Transcript The Neurobiology of Free Will In Addictive Disorders

The Neurobiology of Free Will In
Nora D. Volkow, M.D.
Director
National Institute on Drug Abuse
frontal
cortex
AMPHETAMINE
0
VTA/SN
% of Basal Release
nucleus
accumbens
% of Basal Release
Dopamine
Neurotransmission
1100
1000
900
800
700
600
500
400
300
200
100
0
1
2
3
4
Time After Amphetamine
5 hr
FOOD
200
150
100
50
0
Empty
Box Feeding
0
60
120
180
Time (min)
Di Chiara et al.
DA
DA
TYROSINE
TYROSINE
DOPA
DOPA
DA
DA
DA
DA
DA
raclopride
R
R
Self-Reports
(0-10)
DA and Drug Reinforcement
DA
Change in Dopamine
Bmax/kd (Placebo - MP)
DA
DA
DA
DA
R
R
R
methylphenidate
DA
DA DA
DA
DA DA
R
“High”
10
8
6
4
2
0
-2 -10 0 10 20 30 40
raclopride
DA initiates and maintains
responses to salient stimuli
such as drugs
Volkow et al., JPET 291(1):409-415, 1999.
1. Reward Circuit
•
•
NAcc
In laboratory animals
repeated exposure to the drug
results in enhanced responses
to it (sensitization) that have
been hypothesized to underlie addiction.
REWARD
VP
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)
Self Reports of Drug Effects After iv MP in
Controls and in Cocaine Abusers
Craving
P < 0.001
6
4
2
0
10
8
(0-10)
8
(0-10)
Self Report
10
Self Report Craving
High
Abusers
P <0.001
6
4
2
0
Controls
Placebo
MP
Controls
Abusers
Cocaine abusers showed decreased drug induced increases in
rewarding responses and enhanced drug craving
Volkow et al., Nature 386:830-833, 1997.
Normal Control
Cocaine Abuser
% Change Bmax/Kd
Methylphenidate-induced Increases in Striatal
DA in Controls and in Cocaine Abusers
Placebo
MP
35
P < 0.003
30
25
20
15
21%
10
5
0
9%
Controls
(n = 20)
Abusers
(n = 20)
Cocaine abusers showed
decreased DA increases and
reduced reinforcing
responses to MP
Volkow et al., Nature 386:830-833, 1997.
2. Memory circuit
In rats when a neutral stimulus is
Hipp
repeatedly paired with the drug
(conditioned), it elicits DA increases
and reinstates drug self- administration.Amyg MEMORY/
LEARNING
DA Release NAc
•
In training the cue was
paired with cocaine
Auditory cue
In training the cue was not
paired with cocaine
Philipps et al Nature 422, 614-618
Here we tested if conditioned stimuli increase DA in
addicted subjects and its relationship to drug craving
[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.
Relationship between Cue-Induced Decreases in
[11C]raclopride Binding and Cocaine Craving
Bmax/Kd
P < 0.01
3.00
P < 0.05
2.50
2.0
1.5
1.0
0.50
0.0
-0.50
Putamen
Caudate
2.00
P < 0.002
2.5
(Pre - Post)
3.50
Putamen
Change in Craving
Neutral
Cocaine-Cues
30
20 10
0
-10 -20 -30 -40
% Change Bmax/Kd
Volkow et al J Neuroscience 2006.
Cue-induced increases in DA were associated with craving
3. 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.
EXECUTIVE
FUNCTION
PFC
INHIBITORY
CONTROL
ACG
OFC
SCC
MOTIVATION/
DRIVE
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
Dopamine Measures Obtained
DA D2 Receptors
DA DA
Anatomy
DA
DA DA
DA
DA
signal
Dopamine Synapse
Metabolism
Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.
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): 169-177, 1993.
DA D2 Receptors in Controls and
in Cocaine Abusers (NMS)
Normal Controls
Cocaine Abusers
3.2
3
4
Bmax/Kd
DA D2 Receptors
(Ratio Index)
4.5
3.5
3
2.5
2.8
2.6
2.4
2.2
2
2
1.8
1.5
15
1.6
20
20
25
30
35
40
45
50
25
30
Age (years)
Volkow et al., Neuropsychopharmacology 14(3):159-168, 1996.
35
40
45
50
Dopamine D2 Receptors are Lower in Addiction
DADA
Cocaine
DA
DA DA
DA
DADA
DA
DA
DA DA
Reward Circuits
Meth
Non-Drug Abuser
DA
DA
Alcohol
DA
DA
DA
DA
Reward Circuits
Drug Abuser
Heroin
control
addicted
Adapted from Volkow et al.,
Neurobiology of Learning and
Memory 78:610-624, 2002.
50
40
p < 0.0005
p < 0.0005
p < 0.005
30
20
p < 0.005
p < 0.10
10
0
0
4
6
8
10
24
0
Null Vector
60
2nd D2R Vector
1st D2R Vector
Overexpression of
DA D2 receptors
reduces alcohol
self-administration
Percent Change in D2R
Effects of Tx with an Adenovirus Carrying a DA D2
Receptor Gene into NAc in DA D2 Receptors
-20
-40
p < 0.01
p < 0.01
-60
p < 0.001
-80
-100
p < 0.001
p < 0.001
0
Thanos, PK et al., J Neurochem, 78, pp. 1094-1103, 2001.
4
6
8 10
Time (days)
24
Brain Glucose Metabolism
in Cocaine Abusers (n=20) and Controls (n=23)
CG
CG
micromol/100g/min
60
55
50
45
40
Controls
Abusers
micromol/100g/min
P < 0.01
60
OFC
55
50
45
40
Controls
Volkow et al., AJP 156:19-26, 1999.
Abusers
P < 0.005
CG
PreF
Striatum
umol/100g/min
OFC
Correlations Between D2 Receptors in Striatum
and Brain Glucose Metabolism
OFC
65
60
55
50
45
40
35
30
1.8
Cocaine
Abusers
r = 0.7, p < 0.001
2
2.2
2.4
2.6
2.8
3
3.2
3.4
umol/100gr/min
OFC
DA D2 Receptors (Ratio Index)
90
80
Volkow et al., Synapse 14(2):169-177, 1993.
METH
Abusers
70
60
50
r = 0.7, p < 0.005
40
302.9
control
cocaine abuser
3
3.1
3.2
3.3
DA D2 Receptors
3.4
3.5
(Bmax/kd)
3.6
Volkow et al., AJP 158(3):377-382, 2001.
1.30
1.25
1.20
1.15
1.10
1.05
1.00
0.950
0.900
4.0
1.05
CG
Relative metabolism
OFC
Relative metabolism
DA D2 Receptors and Relationship to Brain Metabolism
in Subjects with Family History for Alcoholism
4.2 4.4
4.6 4.8 5.0
1.00
0.950
0.900
0.850
0.800
Correlations between Metabolism and D2R
P <0.005
0.750
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.
Non-Addicted
Brain
Addicted
Brain
Control
Control
CG
STOP
Saliency
NAc
Drive
OFC
Memory
Amygdala
Adapted from: Volkow et al.,
J Clin Invest 111(10):1444-1451, 2003.
Saliency
Drive
GO
Memory
Medications for Relapse Prevention
Non-Addicted
Brain
Addicted Brain
Control
Control
Strengthen reinforcing
effects of non-drug
reinforcers
Strengthen inhibitory
control
Saliency
Saliency
STOP
GO
Drive
Drive
Strengthen prefrontalstriatal communication
Interfere with conditioned
memories (craving)
Memory
Memory
Counteract stress responses
that lead to relapse
Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.
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