NEUROBIOLOGICAL RESEARCH ON ADDICTION - National Drug Strategy

241 Pages·2011·1.31 MB·English

NEUROBIOLOGICAL RESEARCH ON ADDICTION
A Review of the Scientific, Public Health and Social Policy
Implications for Australia

Final Report
30th January 2009

Project Team
Adrian Carter 1,2
Prof Wayne Hall 1,3
Dr Ben Capps 4
Dr Mark Daglish 5

1. The University of Queensland, UQ Centre for Clinical Research
2. The University of Melbourne, School of Psychological Sciences
3. The University of Queensland, Queensland Brain Institute
4. The University of Singapore, Centre for Medical Ethics
5. The University fo Queensland, School of Psychiatry

Ministerial Council on Drug Strategy – Cost Shared Funding Model project

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Table of Contents
TABLE OF FIGURES 3
TABLE OF TABLES 4
ABBREVIATIONS 5
KEY RECOMMENDATIONS 8
EXECUTIVE SUMMARY 9
INTRODUCTION 25
ADDICTION AND DRUG USE IN AUSTRALIA 27
THE NEUROBIOLOGY OF ADDICTION 31
NEUROBIOLOGICAL TREATMENTS OF ADDICTION 80
ETHICAL AND POLICY ISSUES IN THE APPLICATION OF
NEUROBIOLOGICAL RESEARCH ON ADDICTION 110
AUDIT OF AUSTRALIAN ADDICTION NEUROSCIENCE RESEARCH 134
RECOMMENDATIONS 165
REFERENCES 168
GLOSSARY 193
APPENDIX 1: TAXONOMY OF AUSTRALIAN ADDICTION
NEUROSCIENCE RESEARCH GROUPS 204
APPENDIX 2: AUSTRALIAN ADDICTION NEUROSCIENCE
PUBLICATIONS 208
APPENDIX 3: BIBLIOGRAPHY OF ADDICTION NEUROBIOLOGY
RESEARCH 231
INDEX 237

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Table of Figures

FIGURE 1. THE CYCLE OF ADDICTION................................................................32
FIGURE 2. PROJECTIONS FROM THE MIDBRAIN TO THE NAcc AND
FOREBRAIN......................................................................................................40
FIGURE 3. PSYCHOSTIMULANT INCREASE OF DOPAMINE ACTIVITY AT THE
ACCUMBENS....................................................................................................43
FIGURE 4. ACTIONS OF DRUGS ON ACCUMBAL DOPAMINE ACTIVITY..........44
FIGURE 5. REWARDING ACTIVITIES INCREASE DOPAMINE SIGNALLING.....45
FIGURE 6. OREXINS ROLE IN ASSOCIATIVE LEARNING IN ADDICTION.........58
FIGURE 7. SCHEMATIC DIAGRAM OF MOLECULAR CHANGES IN NEURAL
CELLS IN RESPONSE TO DRUG USE............................................................61
FIGURE 8. NMDA -DEPENDENT LONG-TERM POTENTIATION.........................63
R
FIGURE 9. DECREASED DOPAMINE RECEPTORS DUE TO DRUG ABUSE......68
FIGURE 10. PLASTIC CHANGES IN THE NEUROANATOMY OF ADDICTION...70
FIGURE 11. LEVELS OF NEUROBIOLOGICAL STUDY OF ADDICTION...........140
FIGURE 12. HUMAN VS. ANIMAL ADDICTION NEUROBIOLOGY RESEARCH IN
AUSTRALIA....................................................................................................153
FIGURE 13. TYPES OF ADDICTION NEUROBIOLOGY RESEARCH IN
AUSTRALIA....................................................................................................154
FIGURE 14. QUANTITATIVE ANALYSIS OF ADDICTION NEUROBIOLOGY
RESEARCH BY RESEARCH GROUP (SINCE 1997)....................................155
FIGURE 15. QUANTITATIVE ANALYSIS OF ADDICTION NEUROBIOLOGY
RESEARCH BY RESEARCH GROUP (SINCE 2005)....................................156
FIGURE 16. QUANTITATIVE ANALYSIS OF ADDICTIVE DRUGS RESEARCHED
IN AUSTRALIA (SINCE 1997)........................................................................157
FIGURE 17. AVERAGE IMPACT FACTOR FOR EACH RESEARCH GROUP IN
AUSTRALIA....................................................................................................158
FIGURE 18. SUMMED IMPACT FACTOR FOR EACH RESEARCH GROUP IN
AUSTRALIA....................................................................................................159
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Table of Tables

