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