NATIONAL INSTITUTE
ON DRUG ABUSE
NIDA NIAAANational Institute Alcohol
Abuse and Alcoholism
Nora D. Volkow, M.D.Director, National Institute on Drug Abuse
Nora D. Volkow, M.D.Director, National Institute on Drug Abuse
Dopamine’s Role inDopamine’s Role in
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
TYROSINE
DA
DOPA
DA
DA
DA
DA
TYROSINE
DA
DOPA
DA
DA
DA
D AD A D A D A
D AD AD A
methylphenidate
RRRRRR
-10 0 10 20 30 40-202468
10
Hig
h(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
• The mechanism(s) underlying the intense desire for the drug when addicted subjects are exposed to drug cues (places, people and paraphernalia linked with the drug), is still unknown.
• Since DA is involved with reward and with
prediction of reward, it could underlie craving
• The mechanism(s) underlying the intense desire for the drug when addicted subjects are exposed to drug cues (places, people and paraphernalia linked with the drug), is still unknown.
• Since DA is involved with reward and with
prediction of reward, it could underlie craving
BackgroundBackground
In rodents when a neutral stimuli is repeatedly paired with the drug (conditioned), it elicits DA increases.
In rodents when a neutral stimuli is repeatedly paired with the drug (conditioned), it elicits DA increases.
Philipps et al Nature 422, 614-618Philipps et al Nature 422, 614-618
DA
Rele
ase
NA
c
Auditory cue
In training the cue was paired with cocaine
In training the cue was not paired with cocaine
Eighteen cocaine abusers
Inclusion criteria: – DSM- IV criteria for cocaine dependence– active use for at least the prior 6 months – free-base or crack– at least "four grams" a week
Exclusion criteria: – past or present neuro and psychiatric
diseases other than cocaine dependence – past or present endocrinological disease– head trauma with loss of consciousness– current medical illness
Eighteen cocaine abusers
Inclusion criteria: – DSM- IV criteria for cocaine dependence– active use for at least the prior 6 months – free-base or crack– at least "four grams" a week
Exclusion criteria: – past or present neuro and psychiatric
diseases other than cocaine dependence – past or present endocrinological disease– head trauma with loss of consciousness– current medical illness
1. Subjects1. Subjects
Gender 17 males, 1 femaleAge 43 6 yearsEthnicity 15 AA, 3 CaucasiansEducation 13 2 years of educationYears used 15 7 years Route 18 smoked cocaineDose used 2.8 1.6 grams a dayLast used 2 1.4 days (range 1 & 6 days)
Cigarette smokers 15 current smokers
Gender 17 males, 1 femaleAge 43 6 yearsEthnicity 15 AA, 3 CaucasiansEducation 13 2 years of educationYears used 15 7 years Route 18 smoked cocaineDose used 2.8 1.6 grams a dayLast used 2 1.4 days (range 1 & 6 days)
Cigarette smokers 15 current smokers
2. Subjects
Methods: VideosMethods: Videos
The neutral video featured non-repeating segments of nature scenes
The cocaine-cue video featured non repeating scenes that simulated purchase, preparation,
and smoking of cocaine
The neutral video featured non-repeating segments of nature scenes
The cocaine-cue video featured non repeating scenes that simulated purchase, preparation,
and smoking of cocaine
Videos were shown 10 min prior to radiotracer injection for a total of 40 min
Videos were shown 10 min prior to radiotracer injection for a total of 40 min
Self-reports of craving during the neutral and the cocaine-cue video
Self-reports of craving during the neutral and the cocaine-cue video
2.002.00
2.502.50
3.003.00
3.503.50
4.004.00
4.504.50
5.005.00
Coc
ain
e C
ravi
ng
Coc
ain
e C
ravi
ng P < 0.01P < 0.01
Bef
ore
Bef
ore
Aft
erA
fter
Cocaine cues increased self reports of cocaine craving in cocaine abusers
Cocaine cues increased self reports of cocaine craving in cocaine abusers
2.002.00
2.502.50
3.003.00
3.503.50
4.004.00
4.504.50
5.005.00
Coc
ain
e C
ravi
ng
Coc
ain
e C
ravi
ng
(1-7
)(1
-7)
Bef
ore
Bef
ore
Aft
erA
fter
Neutral VideoNeutral Video Cocaine-Cue VideoCocaine-Cue Video
Source: Volkow, ND et al., Journal of Neuroscience, 26(24):6583-6588, 2006.Source: Volkow, ND et al., Journal of Neuroscience, 26(24):6583-6588, 2006.