TABLE 1: CONTRIBUTION OF TOBACCO, ALCOHOL AND ILLICIT DRUGS TO
BURDEN OF DISEASE IN AUSTRALIA IN 2003.............................................28
TABLE 2. SUMMARY OF THE MAJOR THEORIES OF ADDICTION....................35
TABLE 3. SUMMARY OF ANIMAL MODELS OF ADDICTION..............................38
TABLE 4. THE NEUROCHEMICAL SITES AT WHICH DRUGS OF ADDICTION
ACT....................................................................................................................41
TABLE 5. MOLECULAR TARGETS OF DRUGS OF ADDICTION AND
PHARMACOLOGICAL APPROACHES...........................................................84
TABLE 6. A SUMMARY OF CURRENT OR DEVELOPING TREATMENTS OF
ADDICTION.....................................................................................................100

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Abbreviations

AC Adenyl Cyclase
aCG Anterior Cingulate Gyrus
AIDS Acquired Immune Deficiency Syndrome
ADHD Attention Deficit Hyperactivity Disorder
ALDH Aldehyde Dehydrogenase 2
AMPA -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
BBV Blood Borne Virus
BDNF Brain-derived Neurotrophic Factor
BLA Basolateral Amygdala
BNST Bed Nucleus of the Stria Terminalis
BOD Burden of Disease
CaMkII Calcium/calmodulin-dependent Protein-kinase II
cAMP Cyclic AMP
CART Cocaine and Amphetamine Regulated Transcript
CB1 Cannabinoid Receptor 1
Cdk5 Cyclin-dependent Kinase 5
CeA Central Amygdala
COMT Catechol-O-methyl Transferase
CPP Consditioned Palce Preference
CRF Corticotropin Releasing Factor
D1, D2, D3, D4 Dopamine Receptors 1, 2, 3, and 4
DA Dopamine
DAT Dopamine Transporter
DBS Deep Brain Stimulation
DD Drug Discrimination
dmPFC Dorsomedial Prefrontal Cortex
DNA Deoxyribonucleic Acid
DSM-IV-TR Diagnostic and Statistical Manual for Mental Illness, 4th Edition, Text
Revised
EEG Electroencephalograph
fMRI Functional Magnetic Resonance Imaging
FOS Fructooligosaccharide
GABA Gamma-aminobutyric Acid
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GHB Gamma-hydroxybutyric Acid
HIV Human Immunodeficiency Virus
HCV Hepatitis C Virus
HPA axis Hypothalamic Pituitary Adrenal Axis
HRT Hormone Replacement Therapy
ICD-10 International Classification of Disease
ICER Incremental Cost-effectiveness Ratio
ICSS Intracranial Self-stimulation
IDU Injecting Drug User
LC Locus Coeruleus
LSD Lysergic Acid Diethylamide
LTD Long Term Depression
LTP Long Term Potentiation
MAOI Monoamine Oxidase Inhibitors
MDMA 3,4-Methylenedioxy-N-methylamphetamine
MEG Magnetoencephalograph
MMT Methadone Maintenance Treatment
NAC N-acetylcystein
NAcc Nucleus Accumbens
NGO Non-Government Organisations
NIDA National Institute on Drug Abuse
NIAAA National Institute on Alcoholism and Alcohol Abuse
NMDA N-methyl-D-aspartic Acid
NRT Nicotine Replacement Therapy
NPY Neuropeptide Y
OCD Obsessive Compulsive Disorder
6-OHDA 6-Hydroxydopamine
OFC Orbitofrontal Cortex
PET Positron Emission Tomography
PFC Prefrontal Cortex
PKC Protein Kinase C
PMA Phorbol Myristate Acetate
PTSD Post-traumatic Stress Disorder
SPECT Single Photon Emission Computed Tomography
SSRI Serotonin Selective Reuptake Inhibitors
TMS Transcranial Magnetic Stimulation
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UK United Kingdom
UN United Nations
UROD Ultra-rapid Opioid Detoxification
US United States
VTA Ventral Tegmental Area
WHO World Health Organization

