Transcript Document

Imaging the
Addicted Brain
Nora D. Volkow, M.D.
Director
National Institute on Drug Abuse
National Institutes of Health
frontal
cortex
% of Basal Release
Natural and Drug Reinforcers
Increase Dopamine in NAc
1100
1000
900
800
700
600
500
400
300
200
100
0
AMPHETAMINE
0
VTA/SN
Drugs of abuse increase DA in the Nucleus
Accumbens, which is believed to trigger the
neuroadaptions that result in addiction
% of Basal Release
nucleus
accumbens
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
High
(0-10)
DA and the Rewarding
Effects of Drugs in Humans
Intravenous MPH
(1 min)
10
8
6
4
2
0
-2 -10 0 10 20 30 40
Volkow et al., JPET 291:409-415, 1999.
DA
Oral MPH
10
DA
R
R
DA
DA
DA
DA
R
R
R
DA
methylphenidate
DA
DA
DA DA
R
raclopride
High
(0-10)
raclopride
DA
(60 minutes)
8
6
4
2
0
0
10 20 30 40 50
Change in DA
(% change Bmax/Kd)
DA increases induced by intravenous but not by oral administration of MPH
were associated with the “high”. WHY?
N
CO2CH3
O
O
[11C]Cocaine
100
% Peak
H3C
80
60
40
20
0
"High"
0 10 20 30 40 50 60 70 80
100
80
CO2CH3
[11C]Methylphenidate
% Peak
H
N
60
40
20
"High"
0
0 10 20 30 40 50 60 70 80
Time (min)
How are the different
brain circuits regulated
by Tonic and Phasic DA
involved in addiction?
Pharmacokinetics of Oral and
iv MPH in Baboon Brain
MP in Striatum
(peak concentration)
Thus the reinforcing effects of
drugs are due to their ability to
induce FAST DA increases that
emulate phasic DA cell signaling
(15-30 Hz), which are implicated in
reward and conditioning rather
than tonic DA cell signaling (2-10
Hz), which are implicated in
cognitive, motivational and motoric
systems.
100
80
60
40
20
00
Oral (slow: NO “high”)
iv (fast: intense “high”)
20 40 60 80 100120
Time (min)
EXECUTIVE
FUNCTION
PFC
ACG
INHIBITORY
CONTROL
Hipp
OFC
SCC
NAcc
Amyg
MOTIVATION/
DRIVE
VP
REWARD
MEMORY/
LEARNING
1. Reward Circuit in Addiction
NAcc
TYROSINE
DOPA
DOPA
DA
DA
DA
DA
DA
raclopride
R
R
DA
DA
DA
DA
DA
R
R
R
VP
DA
DA
methylphenidate
DA
DA
DA DA
R
raclopride
Self-Reports
(0-10)
DA
DA
TYROSINE
REWARD
“High”
10
8
6
4
2
0
-2 -10 0 10 20 30 40
Change in Dopamine
Bmax/kd (Placebo - MP)
Volkow et al., JPET 291(1):409-415, 1999.
8
(0-10)
Self Report
10
P < 0.001
6
4
2
Craving
10
8
(0-10)
High
Self Report Craving
Self-Reports of Drug Effects After iv MPH in Controls
(n=20) and in Detoxified Cocaine Abusers (n=20)
Placebo
MP
P <0.001
6
4
2
0
Controls
Abusers
0
Controls
Abusers
Cocaine abusers showed decreased drug induced increases in
rewarding responses and enhanced drug craving
Volkow et al., Nature 386:830-833, 1997.
Placebo
MP
Normal Control
Cocaine Abuser
% Change Bmax/Kd
Methylphenidate-induced Increases in Striatal DA
in Controls and in Detoxified Cocaine Abusers
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.
Methylphenidate-induced Increases in Striatal
DA in Controls and in Alcoholic Subjects
Control Subjects
50
40
4
Putamen
P < 0.05
10
0
DVR
p < 0.002
20
8
10
0
50
40
Ventral Striatum
P < 0.003
6
4
2
30
20
0
Controls Alcoholics
10
Placebo
High (1-10)
Alcoholic Subjects
% Change Bmax/Kd
30
0
MP
Controls Alcoholics
(n=20) (n=20)
Alcoholics had decreased DA release and decreased reinforcing
Volkow, ND et al., J Neuroscience 27(46), pp. 12700-12706, 2007.
responses to MP
MPH-induced Increases in Striatal DA in Controls
(n=17) and in Active Cocaine Abusers (n=17)
Placebo
MPH
P < 0.001
P < 0.001
10
20
15
10
5
Control subject
0
14%
Controls
Cocaine abuser
Volkow et al., unpublished.
