Addiction as a Brain Disease:

NIDA Research
From Molecules…

…To Managed Care

…Drug Courts
…Community Coalitions
 Social Network

Organism

Organ

Cell

Proteins/pathways

Gene

Adapted from Pennisi Science 2003

What have we
learned?
 Why do people take drugs?

To feel good To feel better

To have novel: To lessen:
Feelings Anxiety
Sensations Worries
Experiences Fears
AND Depression
To share them Hopelessness
Withdrawal
A Major Reason People Take
a Drug is They Like What
it Does to Their Brains
 Drug Addiction:
A Complex Behavioral and Neurobiological Disorder
HISTORICAL PHYSIOLOGICAL
- previous history
- expectation
DRUGS - genetics
- circadian rhythms
- learning - disease states
- gender
ENVIRONMENTAL
- social interactions
- stress
- conditioned stimuli
BRAIN
MECHANISMS

BEHAVIOR

ENVIRONMENT
What have we learned
about Vulnerability?
Why do some people become
addicted while others do not?
Drug Abuse Risk Factors
Community

Peer Cluster

Family

Individual
 Drug Abuse
Drug/Alcohol
Related Traffic Delinquency
Accidents
Community
Sexually Academic
Transmitted Peer Cluster Failure and
Diseases Dropping
(Including Out of School
HIV/AIDS)
Family
Suicidal Juvenile
Behavior Individual Depression

Unwanted Running Away

Pregnancies From Home
 We Know There’s A
Big Genetic Contribution To
Drug Abuse and Addiction…
And the Nature of this Contribution
Is Extremely Complex
 DA Receptor Levels and Response to MP

2.5
unpleasant response

pleasant response

Subjects with low receptor levels found MP pleasant while those with
high levels found MP unpleasant
 High Levels of Dopamine D2 Receptors May Provide Protection
Against Alcoholism in Unaffected Members of Alcoholic Families

Researchers also
found that
increased D2
receptors in the
family positive
subjects
correlated with
metabolism in the
frontal regions
and with positive
emotionality

Volkow, N. D. et al. Arch Gen Psychiatry 2006;63:999-1008.

What have we learned about
other aspects of vulnerability?
 Addiction Is a Developmental Disease
starts in childhood and adolescence
1.8
TOBACCO
THC
% in each age group to develop

1.6

1.4
ALCOHOL
first-time dependence

1.2

1.0

0.8

0.6

0.4

0.2

0.0
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75
Age
Age at tobacco, at alcohol and at cannabis dependence, as per DSM IV
National Epidemiologic Survey on Alcohol and Related Conditions, 2003
 The Adolescent Brain Is Still
Undergoing Development
Amygdalo-cortical Sprouting
Continues Into Early Adulthood

Brain areas where volumes are During Adolescence the

smaller in adolescents than COGNITION-EMOTION
young adults Connection is Still Forming
Source: Sowell, E.R. et al., Nature Neuroscience, Source: Cunningham, M et al., J Comp Neurol
2(10), pp. 859-861, 1999. 453, pp 116-130, 2002.
Gogtay, Giedd, et al. (2004) Proc. Natl. Acad. Sci. USA 101, 8174-8179
 Right Lateral and Top Views of the
Dynamic Sequence of GM Maturation
Over the Cortical Surface

Source: Gogtay, Nitin et al. (2004) Proc. Natl. Acad. Sci. USA 101, 8174-8179
Copyright ©2004 by the National Academy of Sciences
 Frontal and Amygdalar Activity Differ in
Adults and Adolescents
Correlation Between Age and PFC Activity
During Fear Face Processing

Adjusted FMRI Response

1.0
0.8
0.6
0.4
Teen [42,44,6] 0.2
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
7 8 9 10 11 12 13 14 15 16
Adult Age
When Reading Emotion… When Reading Emotion…
Adults Rely More on Frontal Cortex Frontal Activation Increases with Age
Teens Rely More on the Amygdala
Yurgelun-Todd et al., Percept Mot Skills, 99:2, 2004
Killgore et al., NeuroReport, v12(2), 2001
• Exposure to drugs of abuse during adolescence could
have profound effects on Brain Development & Brain
Plasticity

• Understanding drug abuse and addiction from a

Development Perspective has important implications
for their Prevention & Treatment
 The Adolescent Brain Responds to Drugs
Differently than the Adult Brain
Treatment of adolescent rats (but not young adults) with Nicotine 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.