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Key Recommendations

In order to realise the promise of neuroscience and genetic research on addiction, we
make the following recommendations:
(1) Ministerial Council on Drug Strategy (MCDS) and Intergovernmental Committee
on Drugs (IGCD) advocate for increased ARC and NHMRC investment in
addiction neuroscience research, with a focus on increasing opportunities for:
 Further neuroimaging and longitudinal studies
 Collaborations between clinical and epidemiological researchers and
neuroscience researchers working in each of the major fields of addiction
neuroscience (animal studies, neuroimaging, genetics and translational
research)
 Research on the ethical and social implications of potential applications of
addiction neuroscience
 Translational research into the development and testing of new drug
treatments suggested by addiction neuroscience research; bridging the
gap between lab bench and bedside.
(2) Developing a greater awareness of research in the clinical community, and
fostering more integrated and collaborative relationships between the research
and clinical communities to deliver the most clinically appropriate and effective
treatments of addiction by:
 Including addiction neuroscience research in undergraduate and
postgraduate medical and other health sciences curricula
 Funding the Chapter of Addiction Medicine and the Australasian
Professional Society on Alcohol and Other Drugs (APSAD) to promote the
revision of curricula
 Forming a working group to oversee and facilitate research collaborations,
such as the Addiction Neuroscience Network Australia (ANNA)
 Fostering a wider public, professional and political recognition that
addiction is a public health issue and that neuroscience research can
make a major contribution to treating addiction more effectively by, for
example, publishing a simplified version of the report suitable for the
general public.

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Executive Summary

Addiction is a disorder in which individuals’ control over their drug use is impaired.
Individuals with an addiction continue to use alcohol, tobacco and other drugs in
ways that cause significant physical, psychological or social harm to themselves or
others. Over the past several decades, animal, and more recently human research,
has increasingly suggested that human addictive behaviours have a genetic and
neurobiological basis. These discoveries raise the potential for providing new and
more effective medical treatments of addiction.

Many addiction neuroscience researchers also express the hope that an increased
understanding of the neurobiological basis of addiction will lead to social policies that
recognise addiction as a neuropsychiatric condition that should be treated
therapeutically. This optimistic view needs to be balanced by anticipation of potential
misuses and misrepresentations of this research that may impede the realisation of
the potential for neuroscience and genetic research to reduce the harm associated
with drug use and addiction.

This report has the following goals:

First, it aims to provide a concise and accessible summary of key findings from
recent genetic and neuroscience research on addiction and of the treatment and
preventive technologies that may emerge from this research.

Second, the report outlines some of the key social and ethical questions that are
raised by neurobiological research on addiction, with the aim of ensuring that these
technologies are translated quickly and appropriately into the treatment and
prevention of addiction, and into effective public health policies towards drug use and
addiction.

Third, it aims to describe existing neurobiological research on addiction in Australia
with the aim of identifying ways in which the quantity and quality of this type of
research can be increased.

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Prevalence and Burden of Drug Use in Australia

In Australia, as in most other developed countries, a significant proportion of the
population are addicted to drugs. This includes: 17% of Australians who are
dependent on tobacco; 8% of Australians who are dependent on alcohol; and 4-6%
who are dependent on illicit drugs (such as cannabis, amphetamines and heroin).

Tobacco use is the largest contributor to the burden of disease in Australia,
accounting for 7.7% of the total Burden Of Disease (BOD). Most of this is attributable
to nicotine dependence that results in: lung cancer, chronic obstructive pulmonary
disease, ischaemic heart disease, stroke and oesophageal cancer. Tobacco smoking
is also the single largest contributor to the social costs of drug use (accounting for
approximately $31.5 billion per annum).

Alcohol abuse contributes 2.3% of the Australian BOD. In younger users, the major
contributors to disease burden are accidents, injuries, and suicide attributable to the
effects of intoxication. In older adults, alcohol use contributes to disease burden via
alcohol dependence, liver cirrhosis, and psychosis. Alcohol use costs Australian
society approximately $15.3 billion per year.

The use of illicit drugs contributes around 2.0% of the total BOD. Dependent heroin
use is the major contributor (accounting for approximately 60% of the illicit BOD).
Illicit drug use costs the Australian community approximately $3.8 billion per year.

Given the enormous health, economic and social burden arising from alcohol,
tobacco, and other drug use in Australia, there is an urgent need for more effective
social policies to reduce the burden of drug use and to develop more effective
treatments for persons who abuse drugs or develop addictions. Neuroscience and
genetic research on addiction has the potential to contribute to both goals and to
thereby significantly reduce the burden of drug use and addiction.

What is Neurobiological Research?

Neurobiological research is a broad, interdipliscinary field that encompasses a
diverse range of scientific approaches. This is particularly true of the study of
addiction which is understood to have biological, psychological and sociological
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