Common Brain Mechanisms in

ADDICTION

Common Brain Mechanisms in

ADDICTION

Nora D. Volkow, M.D.Director

National Institute on Drug Abuse

Nora D. Volkow, M.D.Director

National Institute on Drug Abuse

and

OBESITYand

OBESITY

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

AnatomyAnatomy

DA

DA

DA

DA DA DA

DA

signal

Dopamine CellDopamine Cell

DA TransportersDA Transporters

DA ReceptorsDA Receptors

MetabolismMetabolism

Is DA Involved in Addiction and Obesity?Is DA Involved in Addiction and Obesity?

normal subject

cocaine abuser (1 month post)

cocaine abuser (4 months post)

Effect of Cocaine Abuse on Dopamine D2 Receptors

1.5

2

2.5

3

3.5

4

4.5

1515 2020 2525 3030 3535 4040 4545 5050

Cocaine AbusersCocaine AbusersNormal ControlsNormal Controls

DA

D2

Rec

epto

rsD

A D

2 R

ecep

tors

(Bm

ax/K

d)

(Bm

ax/K

d)

Age (years)Age (years)

DA D2 Receptors in Controls and in Cocaine Abusers (NMS)

DA D2 Receptors in Controls and in Cocaine Abusers (NMS)

Dopamine D2 Receptors are Lower in Addiction

DA

D2

Rec

epto

r A

vaila

bili

tycontrol addicted

Cocaine

Heroin

Alcohol

DA

DA

DA

DA DA DA

DA

Reward Circuits

DA DA DA DA

DA

Reward Circuits

DA

DA

DA

DA DA

DA

Drug Abuser

Non-Drug Abuser

2nd

D2R

Vec

tor

2nd

D2R

Vec

tor

Effects of Tx with an Adenovirus Carrying a DA D2 Receptor Gene into NAc in DA D2 ReceptorsEffects of Tx with an Adenovirus Carrying a DA D2 Receptor Gene into NAc in DA D2 Receptors

00

1010

2020

3030

4040

5050

6060

Per

cen

t C

han

ge in

D2R

Per

cen

t C

han

ge in

D2R

44 66 88 1010 2424

p < 0.0005

p < 0.0005

p < 0.005

p < 0.10

p < 0.005

1st

D2R

Vec

tor

1st

D2R

Vec

tor

00

Nul

l Vec

tor

Nul

l Vec

tor

-100-100

-80-80

-60-60

-40-40

-20-20

0 0

Time (days)Time (days)44 66 88 1010 2424

p < 0.001p < 0.001% C

han

ge in

Alc

ohol

In

tak

e%

Ch

ange

in A

lcoh

ol I

nta

ke

p < 0.001p < 0.001

p < 0.001p < 0.001

p < 0.01p < 0.01p < 0.01p < 0.01

00

Overexpression of DA D2 receptors reduces alcoholself-administration

Overexpression of DA D2 receptors reduces alcoholself-administration

Source: Thanos, PK et al., J Neurochem, 78, pp. 1094-1103, 2001.Source: Thanos, PK et al., J Neurochem, 78, pp. 1094-1103, 2001.

DADA

DA

DA DA

DA

DA

DA

Compulsive overeating shares many of the same characteristics as drug addiction.

Compulsive overeating shares many of the same characteristics as drug addiction.

Obesity

Do obese subjects have abnormal levels of D2-R?Do obese subjects have abnormal levels of D2-R?

10 severely obese subjects (BMI: 51±5 kg/m2)10 age-matched controls (BMI: 25±3 kg/m2)

Control Subjects2.99 (Sd 0.41)

2

0

ml/gm

Obese Subjects2.47 (Sd 0.36)

Dopamine D2 ReceptorsDopamine D2 Receptors[11C]raclopride

Wang et al, Lancet 2001P < 0.008

20202525

3030

3535

4040

4545

5050

5555

6060

65

1.81.8 22 2.22.2 2.42.4 2.62.6 2.82.8 33 3.23.2 3.43.4 3.63.6 3.83.8

p < 0.002

• Obese subjects• Obese subjects• Control subjects• Control subjects

DA D2 Receptors and BMI in Controls and Obese Subjects

DA D2 Receptors and BMI in Controls and Obese Subjects

Bmax/KdBmax/Kd

BM

IB

MI

p = 0.3

DA D2-R in Zucker Lean and Zucker Obese (fa/fa) Rats

0.00100200300400500600700

Lean Obese

Wei

ght (

gram

s)

