SUBSTANCE ABUSE

1
Cutting-Edge Research on Prevention and
Treatment of
SUBSTANCE ABUSE
Nora D. Volkow, M.D. Director National Institute
on Drug Abuse
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Addiction
Medical
NEUROTOXICITY OBESITY AIDS CANCERMENTAL ILLNESS
DRUGS
Economic
Social
HEALTH CARE COSTS PRODUCTIVITY
LOSS ACCIDENTS
HOMELESSNESS CRIME VIOLENCE
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• ADDICTION IS A DISEASE OF THE BRAIN
• as other diseases it affects the tissue function

Decreased Heart Metabolism in Heart Disease
Patient
Healthy Heart
Diseased Heart
Sources From the laboratories of Drs. N. Volkow
and H. Schelbert
4
2. ADDICTION IS A DEVELOPMENTAL DISEASE starts
in adolescence and childhood
1.6
1.4
1.2
in each age group who develop first-time
cannabis use disorder
1.0
0.6
0.8
0.4
0.2
0.0
5
10
15
18
25
30
35
40
45
50
55
60
65
70
Age
Age at cannabis use disorder as per DSM IV
NIAAA National Epidemiologic Survey on Alcohol
and Related Conditions, 2003
5
3. ADDICTION INVOLVES MULTIPLE FACTORS
Biology/Genes
Environment
DRUG
Brain Mechanisms
Addiction
6
Drugs of Abuse Engage Systems in the Motivation
and Pleasure Pathways of the Brain
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Dopamine
movement
8
Dopamine Neurotransmission
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Brain Dopamine System
DA Receptors
DA
Anatomy
DA
DA
DA
DA
DA
DA
signal
Dopamine Cell
Metabolism
10
Effect of Cocaine Abuse on Dopamine D2 Receptors
normal subject
cocaine abuser (1 month post)
cocaine abuser (4 months post)
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Dopamine D2 Receptors are Lower in Addiction
Cocaine
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
Meth
Reward Circuits
Non-Drug Abuser
DA D2 Receptor Availability
Alcohol
Heroin
Drug Abuser
control
addicted
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Effects of Tx with an Adenovirus Carrying a DA D2
Receptor Gene into NAc in DA D2 Receptors
Overexpression of DA D2 receptors reduces
alcohol self-administration
60
1st D2R Vector
2nd D2R Vector
p lt 0.0005
50
p lt 0.0005
40
p lt 0.005
p lt 0.005
30
Percent Change in D2R
20
p lt 0.10
10

0
Null Vector
6
10
4
8
24
0
0
-20
DA
DA
-40
p lt 0.01
DA
DA
Change in Alcohol Intake
p lt 0.01
DA
-60
DA
p lt 0.001
DA
-80
DA
p lt 0.001
p lt 0.001
-100
0
4
6
8
10
24
Time (days)
Source Thanos, PK et al., J Neurochem, 78, pp.
1094-1103, 2001.
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Effects of a Social Stressor on Brain DA D2
Receptors and Propensity to Administer Drugs
Individually Housed
Group Housed
Dominant
Subordinate
50
Becomes Dominant No longer stressed
40
30

Reinforcers (per session)

