1. The Neurobiology of Free Will In National Institute on Drug Abuse
ADDICTIVE DISORDERS
Nora D. Volkow, M.D.
Director
National Institute on Drug Abuse

2. Dopamine Neurotransmission
100
200
300
400
500
600
700
800
900
1000
1100 1 2 3 4
5 hr
Time After Amphetamine
% of Basal Release
AMPHETAMINE
Dopamine
Neurotransmission
VTA/SN
nucleus
accumbens
frontal
cortex 50
100
150
200 60
120
180
Time (min)
% of Basal Release
Empty
Box
Feeding
Di Chiara et al.
FOOD

3. DA and Drug Reinforcement
“High”
-10 10 20 30 40 -2 2 4 6 8
Self-Reports
(0-10)
Change in Dopamine
Bmax/kd (Placebo - MP) T Y R O S I N E T Y R O S I N E D O P A D O P A D A D A DA D A DA D A D A D A D A
raclopride D A D A D A m e t h y l p n i d a D A D A
raclopride D A R R D A D A D A R R R R
DA initiates and maintains responses to salient stimuli such as drugs
Volkow et al., JPET 291(1): , 1999.

4. Reward Circuit In laboratory animals repeated exposure to the drug
NAcc VP
REWARD
Reward Circuit
In laboratory animals
repeated exposure to the drug
results in enhanced responses
to it (sensitization) that have
been hypothesized to underlie addiction.
Here we tested if, in humans addicted to cocaine, there is an enhancement of DA release and of the reinforcing effects of the drug.
For this purpose we compared the changes in DA and the behavioral effects of intravenous MP between cocaine abusers (n=20) and controls (n=20)

5. Self Reports of Drug Effects After iv MP in Controls and in Cocaine Abusers
High
Craving
Placebo MP 2 4 6 8 10 2 4 6 8 10
P < 0.001
P <0.001
Self Report
Self Report Craving
(0-10)
(0-10)
Controls
Abusers
Controls
Abusers
Cocaine abusers showed decreased drug induced increases in rewarding responses and enhanced drug craving
Volkow et al., Nature 386: , 1997.

6. Methylphenidate-induced Increases in Striatal DA in Controls and in Cocaine Abusers
Normal Control
Cocaine Abuser
Placebo MP 5 10 15 20 25 30 35
P < 0.003
% Change Bmax/Kd
21% 9%
Controls
(n = 20)
Abusers
(n = 20)
Cocaine abusers showed decreased DA increases and reduced reinforcing responses to MP
Volkow et al., Nature 386: , 1997.

7. In rats when a neutral stimulus is repeatedly paired with the drug
Hipp
Amyg
MEMORY/
LEARNING
2. Memory circuit
In rats when a neutral stimulus is
repeatedly paired with the drug
(conditioned), it elicits DA increases
and reinstates drug self- administration.
DA Release NAc
Auditory cue
In training the cue was paired with cocaine
In training the cue was not paired with cocaine
Philipps et al Nature 422,
Here we tested if conditioned stimuli increase DA in
addicted subjects and its relationship to drug craving

8. Volkow et al. J Neuroscience 2006.
[11C]Raclopride Binding In Cocaine Abusers (n=18) Viewing a Neutral and a Cocaine-Cue Video
Neutral video
Viewing a video of cocaine scenes decreased specific binding of [11C]raclopride presumably from DA increases
Volkow et al. J Neuroscience 2006.

9. Cue-induced increases in DA were associated with craving
Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving
-0.50
0.0
0.50
1.0
1.5
2.0
2.5
-40
-30
-20
-10 10 20 30
Putamen
Neutral
P < 0.002
Cocaine-Cues
Change in Craving
(Pre - Post)
2.00
2.50
3.00
3.50
P < 0.01
Bmax/Kd
P < 0.05
Caudate
Putamen
% Change Bmax/Kd
Volkow et al J Neuroscience 2006.
Cue-induced increases in DA were associated with craving

10. Motivation & Executive Control Circuits
ACG
OFC
SCC
INHIBITORY
CONTROL
EXECUTIVE
FUNCTION
PFC
MOTIVATION/
DRIVE
Motivation & Executive
Control Circuits
DA is involved not only with reward and prediction of reward but also with motivation and executive function via its regulation of frontal activity.
Here we tested if, in addicted subjects, changes in DA function were linked with disruption of frontal activity as assessed by brain glucose metabolism.
We assessed the relationship between DA markers and
frontal activity in cocaine (n=20) and in methampethamine abusers (n =20) and controls

11. Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.
Dopamine Measures Obtained
DA D2 Receptors
Anatomy DA DA DA DA DA DA DA
signal
Metabolism
Dopamine Synapse
Adapted from: Volkow et al., J Clin Invest 111(10): , 2003.

