Neurobiology of drug abuse and addiction_NIDA

Bringing the
Full Power of Science
to Bear on
Drug Abuse
& Addiction

Homelessness
Crime
Violence
Neurotoxicity
AIDS, Cancer
Mental illness
Health care
Productivity
Accidents

4 Out of 10 U.S. AIDS Deaths Are
Related to Drug Abuse

Estimated Economic Cost to Society
Due to Substance
Abuse and Addiction:
Illegal drugs: $181 billion/year
Alcohol: $185 billion/year
Tobacco: $158 billion/year
Total: $524 billion/year
Surgeon General’s Report, 2004; ONDCP, 2004; Harwood, 2000.

What is Addiction?
Addiction is A Brain Disease
• Characterized by:
– Compulsive Behavior
– Continued abuse of drugs despite negative consequences
– Persistent changes in the brain’s structure and function

Advances in science have
revolutionized our fundamental
views of drug abuse and addiction.

Your Brain on Drugs in the 1980’s

Your Brain on Drugs Today
YELLOW
shows places in
brain where
cocaine binds
(e.g., striatum)
Fowler et al., Synapse, 1989.

Addiction is Like Other Diseases…
 It is preventable
 It is treatable
 It changes biology
 If untreated, it can last a lifetime
Healthy Brain Diseased Heart
Decreased Heart Metabolism
in Heart Disease Patient
Decreased Brain Metabolism
in Drug Abuser
Diseased Brain/
Cocaine Abuser
Healthy
Heart
High
Low
Research supported by NIDA addresses all of these
components of addiction.

Addiction Involves Multiple Factors

National Epidemiologic Survey on Alcohol and Related Conditions, 2003.
Age
0.0%
0.0%
0.2%
0.2%
0.4%
0.4%
0.6%
0.6%
0.8%
0.8%
1.0%
1.0%
1.2%
1.2%
1.4%
1.4%
1.6%
1.6%
1.8%
1.8%
5
5 10
10 15
15 21
21 25
25 30
30 35
35 40
40 45
45 50
50 55
55 60
60 65
65
%
in
each
age
group
who
develop
first-time
dependence
CANNABIS
ALCOHOL
TOBACCO
Addiction Is A Developmental Disease
that starts in adolescence and childhood
Age at tobacco, alcohol, and cannabis dependence per DSM IV

Why Do People Take Drugs in The
First Place?
To Feel Good
To have novel:
feelings
sensations
experiences
AND
to share them
To Feel Better
To lessen:
anxiety
worries
fears
depression
hopelessness

Drugs of Abuse
Engage Motivation and
Pleasure Pathways
of the Brain
Why Do People
Abuse Drugs?

Drugs can be “Imposters” of
Brain Messages

Addiction Reward & well-being
Motivation
Movement
Dopamine

Donald Bliss, MAPB, Medical Illustration
The Neuron: How the Brain’s
Messaging System Works
Terminal
branches of
axon
Cell body
(the cell’s life
support
center)
Dendrites
Myelin
sheath
Axon
Neuronal Impulse

Neurobiology of drug abuse and addiction_NIDA

Di Chiara et al., Neuroscience, 1999.,Fiorino and Phillips, J. Neuroscience, 1997.
Natural Rewards Elevate
Dopamine Levels
0
50
100
150
200
0 60 120 180
Time (min)
%
of
Basal
DA
Output
NAc shell
Empty
Food Sex
Box Feeding
100
150
200
DA
Concentration
(%
Baseline)
Sample
Number
1 2 3 4 5 6 7 8
Female Present

