the neurobiology of free will in nora d. volkow, m.d. director national institute on drug abuse nora...
TRANSCRIPT
The Neurobiology of Free Will In The Neurobiology of Free Will In
Nora D. Volkow, M.D.Director
National Institute on Drug Abuse
Nora D. Volkow, M.D.Director
National Institute on Drug Abuse
Dopamine Neurotransmission
VTA/SNVTA/SNnucleus accumbensnucleus accumbens
frontalcortexfrontalcortex
00100100200200300300400400500500600600700700800800900900
1000100011001100
00 11 22 33 44 5 hr5 hrTime After AmphetamineTime After Amphetamine
% o
f B
as
al
Re
lea
se
% o
f B
as
al
Re
lea
se
AMPHETAMINEAMPHETAMINE
00
5050
100100
150150
200200
00 6060 120120 180180Time (min)Time (min)
% o
f B
asal
Re
lea
se%
of
Bas
al R
ele
ase
EmptyEmptyBoxBox FeedingFeeding
Di Chiara et al.Di Chiara et al.
FOODFOOD
TYR OSINE
DA
DOPA
DA
DA
DA
DA
TYR OSINE
DA
DOPA
DA
DA
DA
D AD A D A D A
D AD AD A
methylphenidate
RRRRRR
-10 0 10 20 30 40-20246810
Self-Reports
(0-10)
Change in DopamineBmax/kd (Placebo - MP)
“High”
DA and Drug Reinforcement
racloprideraclopride
DA DA
DA initiates and maintains responses to salient stimuli such as drugs
DA initiates and maintains responses to salient stimuli such as drugs
Volkow et al., JPET 291(1):409-415, 1999. Volkow et al., JPET 291(1):409-415, 1999.
NAccNAccVPVP
REWARDREWARD• 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.
• 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)
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)
1. Reward Circuit 1. Reward Circuit
00
22
44
66
88
1010
ControlsControls AbusersAbusers
PlaceboPlaceboMPMP
Sel
f R
epor
t C
ravi
ng
Sel
f R
epor
t C
ravi
ng
(0-1
0)(0
-10)
00
22
44
66
88
1010
ControlsControls AbusersAbusers
Sel
f R
epor
tS
elf
Rep
ort
(0-1
0)(0
-10)
Self Reports of Drug Effects After iv MP in Controls and in
Cocaine Abusers
Self Reports of Drug Effects After iv MP in Controls and in
Cocaine Abusers
P < 0.001P < 0.001
P <0.001P <0.001
High Craving
Cocaine abusers showed decreased drug induced increases in rewarding responses and enhanced drug craving
Cocaine abusers showed decreased drug induced increases in rewarding responses and enhanced drug craving
Volkow et al., Nature 386:830-833, 1997.Volkow et al., Nature 386:830-833, 1997.
0
5
10
15
20
25
30
35
% C
han
ge B
max
/Kd
% C
han
ge B
max
/Kd
Controls(n = 20)Controls(n = 20)
Abusers (n = 20)Abusers (n = 20)
P < 0.003P < 0.003
Cocaine abusers showed decreased DA increases and
reduced reinforcing responses to MP
Cocaine abusers showed decreased DA increases and
reduced reinforcing responses to MP
Normal Control
Cocaine Abuser
Placebo MP
Methylphenidate-induced Increases in Striatal DA in Controls and in
Cocaine Abusers
Methylphenidate-induced Increases in Striatal DA in Controls and in
Cocaine Abusers
21%
9%
Volkow et al., Nature 386:830-833, 1997.Volkow et al., Nature 386:830-833, 1997.
HippHipp
AmygAmyg MEMORY/LEARNING MEMORY/
LEARNING
Philipps et al Nature 422, 614-618Philipps et al Nature 422, 614-618
In training the cue was paired with cocaine
In training the cue was not paired with cocaine
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.
• In rats when a neutral stimulus is repeatedly paired with the drug (conditioned), it elicits DA increases and reinstates drug self- administration.
Here we tested if conditioned stimuli increase DA in
addicted subjects and its relationship to drug craving
Here we tested if conditioned stimuli increase DA in
addicted subjects and its relationship to drug craving
DA
Rel
ease
NA
c
Auditory cue
[11C]Raclopride Binding In Cocaine Abusers (n=18) Viewing a Neutral and a Cocaine-Cue Video
[11C]Raclopride Binding In Cocaine Abusers (n=18) Viewing a Neutral and a Cocaine-Cue Video
Viewing a video of cocaine scenes decreased specific binding of [11C]raclopride presumably from DA increases
Viewing a video of cocaine scenes decreased specific binding of [11C]raclopride presumably from DA increases
Neutral video
Volkow et al. J Neuroscience 2006.Volkow et al. J Neuroscience 2006.
