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NATIONAL INSTITUTE
ON DRUG ABUSE
NIDA NIAAANational Institute Alcohol
Abuse and Alcoholism
Nora D. Volkow, M.D.Director, National Institute on Drug Abuse
Dopamine’s Role in
Dopamine Neurotransmission
VTA/SNnucleus accumbens
frontalcortex
0100200300400500600700800900
10001100
0 1 2 3 4 5 hrTime After Amphetamine
% o
f Bas
al R
elea
se AMPHETAMINE
0
50
100
150
200
0 60 120 180Time (min)
% o
f Bas
al R
elea
seEmpty
Box Feeding
Di Chiara et al.
FOOD
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 40-20246810
High
(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
• 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
In rodents when a neutral stimuli is repeatedly paired with the drug (conditioned), it elicits DA increases.
Philipps et al Nature 422, 614-618
DA R
elea
se N
Ac
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
1. Subjects
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
2.00
2.50
3.00
3.50
4.00
4.50
5.00
Coc
aine
Cra
ving
P < 0.01
Bef
ore
Aft
er
Cocaine cues increased self reports of cocaine craving in cocaine abusers
2.00
2.50
3.00
3.50
4.00
4.50
5.00
Coc
aine
Cra
ving
(1-7
)
Bef
ore
Aft
er
Neutral Video Cocaine-Cue Video
Source: Volkow, ND et al., Journal of Neuroscience, 26(24):6583-6588, 2006.
Cue-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
-0.50
0.0
0.50
1.0
1.5
2.0
2.5
-40-30-20-100102030
Cha
nge
in C
ravi
ng(P
re -
Post
)
Caudate
Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving
P < 0.05
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
Stimuli 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
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
(Bm
ax/K
d)2.5
3
3.5
4
Placebo/Neutral MP/Food
p < 0.005
1.5
0
ml/g
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 30-202468
10
Hun
ger
-202468
10
0 5 10 15 20 25 30
Des
ire
for
Food
% 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
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
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
Brain Dopamine Response to Food Stimulation(B
max
/Kd)
2.5
3
3.5
4
Placebo/Neutral MP/Food
p < 0.005
1.5
0
ml/g
Source: Volkow, et al., Synapse 2002.
-2
0
2
4
6
8
10
0 5 10 15 20 25 30D
esir
e fo
r Fo
od
% Change Bmax/kdp < 0.01
Neutral Food
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
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