0
100
200
300
400
500
600
700
800
900
1000
1100
0 1 2 3 4 5 hr
%
of
Basal
Release
DA
DOPAC
HVA
Accumbens
Amphetamine
0
100
200
300
400
0 1 2 3 4 5 hr
%
of
Basal
Release
DA
DOPAC
HVA
Accumbens
Cocaine
Time After Drug
Morphine
0
100
150
200
250
0 1 2 3 hr
Time After Drug
%
of
Basal
Release
Accumbens
Caudate
Nicotine
Di Chiara and Imperato, PNAS, 1988
Effects of Drugs on Dopamine Release
%
of
Basal
Release
0
100
150
200
250
0 1 2 3 4 5 hr
Accumbens
0.5
1.0
2.5
10
Dose
mg/kg
mg/kg
mg/kg
mg/kg

But Dopamine is only Part of the Story
• Scientific research has shown that other
neurotransmitter systems are also affected:
–Serotonin
–Regulates mood, sleep, etc.
–Glutamate
–Regulates learning and memory, etc.

Prolonged Drug Use Changes
the Brain In Fundamental
and Long-Lasting Ways
Science Has Generated Much
Evidence Showing That…

We Have Evidence That
These Changes Can Be Both
Structural and Functional
AND…

Amph
Neuronal Dendrites in the
Nucleus Accumbens
Saline
Robinson & Kolb, Journal of Neuroscience, Volume: 1997
Structurally…

Control Addicted
Dopamine D2 Receptors are Decreased by Addiction
Functionally…
Cocaine
Alcohol
Heroin
Meth

Dopamine Transporters in Methamphetamine Abusers
Normal Control
Methamphetamine Abuser
Motor Task
Loss of dopamine
transporters in
methamphetamine
abusers may result in
slowing of motor
reactions.
Memory Task
Loss of dopamine
transporters in
methamphetamine
abusers may result
in memory impairment.
7 8 9 10 11 12 13
1.0
1.2
1.4
1.6
1.8
2.0
Time Gait
(seconds)
4
6
8
10
12
14
16
1.0
1.2
1.4
1.6
1.8
2.0
Delayed Recall
(words remembered)
Dopamine
Transporter
Bmax/Kd
Volkow et al., Am. J. Psychiatry, 2001.

Implication?
Brain changes resulting from
prolonged use of drugs
may compromise
mental AND motor function.

Circuits Involved In Drug Abuse and Addiction
All of these brain regions must be considered in developing
strategies to effectively treat addiction

Prevention Research (Children & Adolescents)
genetics
environment
development
co-morbidity
Priority Areas for NIDA
Treatment Research
(New Targets & New Strategies)
HIV/AIDS Research

Addiction is a Developmental Disease:
It Starts Early
1
10
100
Child Teen Young Adult Adult
67%
1.5%
5.5%
<12 12-17 18-25 >25
26%

Basic Science Tells Us that
Adolescents’ Brains
Are Still Developing…

Copyright ©2004 by the National Academy of Sciences Gogtay, Giedd, et al. Proc. Natl. Acad. Sci., 2004
MRI Scans of Healthy
Children and Teens Over Time

When Reading Emotion…
Adults Rely More on the Frontal Cortex
While Teens Rely More on the Amygdala
Deborah Yurgelon-Todd 2000.

Do Adolescents React Differently
than Adults to
Substances of Abuse?

Rats Exposed to Nicotine in Adolescence
Self-Administer More Nicotine
Than Rats First Exposed as Adults
Collins et al, Neuropharmacology, 2004, Levin et al, Psychopharmacology, 2003

Do We Need Fundamentally
Different Strategies At
Different Stages of Adolescence?

Why do some people
become addicted to drugs
while others do not?
Vulnerability

high
low
High DA
receptor
Low DA receptor
Individual Differences in Response to
Drugs: DA Receptors influence drug liking
As a group, subjects with low receptor levels found MP pleasant while those
with high levels found MP unpleasant
Adapted from Volkow et al., Am. J. Psychiatry, 1999.