Cue-induced increases in DA were associated with cravingCue-induced increases in DA were associated with craving
P < 0.002
% Change Bmax/Kd
-0.50
0.0
0.50
1.0
1.5
2.0
2.5
-40-30-20-100102030
Putamen
Ch
ange
in C
ravi
ng
(Pre
- P
ost)
Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving
Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving
Cau
date
Cau
date
Pu
tam
enP
uta
men
2.002.00
2.502.50
3.003.00
3.503.50
NeutralNeutralCocaine-CuesCocaine-Cues
Bm
ax/K
dB
max
/Kd
P < 0.05P < 0.05
P < 0.01P < 0.01
Volkow et al J Neuroscience 2006.Volkow et al J Neuroscience 2006.
We assessed the relationship between DA markers and frontal activity in cocaine (n=20) and in
methampethamine abusers (n =20) and controls
We assessed the relationship between DA markers and frontal activity in cocaine (n=20) and in
methampethamine abusers (n =20) and controls
3.Motivation & Executive Control Circuits3.Motivation & Executive Control Circuits ACGACG
OFCOFCSCCSCC
INHIBITORY CONTROL
INHIBITORY CONTROL
EXECUTIVEFUNCTIONEXECUTIVEFUNCTION
PFCPFC
MOTIVATION/DRIVE
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.
Here we tested if, in addicted subjects, changes in DA function were linked with disruption of frontal activity as assessed by brain glucose metabolism.
DA is involved not only with reward and prediction of reward but also with motivation and executive function via its regulation of frontal activity.
AnatomyAnatomy DA
DA
DA
DA DA DA
DA
signal
Dopamine SynapseDopamine Synapse
DA D2 ReceptorsDA D2 Receptors
MetabolismMetabolism
Dopamine Measures ObtainedDopamine Measures Obtained
Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003. Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.
normal subject
cocaine abuser (1 month post)
cocaine abuser (4 months post)
Effect of Cocaine Abuse on Dopamine D2 Receptors
Volkow et al., Synapse 14(2): 169-177, 1993. Volkow et al., Synapse 14(2): 169-177, 1993.
1.51.5
22
2.52.5
33
3.53.5
44
4.54.5
1515 2020 2525 3030 3535 4040 4545 5050
DA
D2
Rec
epto
rsD
A D
2 R
ecep
tors
(Rat
io I
ndex
)(R
atio
Ind
ex)
DA D2 Receptors in Controls and in Cocaine Abusers (NMS)
DA D2 Receptors in Controls and in Cocaine Abusers (NMS)
Age (years)Age (years)
2020 2525 3030 3535 4040 4545 50501.61.6
1.81.8
22
2.22.2
2.42.4
2.62.6
2.82.8
33
3.23.2
Bm
ax/K
dB
max
/Kd
Normal ControlsNormal ControlsCocaine AbusersCocaine Abusers
Volkow et al., Neuropsychopharmacology 14(3):159-168, 1996.Volkow et al., Neuropsychopharmacology 14(3):159-168, 1996.
DA D2 Receptor
Availability
DA D2 Receptor
Availability
CocaineCocaine
AlcoholAlcohol
Reward Circuits
DA
DA
DA
DA DA
DA
Drug AbuserDrug Abuser
DA
DA
DA
DA DA DA
DA
Reward Circuits
DA DA DA DA
DA
Non-Drug AbuserNon-Drug Abuser
HeroinHeroin
MethMeth
Dopamine D2 Receptors are Lower in Addiction
controlcontrol addictedaddictedAdapted from Volkow et al., Neurobiology of Learning andMemory 78:610-624, 2002.
Adapted from Volkow et al., Neurobiology of Learning andMemory 78:610-624, 2002.
2nd D2R Vector
2nd D2R Vector
Effects of Tx with an Adenovirus Carrying a DA D2 Receptor Gene into
NAc in DA D2 Receptors
Effects of Tx with an Adenovirus Carrying a DA D2 Receptor Gene into
NAc in DA D2 Receptors
00
1010
2020
3030
4040
5050
6060
Per
cen
t C
han
ge in
D2R
Per
cen
t C
han
ge in
D2R
44 66 88 1010 2424
p < 0.0005
p < 0.0005
p < 0.005
p < 0.10
p < 0.005
1st D2R Vector
1st D2R Vector
00
Null Vector
Null Vector
-100-100
-80-80
-60-60
-40-40
-20-20
0 0
Time (days)Time (days)44 66 88 1010 2424
p < 0.001p < 0.001
% Change in Alcohol Intake
% Change in Alcohol Intake
p < 0.001p < 0.001
p < 0.001p < 0.001
p < 0.01p < 0.01p < 0.01p < 0.01
00
Overexpression of DA D2 receptors reduces alcoholself-administration
Overexpression of DA D2 receptors reduces alcoholself-administration
Thanos, PK et al., J Neurochem, 78, pp. 1094-1103, 2001.Thanos, PK et al., J Neurochem, 78, pp. 1094-1103, 2001.