Adolescent Exposure to

Percent baseline firing rate

125
Cannabinoids Alters the
Response of VTA Dopamine 100

Neurons to Drugs of Abuse 75

50 vehicle pretreated
vehicle pretreated CB adolescent
Percent baseline firing rate

250 CB adolescent
CB adult .1 1 10
225 Cocaine (mg/kg)
200
vehicle pretreated
125

Percent baseline firing rate

175 CB adolescent

150 100

125
75
100
50
1 10
Morphine (mg/kg) .1 1
Amphetamine (mg/kg)
Source: Pistis, M. et al., Biol Psychiatry, 56: 86-94, 2004.
Comorbidity is a Reality
What have we learned about
how drugs work?
 Nuclear Circuitry Mediating the Activation of
Goal-Directed Behavior
Medial
dorsal
thalamus

Nucleus
Ventral Prefrontal
accumbens
pallidum cortex
core

Hippocampus
Enter basal
ganglia motor
generator
Ventral
Basolateral
tegmental
Dopamine amygdala
area
Glutamate Extended amygdala
GABA Central amygdala nucleus,
bed nucleus of the stria
GABA/Neuropeptide terminalis nucleus
accumbens shell
Cannabinoid receptors???
Adapted from Kalivas and Volkow, Am J Psychiatry 162:8, Aug 2005
 Natural Rewards Elevate Dopamine Levels
FOOD SEX

DA Concentration (% Baseline)
200 200
NAc shell
% of Basal DA Output

150 150

Copulation Frequency
100 100
15

Empty 10
50
Box Feeding
5

0 0
0 60 120 180 ScrScr Scr Scr
BasFemale 1 Present Female 2 Present
Time (min) Sample 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Number
Mounts
Intromissions
Ejaculations

Source: Di Chiara et al. Source: Fiorino and Phillips

 Effects of Drugs on Dopamine Release
1100 Accumbens AMPHETAMINE Accumbens
COCAINE
1000 400
% of Basal Release

% of Basal Release
900
800 DA
DA 300 DOPAC
700 DOPAC
HVA HVA
600
500 200
400
300
200 100
100
0
0 1 2 3 4 5 hr 0
0 1 2 3 4 5 hr
Time After Amphetamine Time After Cocaine

250
NICOTINE 250 Accumbens MORPHINE
% of Basal Release

% of Basal Release
Dose (mg/kg)
200 Accumbens
200 0.5
Caudate 1.0
150 2.5
150 10
100
100

0
0 1 2 3 hr 0
0 1 2 3 4 5hr
Time After Nicotine Time After Morphine
Source: Di Chiara and Imperato
 Circuits Involved In
Drug Abuse and Addiction
CONTROL PFC
INHIBITORY
ACG
CONTROL
OFC Hipp
SCC REWARD
NAcc

MOTIVATION/ VP

Amyg
DRIVE
MEMORY/
LEARNING
Prolonged Drug Use Changes
The Brain In Fundamental and
Long-Lasting Ways
AND…

We Have Evidence That

These Changes Can Be Both
Structural and Functional
 Normal

Cocaine Abuser (10 Days)

Cocaine Abuser (100 Days)

Sources: Volkow, et al., Synapse, 11:184-190, 1992
& Volkow, et al., Synapse, 14:169-177, 1993
Gray Matter Reductions in Methamphetamine Users

Source: Thompson PM et al., Journal of Neuroscience, 24(26), pp. 6028-6036, June 30, 2004.
 Dopamine D2 Receptors are Lower in Addiction

DA
DA

Cocaine
DA
DA DA DA
DA
DA
DADA DA DA

Meth Reward Circuits

Non-Drug Abuser

DA

Alcohol DA

DA
DA DA
DA

Heroin Reward Circuits

control addicted Drug Abuser
 Repeated drug
exposure

(e.g., via
neurotrophic
factors,
ΔFosB,
CREB?)