Genetics is a Big Contributor to the
Risk of Addiction…
And…
The Nature of this Contribution
Is Extremely Complex

Gene Cluster is Associated with Nicotine
Dependence

What Other Biological Factors
Contribute to Addiction--Comorbidity
Prevalence of Drug Disorders
Percent
Prevalence of
Nicotine Addiction
0
20
40
60
80
Percent
0
5
10
15
20
25
30
35
40

Why do Mental Illnesses and
Substance Abuse Co-occur?
• Self-medication
– substance abuse begins as a
means to alleviate symptoms of
mental illness
• Causal effects
– Substance abuse may increase
vulnerability to mental illness
• Common or correlated causes
– the risk factors that give rise to
mental illness and substance
abuse may be related or overlap

What Environmental
Factors Contribute to Addiction?
• Stress
• Early physical or sexual abuse
• Witnessing violence
• Peers who use drugs
• Drug availability

Becomes Subordinate
Stress remains
Becomes Dominant
No longer stressed
Individually
Housed
Group
Housed
Social Stressor Affects Brain DA D2
Receptors and Drug Self-Administration
Morgan, D. et al., Nature Neuroscience, 2002.
Cocaine (mg/kg/injection)
*
*
S.003 .01 .03 .1
0
10
20
30
40
50
Dominant
Subordinate

Prevention Works:
Knowledge of Risk and Protective
Factors Has Led to the
Development of Effective
Prevention Strategies

Changes in Attitudes Lead to
Changes in Use
0
10
20
30
40
50
60
75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07
Past Year Use Perceived Risk
Monitoring the Future Study, 2007.

Treatment Research
(New Targets & New Strategies)
Prevention Research (Children & Adolescents)
genetics
environment
development
co-morbidity
HIV/AIDS Research
Priority Areas for NIDA

Adapted from Volkow et al., Neuropharmacology, 2004.
Drive
Saliency
Memory
Control
Non-Addicted Brain
NO
GO
Addicted Brain
Drive
Memory
Control
GO
Saliency
Why Can’t Addicts Just Quit?
Because Addiction Changes Brain Circuits

This is why treatment is essential.
This is why addicts can’t just quit.
and…

Treating a Biobehavioral Disorder Must Go
Beyond Just Fixing the Chemistry
Pharmacological
Treatments
(Medications)
We Need to Treat the
Whole Person!
In Social Context
Behavioral Therapies
Social Services
Medical Services

• No single treatment is appropriate for all
individuals.
• Treatment needs to be readily available.
• Treatment must attend to multiple needs of
the individual, not just drug use.
• Multiple courses of treatment may be
required for success.
• Remaining in treatment for an adequate
period of time is critical for treatment
effectiveness.
Treatment Can Work!
NIDA’s Principles of Treatment

We Are Using Science to
Develop Even Better Treatments
Genetics Mechanisms Treatments

CB1 Antagonists
Inhibitors of
metabolizing enzymes
CRF Antagonists
Medication
Basic Research
Agonist Therapy
Methadone
Buprenorphine
Opiate agonists stabilize brain
function in heroin addicts
CB1 KO mice have decreased
responses to multiple drugs of abuse
Smokers who are poor nicotine
metabolizers smoke less
Stress triggers relapse in animal models
of addiction and CRF antagonists
interfere with the response to stress

But, drug addiction is a chronic illness
with relapse rates similar to those of
hypertension, diabetes, and asthma.
McLellan et al., JAMA, 2000.

Relapse Rates Are Similar for Drug
Addiction & Other Chronic Illnesses
Type I
Diabetes
Drug
Addiction
0
10
20
30
40
50
60
70
80
90
100
Hypertension Asthma
40
to
60%
30
to
50%
50
to
70%
50
to
70%
Percent
of
Patients
Who
Relapse
McLellan et al., JAMA, 2000.

Addiction is Similar to Other
Chronic Illnesses Because:
• It has biological and behavioral components, both of which must be
addressed during treatment.
• Recovery from it--protracted abstinence and restored functioning--is often a
long-term process requiring repeated episodes of treatment.
• Relapses can occur during or after treatment, and signal a need for
treatment adjustment or reinstatement.
• Participation in support programs during and following treatment can be
helpful in sustaining long-term recovery
Therefore…

Full recovery is a challenge
but it is possible …

Extended Abstinence
is Predictive of Sustained Recovery
It takes a year
of abstinence
before less than
half relapse
Dennis et al, Eval Rev, 2007
After 5 years – if you are sober,
you probably will stay that way.