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00

Lean(n=10)

Obese(n=10)

DA

D2

Rec

epto

rsS

tria

tum

/Cer

ebel

lum

Thanos et al 2005

P < 0.05

P < 0.05

0.00

100

200

300

400

500

600

Lean Obese

Loc

omot

or A

ctiv

ity

(bea

m c

ross

ings

)

P < 0.05

3H-Spiperone

Weight Locomotion

D2-Receptors

AnatomyAnatomy

DA

DA

DA

DA DA DA

DA

signal

Dopamine CellDopamine Cell

DA ReceptorsDA Receptors

MetabolismMetabolism

What is the functional significance of low D2-R?What is the functional significance of low D2-R?

Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism

Striatum

CGCG

PreF

OFCOFC30354045

50556065

1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4DA D2 Receptors (Ratio Index)DA D2 Receptors (Ratio Index)

OF

CO

FC

u

mol

/100

g/m

in

um

ol/1

00g/

min

r = 0.7, p < 0.001

30

40

50

60

70

80

90

2.9 3 3.1 3.2 3.3 3.4 3.5 3.6

OF

CO

FC

umol

/100

gr/m

inum

ol/1

00gr

/min

DA D2 ReceptorsDA D2 Receptors (Bmax/kd)(Bmax/kd)

Cocaine AbusersCocaine Abusers

r = 0.7, p < 0.005

METHAbusersMETHAbusersSalience AttributionSalience Attribution

Inhibitory ControlInhibitory Control

control cocaine abuser

MP

85

0

µmole/100g/min

Brain Activation with Methylphenidate Induced Cocaine Craving

Brain Activation with Methylphenidate Induced Cocaine Craving

Placebo

Orbitofrontal Activation

Volkow et al Am J Psychiatry 1999

-30

-20

-10

0.0

10

20

30

0.0 2.0 4.0 6.0 8.0 10

mic

rom

ol/1

00g

/min

(MP

- P

lace

bo)

Self Report Craving

r = 0.79, p < 0.0002

%

Met

abol

ic C

hang

es

-10

-5

0

5

10

15

20

25

-10 0 10 20 30 40 50 60 70 80

% Changes of feeling of hunger

r = 0.84, p = 0.001

85

0

µmole/100g/min

Neutral Stimuli

Food Stimuli

Wang et al, Neuroimage 2004

Orbitofrontal Activation

Brain Activation with Food Stimuli

FOOD

What Provides the Specificity?

Drugs

55

0µmol/100g/min

Control subjectsControl subjects Obese subjectsObese subjects

Averaged FDG imagesAveraged FDG images

What brain regions differ?What brain regions differ?

Regions that are More Active in Obese than Controls

Right HemisphereRight Hemisphere Left HemisphereLeft Hemisphere

The specificity may be determined by an enhanced brain sensitivity to food as a reinforcer

The specificity may be determined by an enhanced brain sensitivity to food as a reinforcer

The increased activity in somatosensory cortex for mouth, tongue and lips in obese subjects suggests

that enhanced sensitivity in these regions, which are involved in the sensory processing of food

may make them more vulnerable tothe reinforcing properties of food

The increased activity in somatosensory cortex for mouth, tongue and lips in obese subjects suggests

that enhanced sensitivity in these regions, which are involved in the sensory processing of food

may make them more vulnerable tothe reinforcing properties of food

The specificity for a particular drug or stimuli may be determined by an enhanced brain sensitivity

to that particular reinforcer

The specificity for a particular drug or stimuli may be determined by an enhanced brain sensitivity

to that particular reinforcer

Addicted BrainAddicted Brain

Control

DriveSaliency

Memory

STOPSTOP

Non Addicted BrainNon Addicted Brain

GOGO

Control

DriveSaliency

Memory

BNL PET Group (Support DOE, NIDA)

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

Measuring Changes in Dopamine

TYROSINE

DA

DOPA

DA

DA

DA

MAO

DOPAC

DA

TYROSINE

DA

DOPA

DA

DA

DA

MAO

DOPAC

DA

DADA DA DA

DA

DADAmethylphenidate

CONHCH2

ClCl

O11CH3HONC2H5

H

[11C]raclopride

CONHCH2

ClCl

O11CH3HONC2H5

H

[11C]raclopride

RRRRRR

Dopamine Stress Test

-10 0 10 20 30 40-202468

10

Sel

f-R

epor

ts(0

-10)

Change in DopamineBmax/kd (Placebo - MP)

“High”

Increases in DA by iv Methylphenidate are Associated with its Reinforcing Effects

DA regulates food consumption in part by modulating its reinforcing properties through NAc

• DA increases in NAc during food expectation and food consumption.