Normal responses to drugs Use-dependent plasticity leading to

sensitized responses to drug and
environmental cues

Nestler, 2001
Chronic cocaine increases density of dendritic spines and
neuronal branching in the nucleus accumbens

11 60

10 55

Branches
COC

9 50

CTL
8 45
CTL COC CTL COC CTL COC

Robinson, T.E. & Kolb, B. Eur. J. of Neuro. 1999.

Ferrario, C.R. et al. Biol. Psychiatry, 2005.
 Repeated Drug Abuse Increases Genetic
Transcription Resulting in
Long-term Structural Changes

Dopamine

Dendritic
Spines

Adapted from Nestler E.J.

Science & Practice Perspectives,
5(1) 2005.
AND…

We Have Evidence That

These Changes Can Be Both
Structural and Functional
 Dopamine Transporters in Methamphetamine Abusers

2.4

2.2

Dopamine Transporters
2.0

(Bmax/Kd)
1.8
Normal Control 1.6

1.4

1.2

1.0
Normal Meth
Controls Abusers

Methamphetamine Abuser p < 0.0002

Methamphetamine abusers have significant reductions in dopamine transporters.

BNL - UCLA - SUNY
NIDA - ONDCP - DOE
Dopamine Transporters in Methamphetamine Abusers

2.0 Motor Task

1.8 Loss of dopamine transporters
1.6 in the meth abusers may result
Dopamine Transporter

1.4 in slowing of motor reactions.

1.2
1.07
Bmax/Kd

8 9 10 11 12 13
Time Gait
(seconds)
2.0
1.8 Memory Task
1.6 Loss of dopamine transporters
1.4 in the meth abusers may result
1.2 in memory impairment.
1.0
16 14 12 10 8 6 4
Delayed Recall
(words remembered)
BNL/UCLA/SUNY
NIDA, ONDCP, DOE
 Circuits Involved In
Drug Abuse and Addiction
CONTROL PFC
INHIBITORY
ACG
CONTROL
OFC Hipp
SCC REWARD
NAcc

MOTIVATION/ VP

Amyg
DRIVE
MEMORY/
LEARNING
 Research Has Shown that the
Brain Circuitry Involved in Addiction
Has Similarities to that of
Other Motivational Systems
 Cocaine Craving:
Population (Cocaine Users, Controls) x Film (cocaine, erotic)

Cingulate
Signal Intensity (AU)

Ant Cing

Cocaine Film

IFG

Controls Cocaine Users Garavan et al A .J. Psych 2000

 Cocaine Craving:
Population (Cocaine Users, Controls) x Film (cocaine, erotic)

Cingulate
Signal Intensity (AU)

Ant Cing

Cocaine Film
Erotic Film
IFG

Controls Cocaine Users Garavan et al A .J. Psych 2000

 Memories Appear to Be
A Critical Part of Addiction
“People, places and things…”
But Not Just Memories…
Drugs Usurp
Brain Circuits

and
Motivational Priorities
 This Results in
“Motivational Toxicity”
and Compulsive Drug
Use (Addiction)
 Circuits Involved In
Drug Abuse and Addiction
CONTROL PFC
INHIBITORY
ACG
CONTROL
OFC Hipp
SCC REWARD
NAcc

MOTIVATION/ VP

Amyg
DRIVE
MEMORY/
LEARNING
Non Addicted Brain Addicted Brain

Control STOP Control

Saliency Drive Saliency Drive

GO

Memory Memory
 Addiction is the
Quintessential
Biobehavioral Disorder
 Drug Addiction:
A Complex Behavioral and Neurobiological Disorder
HISTORICAL PHYSIOLOGICAL
- previous history
- expectation
DRUGS - genetics
- circadian rhythms
- learning - disease states
- gender
ENVIRONMENTAL
- social interactions
- stress
- conditioned stimuli
BRAIN
MECHANISMS

BEHAVIOR

ENVIRONMENT
 The Brains of Addicts
Are Different From
the Brains of Non-Addicts

…And Those Differences

Are An Essential Element
of Addiction
That’s Why Addicts Can’t Just Quit

That’s Why Treatment Is Essential!

Treating A Biobehavioral Disorder
Must Go Beyond Just
Fixing The Chemistry
 The Most Effective Treatment
Strategies Will Attend to All Aspects
of Addiction:
• Biology

• Behavior

• Social Context
We Need to Treat the
Whole Person!