12. Volkow et al., Synapse 14(2): 169-177, 1993.
Effect of Cocaine Abuse on Dopamine D2 Receptors
normal subject
cocaine abuser (1 month post)
cocaine abuser (4 months post)
Volkow et al., Synapse 14(2): , 1993.

13. DA D2 Receptors in Controls and in Cocaine Abusers (NMS)
Normal Controls
Cocaine Abusers
1.5 2
2.5 3
3.5 4
4.5 15 20 25 30 35 40 45 50
DA D2 Receptors
(Ratio Index)
1.6
1.8 2
2.2
2.4
2.6
2.8 3
3.2
Bmax/Kd 20 25 30 35 40 45 50
Age (years)
Volkow et al., Neuropsychopharmacology 14(3): , 1996.

14. Dopamine D2 Receptors are Lower in AddictionDA
Cocaine DA DA DA DA DA DA DA DA DA DA DA
Reward Circuits
Meth
Non-Drug Abuser
DA D2 Receptor Availability
Reward Circuits DA
Drug Abuser
Alcohol
Heroin
Adapted from Volkow et al.,
Neurobiology of Learning and
Memory 78: , 2002.
control
addicted

15. 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
p <
2nd D2R Vector 50
p < 40
p < 0.005
p < 0.005
Percent Change in D2R 30 20
p < 0.10 10
Null Vector 4 6 8 10 24
-20 DA DA
% Change in Alcohol Intake
-40 DA
p < 0.01 DA
p < 0.01 DA
-60 DA
p < 0.001 DA DA
-80
p < 0.001
p < 0.001
-100 4 6 8 10 24
Thanos, PK et al., J Neurochem, 78, pp , 2001.
Time (days)

16. Brain Glucose Metabolism in Cocaine Abusers (n=20) and Controls (n=23)CG 40 45 50 55 60
Controls
Abusers CG
micromol/100g/min
P < 0.01
OFC 40 45 50 55 60
Controls
Abusers
micromol/100g/min
Volkow et al., AJP 156:19-26, 1999.
P < 0.005

17. DA D2 Receptors (Ratio Index)
Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism 30 35 40 45 50 55 60 65
1.8 2
2.2
2.4
2.6
2.8 3
3.2
3.4
DA D2 Receptors (Ratio Index)
OFC
umol/100g/min
r = 0.7, p < 0.001
Cocaine
Abusers
Striatum CG
PreF
OFC
Volkow et al., Synapse 14(2): , 1993. 30 40 50 60 70 80 90
METH
Abusers
control cocaine abuser
umol/100gr/min
OFC
r = 0.7, p < 0.005
2.9 3
3.1
3.2
3.3
3.4
3.5
3.6
DA D2 Receptors
(Bmax/kd)
Volkow et al., AJP 158(3): , 2001.

18. DA D2 Receptors and Relationship to Brain Metabolism
in Subjects with Family History for Alcoholism
0.900
0.950
1.00
1.05
1.10
1.15
1.20
1.25
1.30
Relative metabolism
OFC
4.0
4.2
4.4
4.6
4.8
5.0
0.750
0.800
0.850
0.900
0.950
1.00
1.05
Relative metabolism CG
Correlations between Metabolism and D2R P <0.005
4.0
4.2
4.4
4.6
4.8
5.0
D2R (Bmax/Kd)
DA D2R were associated with metabolic activity in
OFC, CG and dorsolateral prefrontal cortex
Volkow et al. Arch Gen Psychiatry 2006.

19. GO Non-Addicted Brain Addicted Brain STOP Memory Memory Drive Drive
Saliency
Control
Drive
OFC
Saliency
NAc
Memory
Amygdala
Control CG
Drive
Memory
Saliency
STOP GO
Adapted from: Volkow et al.,
J Clin Invest 111(10): , 2003.

20. STOP GO Medications for Relapse Prevention Drive Addicted Brain
Strengthen reinforcing effects of non-drug reinforcers
Addicted Brain
Drive
Control
Saliency
Memory GO
STOP
Saliency
Drive
Control
Memory
Non-Addicted Brain
Strengthen inhibitory control
Strengthen prefrontal-striatal communication
Interfere with conditioned memories (craving)
Counteract stress responses that lead to relapse
Adapted from: Volkow et al., J Clin Invest 111(10): , 2003.

21. Brookhaven PET Group
F. Telang, R. MacGregor, P. Carter, D. Schlyer, C. Shea, J. Gatley, S. Dewey, C. Redvanly, P. King
L. Caligiuri, G-J Wang, M. Franceschi, Y-S Ding, J. Logan, N. Volkow, J. Fowler, R. Ferrieri, C. Wong
(not shown) D. Alexoff, C. Felder, N. Pappas, D. Franceschi, N. Netusil, V. Garza, R. Carciello, D. Warner, M. Gerasimov