DA may also regulate food consumption through mechanisms other than rewarding circuits.

• DA deficient KO die of starvation unless DA is restored in dorsal striatum but not in NAc.

What is the Role of Dopamine in the Motivation for Food Consumption in Humans?

MP or placebo are given 60’ prior to radiotracer and 45’ prior to neutral or food stimulation.

Ten controls; 8 M and 2 F; 35 ± 8 years

4 scans with [11C]raclopride:Placebo and Neutral StimulationPlacebo and Food StimulationMP (20 mg, po) and Neutral StimulationMP (20 mg, po) and Food Stimulation

DA

DA

DADA DADA

DA

DA

DA

DA

DA

DADA

DADADA

DADA

MPDA

DADA DA

DA

MP was given to amplify stimuli induced DA increases

Brain Dopamine Response to Food StimulationD

A D

2 R

ecep

tor

Availab

ilit

y(B

max/K

d)

2.5

3

3.5

4

Placebo/Neutral Placebo/Food MP/Neutral MP/Food

p < 0.11p < 0.02

p < 0.005

1.5

0

ml/g

Sum images of 10 normal weight subjects ([11C]raclopride)

Volkow, et al, Synapse 2002

Relationship Between Changes in DA and Reports of Hunger and Desire for Food Induced by Food

Stimulation when given with MP

Relationship Between Changes in DA and Reports of Hunger and Desire for Food Induced by Food

Stimulation when given with MP

00 55 1010 1515 2020 2525 3030-2-2

00

22

44

66

88

1010

Hu

nge

rH

un

ger

-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/kdp < 0.01p < 0.01

These results support the role of DA neurotransmission in dorsal striatum in mediating food motivation in human brain.

Implication

Biology/GenesBiology/Genes EnvironmentEnvironment

FoodFood

ObesityObesity

Neurobiology/Metabolism

Brain Glucose Metabolism in Cocaine Abusers (n=20) and Controls (n=23)

Brain Glucose Metabolism in Cocaine Abusers (n=20) and Controls (n=23)

40

45

50

55

60

Controls Abusers

mic

rom

ol/1

00g/

min

mic

rom

ol/1

00g/

min

40

45

50

55

60

Controls Abusers

mic

rom

ol/1

00g/

min

mic

rom

ol/1

00g/

min

CGCG

OFCOFC

CG

P < 0.005

P < 0.01

MP-induced Increases in Metabolism

OFC

1.001.00

1.051.05

1.101.10

1.151.15

1.201.20

1.251.25

1.301.30

ControlsControls AbusersAbusers

BaselineMP

Rec

tal G

yrus

/Bra

inR

ecta

l Gyr

us/B

rain

-4.0-4.0 -2.0-2.0 0.00.0 2.02.0 4.04.0 6.06.0 8.08.0 10.010.0-0.2-0.2

-0.1-0.1

0.00.0

0.10.1

0.20.2

0.30.3

CravingCraving

Rec

tal

Gyr

usR

ecta

l G

yrus

(MP

- P

lace

bo)

(MP

- P

lace

bo)

p < 0.005p < 0.005

Abusers > Controls p = 0.001

p < 0.01p < 0.01

SS

In ST

OF

Statistical Parameter Map of Metabolic Changes between Food and Neutral stimulation

R

Wang et al, Neuroimage 2004

• Twelve normal weight subjects.

• Insula is a brain region modulating emotional responses to appetitive stimuli.

• Orbitofrontal cortex is a brain region involved with salience attribution.

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

Volkow, et al, Synapse 2002

-2-2

00

22

44

66

88

1010

00 55 1010 1515 2020 2525 3030

Des

ire

for

Foo

dD

esir

e fo

r F

ood

% Change Bmax/kd% Change Bmax/kd

p < 0.01p < 0.01

Neutral Food

Addicted Brain

Control

DriveReward

Memory

Output

Non Addicted Brain

Output

Control

DriveReward

Memory