Understanding Nicotine and Tobacco Addiction: Novartis Foundation Symposium 275

283 Pages·2006·6.48 MB·English

by  Novartis Foundation(eds.)

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.
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offers accommodation and meeting facilities to visiting scientists and their
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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
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Novartis Foundation Symposium 275
viii +276 pages,27 figures,11 tables
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ISBN-10 0-470-01657-4
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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)