20
10
Becomes Subordinate Stress remains
0
S
.003
.01
.03
.1
Cocaine (mg/kg/injection)
Morgan, D. et al. Nature Neuroscience, 5
169-174, 2002.
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What is the Functional Significance of the
Decreases in DA D2 Receptors?
control cocaine abuser
DA
DA
Anatomy
DA
DA
DA
DA
DA
signal
DA SYNAPSE
Metabolism
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Correlations Between D2 Receptors in Striatum and
Brain Glucose Metabolism
Inhibitory Control
Cocaine Abusers
65
60
55
OFC
50
umol/100g/min
CG
45
40
PreF
Striatum
r 0.7, P lt 0.001
35
30
1.8
2
2.2
2.4
2.6
2.8
3
3.2
3.4
OFC
DA D2 Receptors (Ratio Index)
METH Abusers
Salience Attribution
OFC
umol/100gr/min
r 0.7, P lt 0.005
DA D2 Receptors
(Bmax/kd)
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Circuits Involved In Drug Abuse and Addiction
CONTROL INHIBITORY CONTROL
PFC
ACG
OFC
SCC
REWARD
MOTIVATION/ DRIVE
MEMORY/ LEARNING
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Priority Areas for NIDA
Prevention Research (Children and
Adolescents) genetics
development environment co-morbidity
Treatment Interventions (New Targets
New Strategies)
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12th Graders Past Year Marijuana Use vs.
Perceived Risk of Occasional Marijuana Use
Source Monitoring the Future Study, 2003.
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The Brain is not Fully Developed Until Early
Adulthood
Brain areas where volumes are smaller in
adolescents than young adults.
Sowell, E.R. et al., Nature Neuroscience, 2
859-861, 1999
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The Adolescent Brain Responds to Drugs
Differently than the Adult Brain
Treatment of adolescent rats with Nicotine but
not young adults leads to
Increases in Nicotine Self Administration
Increases in Nicotine Receptors
Source Adriana, W. et al., J of Neurosci,
23(11), pp. 4712-4716, June 1, 2003.
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Priority Areas for NIDA
Prevention Research (Children and
Adolescents) genetics
development environment co-morbidity
Treatment Interventions (New Targets
New Strategies)
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GENES
PROTEINS
BRAIN
BEHAVIOR
Addiction
TREATMENT
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ROADBLOCK 1
Unique Challenges Involved in Developing Drugs
to Treat Addiction
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Posterior Hippocampi of London Taxi Drivers Were
Significantly Larger Than Those of Controls
Positive Correlation Between Gray Matter Volume
and Time As A Taxi Driver
Source Maguire, E.A. et al., PNAS, 97(8), pp.
4398-4403, 2000.
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Decreases in Metabolism in Anterior Cingulate
Gyrus Orbito Frontal Cortex (OFC)
Impulsivity
Compulsive Drug Intake
control cocaine abuser
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ROADBLOCK 2
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TRANSLATIONAL BOTTLENECK
Source Hyman, S.E. and Fenton, W.S. Science,
299, pp. 350-351, January 17, 2003.
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Percentage of Recommended Care Received
Senile cataract Breast cancer Prenatal care Low
back pain CAD Hypertension Congestive heart
failure Cerebrovascular disease COPD Depression Or
thopedic conditions Osteoarthritis Colorectal
cancer Asthma Benign prostatic hyperplasia Hyperli
pidemia Diabetes mellitus Headache UTI Community-a
cquired pneumonia STDs Dyspepsia and peptic ulcer
disease Atrial fibrillation Hip fracture Alcohol
dependence
0
20
40
60
80
100
Source McGlynn, E.A., NEJM, 348, pp. 2635-2645,
June 26, 2003
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National Drug Abuse Treatment Clinical Trials
Network
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CJ-DATS Criminal Justice Drug Abuse Treatment
Studies
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The Smokers Body
Drugs dont just affect the BRAIN
Smokers have a 35-45 reduction in MAO B in
heart, lungs, kidneys and spleen
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ROADBLOCK 3
Drug Abuse and Addiction Contribute to a Wide
Variety of Medical Diseases

• Mental Illness
• Cancer
• Infectious Diseases (HIV, HCV)
• Cardiac
• Pulmonary
• Learning Disorders
• Obesity
• Cerebrovascular (strokes)
• Trauma (accidents)

But Pediatricians and Other Primary Care
Physicians Are Reluctant to Address Them
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Biology/Genes
Environment
DRUG
Brain Mechanisms

Addiction
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Where Do We Need to Go From Here?
We Need to
Advance the SCIENCE
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DA D2 Receptors in Controls and in Cocaine
Abusers (NMS)
Normal Controls
Cocaine Abusers
DA D2 Receptors
(Bmax/Kd)
Age (years)
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3. MULTIPLE FACTORS ARE INVOLVED IN ADDICTION
ENVIRONMENT
DEVELOPMENTAL HISTORY
GENES
DRUGS
BRAIN MECHANISMS
ADDICTION
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