DAT Recovery
with prolonged
abstinence from
methamphetamine
[C-11]d-threo-methylphenidate
Volkow et al., J. Neuroscience, 2001.
low
high
Normal Control
(1 month abstinent)
(14 months abstinent)

Treatment Reduces
Drug Use and Recidivism
Delaware Work Release Therapeutic Community (CREST) + Aftercare
3 Years After Release (N=448)
p < 0.05,
compared to no treatment group
Percentage
of
Participants

We Need to Keep Our Eye on
the Real Targets!
In Treating Addiction…

Drug Use Has Played a Prominent
Role in the HIV/AIDS Epidemic
In Several Ways
• Disease Transmission
- IV Drug Use—Needle sharing
- Drug Intoxication: Impaired judgment,
disinhibition, leading to risky sexual
behaviors
• Disease Progression
• Neurological Complications

Proportions of AIDS Cases in Adults & Adolescents by
Exposure in the USA
Centers for Disease Control and Prevention (CDC)
Men who have sex with men (MSM)
Injection drug use
MSM who inject drugs
Year of Diagnosis
%
of
Cases
70
60
50
40
30
20
10
0
1985 1987 1989 1991 1993 1995 1997 1999 2001 2003
Drugs of Abuse Have Had A Major Impact
on the HIV/AIDS Epidemic
Heterosexual contact

Convergence of HIV Seroprevalence Among
Injecting and Non-injecting Drug Users
0
5
10
15
20
Current Injectors Non-Injectors
HIV
Prevalence
13%
CI 12-15%
12%
CI 9-16%
Drug Treatment Program
(n=2121 2001-2004)
Respondent-Driven Sampling
(n=448 2004)
0
5
10
15
20
15%
CI 11-19%
17%
CI 12-21%
Source: Des Jarlais et al AIDS, 21: 231-235, 2007.
Current Injectors Non-Injectors

White, not Hispanic
Black, not Hispanic
Hispanic
Asian/Pacific Islander American Indian/
Alaska Native
Year of Diagnosis
%
of
Cases
70
60
50
40
30
20
10
0
Centers for Disease Control and Prevention (CDC)
The AIDS Epidemic Disproportionately
Affects Minority Populations
1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005

Acceleration of HIV Degeneration of
Dopamine Cells With Cocaine

International
Research
Collaboration
NIDA International
Program Components
Post-Doctoral Research Fellowship
Technical
Consultation
Scientific
Exchange
Information Dissemination

Why focus on drug abuse
internationally?
I. Drug abuse is a global phenomenon
5 % of people aged 15-64
II. Intertwined dual-epidemics of drug
addiction & HIV/AIDS
HIV Infections Attributed to
Injection Drug Use and Risky
Sexual Behaviors Related to
Drug Abuse
Millions of Users
160.9
26.2
13.7
15.9
7.9 Cannabis
Amphetamines
Ecstasy
Cocaine
Opiates
UNODC 2005 World Drug Report
III. Take advantage of unique opportunities to advance scientific knowledge
through research

NIDA Supports International Drug Abuse
Research In Numerous Ways
Fund international research
Provide training and exchange opportunities
Set international research priorities
Organize & sponsor conferences and meetings
Binational agreements
Dissemination of information

Where Do We Need
to Go From Here?
We Need to…
Advance the SCIENCE
Erase the STIGMA
and…
Erase the STIGMA
and…

For More Information
NIDA Public Information:
www.nida.nih.gov
www.drugabuse.gov
NIDA International Program:
www.international.drugabuse.gov
www.drugabuse.gov NIDANATIONAL INSTITUTE
ON DRUG ABUSE

Neurobiology of drug abuse and addiction_NIDA

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