1. Director, National Institute on Drug Abuse National Institute Alcohol
Dopamine’s Role in
DRUG CRAVING
Nora D. Volkow, M.D.
Director, National Institute on Drug Abuse
NIDA
NIAAA
NATIONAL INSTITUTE
ON DRUG ABUSE
National Institute Alcohol
Abuse and Alcoholism

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
High
(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

4. 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

5. Background
DA Release NAc
Auditory cue
In rodents when a neutral stimuli is repeatedly paired with the drug (conditioned), it elicits DA increases.
In training the cue was paired with cocaine
In training the cue was not paired with cocaine
Philipps et al Nature 422,

6. 1. Subjects 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

7. 2. Subjects Gender 17 males, 1 female Age 43 6 years
Ethnicity AA, 3 Caucasians
Education 2 years of education
Years used 7 years
Route smoked cocaine
Dose used 1.6 grams a day
Last used 1.4 days (range 1 & 6 days)
Cigarette smokers 15 current smokers

8. Methods: 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
Videos were shown 10 min prior to
radiotracer injection for a total of 40 min

9. Self-reports of craving during the neutral and the cocaine-cue video
Neutral Video
Cocaine-Cue Video
2.00
2.50
3.00
3.50
4.00
4.50
5.00
P < 0.01
2.00
2.50
3.00
3.50
4.00
4.50
5.00
Cocaine Craving
(1-7)
Cocaine Craving
Before
After
Before
After
Cocaine cues increased self reports of cocaine craving in cocaine abusers
Source: Volkow, ND et al., Journal of Neuroscience, 26(24): , 2006.

10. Cue-induced increases in DA were associated with craving
Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving
% Change Bmax/Kd
-0.50
0.0
0.50
1.0
1.5
2.0
2.5
-40
-30
-20
-10 10 20 30
Putamen
Change in Craving
(Pre - Post)
Caudate
P < 0.05
P < 0.002
Cue-induced increases in DA were associated with craving
Source: Volkow, ND et al., Journal of Neuroscience, 26(24): , 2006.

11. 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?

12. Neutral: Subjects were asked to describe their family genealogy.
Ten healthy food deprived controls (15-18 hours food deprivation) tested under neutral and food cue conditions
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 min

13. Brain Dopamine Response to Food Stimulation
Neutral
Food
1.5
2.5 3
3.5 4 -2 2 4 6 8 10 5 15 20 25 30
ml/g
(Bmax/Kd)
p < 0.005
Desire for Food
Placebo/Neutral
MP/Food
% Change Bmax/kd
Source: Volkow, et al., Synapse 2002.
p < 0.01

14. [11C]Raclopride Binding in Food Deprived Controls During Neutral and Food Cues
(Bmax/Kd)
2.5 3
3.5 4
Placebo/Neutral
MP/Food
p < 0.005
1.5
ml/g
Neutral
Bmax/Kd decreased with exposure to food-cues presumably from DA increases
Food Cue
Source: Volkow, et al., Synapse 2002.

15. Relationship Between DA Changes and Self-Reports of Hunger and Desire for Food Induced by Food Cues-2 2 4 6 8 10 5 15 20 25 30 5 10 15 20 25 30 -2 2 4 6 8
Hunger
Desire for Food
% Change Bmax/kd
p < 0.01

16. 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
Cue-induced DA increases were associated with craving for drugs as well as for food, which highlights the automated (reflexes) nature of these responses
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

17. Funded 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