 48 Highland Park Blvd., Thornhill, ON L3T 1B3, Canada The presentations at this meeting break down into five areas. The first is the characterization and definition of nicotine and tobacco addiction.The second deals with nicotinic receptors. The third involves brain pathways and neurotransmitters involved in nicotine and tobacco addiction.Genetic susceptibility is a fourth issue, and the fifth is medications for nicotine and tobacco addiction. In terms of characterizing nicotine and tobacco addiction,there are some imme- diate issues that need discussion. How do we define nicotine and tobacco addic- tion? In my opinion,resolution of this is something that should be high on our list of priorities.If we look across the range of current definitions,there are disparate elements,factors and dimensions being used. How do we reduce tobacco and nicotine addiction to studiable elements? Is there a single concept or definition for the disease but various sub-dimensions,the study of which is logical to advance the field and to advance medication development? What cellular or animal models can we use to achieve such advances in basic biology? How can we deconstruct the disease into logical models for human experi- mental research? And what are appropriate components of the disease in clinical trials? We need to turn our attention to the full set of nicotinic receptors that could be involved in nicotine addiction. An extensive focus on the mid-brain dopamine system has guided some of the focus on the nicotinic receptor subtypes involved in addictive processes. This is only sensible. As the span of neurochemical targets is broadening,however,we should look at how other nicotinic receptors might be involved.Where is this full set of receptors located in the CNS? How do they influ- ence local CNS function, both at the individual cell level and at the local circuitry level? What are the response dynamics of these receptors when ligand binding occurs? At the last of these meetings on this topic,16 years ago (Ciba Foundation 1990), there was clearly a focus on the midbrain dopamine system. This focus has remained,as indeed it has with drug abuse in general.The present meeting affords a good opportunity for us to review where we have been and where we might go with this concept, while at the same time broadening our focus to other neuro- chemical targets. 1 2 CORRIGALL What are the new approaches that exist by which we might make progress in understanding neurochemical pathways involved in nicotine addiction? With regard to genetic susceptibility, the obvious issue is the question of what underlies the high heritability of nicotine addiction. What are the phenotypes of interest? What are the polymorphisms of interest? These relate to the neurochem- ical substrates that have been discovered.However,we have not yet accounted for all of the variance,and there must be other key elements. Finally, we come to medications for nicotine and tobacco addiction. Here we need to examine the mechanisms of the various nicotine-replacement therapies that account for their effectiveness.Also,what is their effectiveness? What are the mechanisms of other non-nicotinic medications? Do all existing medications have essentially the same effectiveness? What are the prospects for medications that have a non-CNS base of action,such as a nicotine vaccine or medications that interfere with the metabolism of nicotine? Also, how can we improve the translation of science to practice? Are there realistic ways to proceed today to help move discov- ery science to development more expeditiously? Through these five key themes of this symposium,there are a number of over- arching issues.The one I would raise at the outset is that we are talking about both nicotine and tobacco. Nicotine addiction may be a large or small part of tobacco addiction.We need to recognize this in medication development.Behavioural influ- ences and sociocultural factors are also important.Is the tobacco-addicted individ- ual in the same situation as a person addicted to cocaine or opioids,for example? A second issue relevant to the whole is that substantial resources will be needed for us to advance this work.This is an issue both for funding agencies and also for those of us who practise in the field.As a part of the research community,we need to think about ways we can contribute to making progress with existing funding realities.And finally it would be valuable to give some thought to how we as a com- munity can help to effect the substantial agreement that will be required to resolve different points of view? These are some of the questions that I hope we will con- sider at this meeting. Reference Ciba Foundation 1990 The biology of nicotine dependence.Wiley,Chichester (Ciba Found Symp 152)

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Cigarette smoking is estimated to lead to 4.9 million premature deaths per year worldwide. This is predicted to rise to 10 million by 2020. In western countries it kills half of all smokers who fail to stop. The prevailing model for tobacco addiction is that nicotine from cigarettes rewards smoking
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