3%
Abusers
8
(1-10)
Self-report High
% Change Bmax/Kd
25
6
4
2
Controls
Abusers
Active cocaine abusers showed a
marked reduction in MPHinduced DA increases and in its
reinforcing effects
2. Memory/conditioning
In rats when a neutral stimuli is
repeatedly paired with the drug
(conditioned), it elicits DA
increases and reinstates
drug self- administration
DA Release NAc
•
Hipp
Amyg
MEMORY/
LEARNING
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
P < 0.002
2.5
(Pre - Post)
3.50
Putamen
Change in Craving
Neutral
Cocaine-Cues
2.0
1.5
1.0
0.50
0.0
-0.50
Putamen
Caudate
2.00
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
•
Here we tested if, in addicted
subjects, changes in DA
function were linked with
disruption of frontal activity
as assessed by multiple tracer
studies that evaluated in the
same subject dopamine D2
receptors and brain glucose
metabolism (marker of brain
function).
EXECUTIVE
FUNCTION
PFC
INHIBITORY
CONTROL
ACG
OFC
SCC
MOTIVATION/
DRIVE
DA DA
DA
DA DA
DA
DA
DA D2 Receptors
signal
Metabolism
Dopamine D2 Receptors are Lower in Addiction
DADA
Cocaine
DA
DA DA DA
DA
DA DA
DADA
DA
Reward Circuits
Non-Drug Abuser
Meth
DA
DA
DA
Alcohol
DA
DA
DA
Reward Circuits
Drug Abuser
Heroin
control
addicted
Adapted from Volkow et al.,
Neurobiology of Learning and
Memory 78:610-624, 2002.
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
35
Age (years)
Volkow et al., Neuropsychopharmacology 14(3):159-168, 1996.
40
45
50
60
50
40
2nd D2R Vector
1st D2R Vector
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
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
Compulsive cocaine SA
Impulsive rats have lower D2R in striatum and are
more vulnerable to compulsive cocaine intake than
non impulsive rats. WHY??????
Impulsive rats have lower D2
receptors in striatum than non
impulsive rats
Dalley JW et al., Science 315, 1267 (2007).
High impulsivity
predicts compulsive
cocaine-taking
Belin D et al., Science 320, 1352 (2008).
Brain Glucose Metabolism
in Cocaine Abusers (n=20) and Controls (n=23)
micromol/100g/min
CG
60
CG
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
PreF
OFC
CG
Striatum
umol/100g/min
Correlations Between D2 Receptors in Striatum
and Brain Glucose Metabolism
OFC
65
60
55
50
45
40
35
30
1.8
umol/100gr/min
OFC
2
2.2
2.4
2.6
2.8
3
3.2
3.4
METH
Abusers
80
70
60
50
40
r = 0.7, p < 0.005
30
2.9
cocaine abuser
r = 0.7, p < 0.001
DA D2 Receptors (Ratio Index)
90
control
Cocaine
Abusers
3
3.1
3.2
3.3
DA D2 Receptors
3.4
3.5
(Bmax/kd)
Volkow et al., AJP 158(3):377-382, 2001.
3.6
DA D2 Receptors and Relationship to Brain Metabolism
in Subjects with Family History for Alcoholism
CG
Relative metabolism
OFC
Relative metabolism
Volkow et al. Arch Gen Psychiatry 2006.
Correlations between Metabolism and D2R
P <0.005
1.30
1.25
1.20
1.15
1.10
1.05
1.00
0.950
0.900
4.0
1.05
4.2 4.4
4.6 4.8 5.0
1.00
0.95
0.90
0.85
0.80
0.75
4.0
4.2
4.4 4.6
4.8
5.0
D2R (Bmax/Kd)
D2R were associated with metabolism in PREFRONTAL regions
the disruption of which results in impulsivity and compulsivity
Addicted Brain
Non-Addicted Brain
Control
Control
CG
STOP
Saliency
Saliency
Saliency
NAc
Drive
Drive
Drive
OFC
Memory
Amygdala
Adapted from: Volkow et al.,
J Clin Invest 111(10):1444-1451, 2003.
GO
Memory
Memory
David Alexoff, Karen Apelskog, Helene Benveniste,Anat Biegon, Elisabeth Caparelli, Pauline Carter, Stephen
Mike Gifford,
Dewey,Congwu Du, Richard Ferrieri, Joanna Fowler, Andrew
Rita Goldstein, Nils Hanik,Fritz hennm
Rich
Jacob Hooker, Bud Jayne, Kun-eek Kil, Sunny Kim, Payton King, Nelly Klein,Hai-Dee Lee, Jean Logan,
Jeming Ma,Martine Mirrione, Lisa Muench, Alicia Reid, Colleen Shea, Wynne Schiffer, Hanno Schieferstein,
Matthias Schonberger, David Schlyer, Mike Schueller,Elena Shumay, Peter Thanos, Dardo Tomasi, Frank
Telang, Paul Vaska, Nora Volkow, Gene-Jack Wang, Donald Warner, Chris Wong, Youwen Xu, Wei Zhu
http://www.bnl.gov/CTN/: supported by DOE-OBER and NIH
Source: Dr. Eric Kandel/Columbia University
Drug addicted subjects have evidence of
DA dyfunction (tonic and phasic) that is
associated with disrupted activity in
prefrontal activity (OFC, CG and DLPF).
Decreased tonic DA signaling results in
impaired prefrontal function including
disrupted executive control.
Enhanced phasic DA signaling to
conditioned stimuli further inhibits
prefrontal striatal regulation triggering
compulsive drug seeking and consuming
behavior.