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 40-20246810

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

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

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

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

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

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