Transcript Nora D. Volkow, MD Director, National Institute on Drug Abuse

Dopamine’s Role in
Nora D. Volkow, M.D.
Director, National Institute on Drug Abuse
NIDA
NATIONAL INSTITUTE
ON DRUG ABUSE
NIAAA
National Institute Alcohol
Abuse and Alcoholism
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
High
(0-10)
DA and Drug Reinforcement
DA
DA
DA
DA R
DA
R
R
methylphenidate
DA
DA DA
DA DA DA R
raclopride
“High”
10
8
6
4
2
0
-2-10 0 10 20 30 40
Change in Dopamine
Bmax/kd (Placebo - MP)
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
Background
DA Release NAc
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
Auditory cue
In training the
cue was not
paired with
cocaine
Philipps et al Nature 422, 614-618
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
2. Subjects
Gender
Age
Ethnicity
Education
Years used
Route
Dose used
Last used
Cigarette smokers
17 males, 1 female
43 6 years
15 AA, 3 Caucasians
13 2 years of education
15 7 years
18 smoked cocaine
2.8 1.6 grams a day
2 1.4 days (range 1 & 6 days)
15 current smokers
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
Self-reports of craving during the neutral
and the cocaine-cue video
4.00
3.50
3.00
Before
2.50
5.00
P < 0.01
4.50
4.00
3.50
3.00
2.50
2.00
Before
4.50
2.00
Cocaine-Cue Video
Cocaine Craving
5.00
(1-7)
Cocaine Craving
Neutral Video
Cocaine cues increased self reports of
cocaine craving in cocaine abusers
Source: Volkow, ND et al., Journal of Neuroscience, 26(24):6583-6588, 2006.
Relationship between Cue-Induced Decreases in
[11C]raclopride Binding and Cocaine Craving
2.5
(Pre - Post)
Change in Craving
Caudate
P < 0.05
Putamen
2.0
2.0
1.5
1.5
1.0
1.0
0.50
0.50
0.0
0.0
-0.50
30 20 10 0 -10 -20 -30 -40
P < 0.002
2.5
-0.50
30 20 10
0 -10 -20 -30 -40
% Change Bmax/Kd
Cue-induced increases in DA were associated with craving
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?
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
Brain Dopamine Response to Food Stimulation
Neutral
Food
1.5
10
0
3.5
ml/g
p < 0.005
3
Desire for Food
(Bmax/Kd)
4
8
6
4
2
0
-2
2.5 Placebo/Neutral
MP/Food
Source: Volkow, et al., Synapse 2002.
0 5 10 15 20 25 30
% Change Bmax/kd
p < 0.01
[11C]Raclopride Binding in Food Deprived
Controls During Neutral and Food Cues
1.5
(Bmax/Kd)
4
3.5
p < 0.005
3
Neutral
0
ml/g
2.5 Placebo/Neutral
MP/Food
Bmax/Kd decreased with
exposure to food-cues
presumably from DA increases
Food Cue
Source: Volkow, et al., Synapse 2002.
Relationship Between DA Changes and SelfReports of Hunger and Desire for Food Induced
by Food Cues
10
8
6
Hunger
Desire for Food
10
8
6
4
2
0
-2
4
2
0
-2
0
5 10 15 20 25 30
0
5 10 15 20 25 30
% Change Bmax/kd
p < 0.01
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
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