DA DADA
DA DA
DA
DA
DA
Brain Glucose Metabolism in Cocaine Abusers (n=20) and Controls
(n=23)
Brain Glucose Metabolism in Cocaine Abusers (n=20) and Controls
(n=23)
40
45
50
55
60
ControlsControls AbusersAbusers
mic
rom
ol/1
00g/
min
mic
rom
ol/1
00g/
min
40
45
50
55
60
ControlsControls AbusersAbusers
mic
rom
ol/1
00g/
min
mic
rom
ol/1
00g/
min
CGCG
OFCOFC
CG
P < 0.005P < 0.005
P < 0.01P < 0.01
Volkow et al., AJP 156:19-26, 1999.Volkow et al., AJP 156:19-26, 1999.
Correlations Between D2 Receptors in Striatum and Brain Glucose
Metabolism
Striatum
CG
PreF
OFC
30
40
50
60
70
80
90
2.9 3 3.1 3.2 3.3 3.4 3.5 3.6
OFC
OFC
umol/100gr/min
umol/100gr/min
DA D2 ReceptorsDA D2 Receptors (Bmax/kd)(Bmax/kd)
3035404550556065
1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4DA D2 Receptors (Ratio Index)DA D2 Receptors (Ratio Index)
OFC
OFC
umol/100g/min
umol/100g/min
r = 0.7, p < 0.001
Cocaine Abusers
r = 0.7, p < 0.005
METHAbusers
control cocaine abuser
Volkow et al., Synapse 14(2):169-177, 1993.Volkow et al., Synapse 14(2):169-177, 1993.
Volkow et al., AJP 158(3):377-382, 2001.Volkow et al., AJP 158(3):377-382, 2001.
0.9000.9000.9500.9501.001.001.051.051.101.101.151.151.201.201.251.251.301.30
4.04.0 4.24.2 4.44.4 4.64.6 4.84.8 5.05.0
OF
CO
FC
Rel
ativ
e m
etab
olis
mR
elat
ive
met
abol
ism
0.7500.750
0.8000.800
0.8500.850
0.9000.900
0.9500.950
1.001.00
1.051.05
4.04.0 4.24.2 4.44.4 4.64.6 4.84.8 5.05.0
CG
CG
Rel
ativ
e m
etab
olis
mR
elat
ive
met
abol
ism
DA D2 Receptors and Relationship to Brain Metabolism in Subjects with Family History for Alcoholism
DA D2R were associated with metabolic activity in OFC, CG and dorsolateral prefrontal cortex
DA D2R were associated with metabolic activity in OFC, CG and dorsolateral prefrontal cortex
D2R (Bmax/Kd)D2R (Bmax/Kd)
Correlations between Metabolism and D2R P <0.005
Correlations between Metabolism and D2R P <0.005
Volkow et al. Arch Gen Psychiatry 2006.Volkow et al. Arch Gen Psychiatry 2006.
DriveOFCDriveOFC
Saliency NAcSaliency NAc
MemoryAmygdalaMemoryAmygdala
Control CG Control CG
Non-Addicted Brain
Non-Addicted Brain
AddictedBrain
AddictedBrain
STOP STOP
GOGODriveDrive
MemoryMemory
Saliency Saliency
ControlControl
DriveDrive
MemoryMemory
Saliency Saliency
Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003. Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.
Medications for Relapse PreventionMedications for Relapse Prevention
Interfere with conditioned memories (craving)Interfere with conditioned memories (craving)
Counteract stress responses that lead to relapseCounteract stress responses that lead to relapse
Strengthen reinforcing effects of non-drug reinforcers
Strengthen reinforcing effects of non-drug reinforcers
Strengthen inhibitory controlStrengthen inhibitory control
Strengthen prefrontal-striatal communicationStrengthen prefrontal-striatal communication
Addicted Brain
Drive
Control
Saliency
Memory
GOSTOPSaliency Drive
Control
Memory
Non-Addicted Brain
Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003. 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
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