Cue-induced increases in DA were associated with cravingCue-induced increases in DA were associated with craving
P < 0.002P < 0.002
% Change Bmax/Kd% Change Bmax/Kd
-0.50-0.50
0.00.0
0.500.50
1.01.0
1.51.5
2.02.0
2.52.5
-40-40-30-30-20-20-10-1000101020203030
PutamenPutamen
-0.50-0.50
0.00.0
0.500.50
1.01.0
1.51.5
2.02.0
2.52.5
-40-40-30-30-20-20-10-1000101020203030
Ch
ange
in C
ravi
ng
Ch
ange
in C
ravi
ng
(Pre
- P
ost)
(Pre
- P
ost)
CaudateCaudate
Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving
Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving
P < 0.05P < 0.05
Source: Volkow, ND et al., Journal of Neuroscience, 26(24):6583-6588, 2006.Source: Volkow, ND et al., Journal of Neuroscience, 26(24):6583-6588, 2006.
Craving of Food
Why is it that the sight of food can elicit the desire for it even when we are not hungry?
Are the responses to cues similar to those that triggered the cocaine in cocaine abusers?
Neutral: Subjects were asked to describe their family genealogy.
Food Cues: The food-cue featured non repeating presentation of favorite foods that had been heated to enhance smell
Neutral: Subjects were asked to describe their family genealogy.
Food Cues: The food-cue featured non repeating presentation of favorite foods that had been heated to enhance smell
Stimuli were presented 10 min prior to radiotracer injection for a total of 40 minStimuli were presented 10 min prior to
radiotracer injection for a total of 40 min
Ten healthy food deprived controls (15-18 hours food deprivation) tested under neutral and food cue conditions
Brain Dopamine Response to Food Stimulation(B
max
/Kd
)(B
max
/Kd
)
2.52.5
33
3.53.5
44
Placebo/NeutralPlacebo/Neutral MP/FoodMP/Food
p < 0.005p < 0.005
1.51.5
00
ml/gml/g
Source: Volkow, et al., Synapse 2002.Source: Volkow, et al., Synapse 2002.
-2-2
00
22
44
66
88
1010
00 55 1010 1515 2020 2525 3030D
esir
e fo
r F
ood
Des
ire
for
Foo
d
% Change Bmax/kd% Change Bmax/kd
p < 0.01p < 0.01
NeutralNeutral FoodFood
Bmax/Kd decreased with exposure to food-cues
presumably from DA increases
Bmax/Kd decreased with exposure to food-cues
presumably from DA increases
Neutral
Food Cue
[11C]Raclopride Binding in Food Deprived Controls During Neutral and Food Cues
[11C]Raclopride Binding in Food Deprived Controls During Neutral and Food Cues
(Bm
ax/K
d)
(Bm
ax/K
d)2.52.5
33
3.53.5
44
Placebo/NeutralPlacebo/Neutral MP/FoodMP/Food
p < 0.005p < 0.005
1.51.5
00
ml/gml/g
Source: Volkow, et al., Synapse 2002.Source: Volkow, et al., Synapse 2002.
Relationship Between DA Changes and Self-Reports of Hunger and Desire for Food Induced
by Food Cues
0 5 10 15 20 25 30-2
0
2
4
6
8
10
Hu
nge
r
-2
0
2
4
6
8
10
0 5 10 15 20 25 30
Des
ire
for
Foo
d
% Change Bmax/kdp < 0.01
DA activation of DS may underlie the “desire” (wanting) that result in the readiness to engage
in the behaviors necessary to procure the desired object whether it’s a drug or food
DA activation of DS may underlie the “desire” (wanting) that result in the readiness to engage
in the behaviors necessary to procure the desired object whether it’s a drug or food
Cue-induced DA increases were associated with craving for drugs as well as for food, which highlights the automated (reflexes) nature of these responses
Cue-induced DA increases were associated with craving for drugs as well as for food, which highlights the automated (reflexes) nature of these responses
Both drug as well as food cues increased DA in dorsal striatum (brain region involved with initiation of action and with learning of habits), suggesting that drugs usurp physiological processes
Both drug as well as food cues increased DA in dorsal striatum (brain region involved with initiation of action and with learning of habits), suggesting that drugs usurp physiological processes
Funded by DOE and NIHFunded by DOE and NIH
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