Neuroimaging studies of obesity and drug addiction · 2016-08-09 · obesity and drug addiction. Brookhaven Science Associates U.S. Department of Energy VTA/SN nucleus accumbens frontal

Brookhaven Science AssociatesU.S. Department of Energy

Gene-Jack Wang, BNL

Nora D. Volkow, NIDA

Joanna S. Fowler, BNL

Neuroimaging studies ofobesity and drug addiction


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

se

EmptyBox Feeding

Di Chiara et al.

FOOD

DopamineNeurotransmission


TYROSINE

DA

DOPA

DA

DA

DA

DA

TYRO SINE

DA

DOPA

DA

DA

DA

D AD A D A D A

D AD AD A

methylphenidate

RRRRRR

-10 0 10 20 30 40-202468

10

Self-

Rep

orts

(0-1

0)

Change in DopamineBmax/kd (Placebo - MP)

“High”

racloprideraclopride

DA DA

Dopamine initiates andmaintains responses tosalient stimuli such asdrugs

Dopamine and Drug Reinforcement

Volkow, ND, et al, Am J Psychiatry 1999


Cue-induced increases in DA were associated with craving

Relationship between Cue-Induced Decreases in[11C]raclopride Binding andCocaine 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

Cha

nge

in C

ravi

ng

(Pre

- Po

st)

Caudate Putamen2.00

2.50

3.00

3.50 NeutralCocaine-Cues

Bm

ax/K

d

P < 0.05

P < 0.01

Volkow, et al, J. Neuroscience 2006


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

0

2

4

6

8

10

0 5 10 15 20 25 30D

esire

for F

ood

% Change Bmax/kd

p < 0.01

Neutral Food


Anatomy

DA

DA

DA

DA DA DA

DA

signal

Dopamine Cell

DA Transporters

DA Receptors

Metabolism

Is DA Involved inAddiction and Obesity?


DA

D2

Rec

epto

r Ava

ilabi

lity

control addicted

Cocaine

Heroin

Alcohol

DA

DA

DA

DA DA DA

DA

DA DA DA DA

DA

DA

DA

DA

DA DA

DA

Drug Abuser

Non-Drug Abuser

Dopamine D2 Receptors are Lower in Addiction

Reward Circuits

Reward Circuits


20 25 30 35 40 45 501.6

1.8

2

2.2

2.4

2.6

2.8

3

3.2

Age (years)

DA

D2

rece

ptor

ava

ilabi

lity

(Bm

ax/K

d)Normal ControlsCocaine Abusers

DA D2 Receptors in Controls & Cocaine Abusers

[11C] Raclopride


DA

D2

rece

ptor

ava

ilabi

lity

unpleasant

pleasant

High receptor level =unpleasant response

Low receptor level =pleasant response

DA D2 Receptors and Response toIntravenous Methylphenidate

High

Low

[11C] Raclopride

Volkow, ND, et al, Am J Psychiatry 1999


2nd

D2R

Vec

tor

0

10

20

30

40

50

60

Perc

ent C

hang

e in

D2R

4 6 8 10 24

p < 0.0005

p < 0.0005

p < 0.005

p < 0.10

p < 0.005

1st D

2R V

ecto

r

0 Nul

l Vec

tor

-100

-80

-60

-40

-20

0

Time (days)4 6 8 10 24

p < 0.001% C

hang

e in

Alc

ohol

Inta

ke

p < 0.001

p < 0.001

p < 0.01p < 0.01

0

Overexpression of DA D2 receptors reduces alcoholself-administration

Thanos, PK et al., J Neurochem, 2001.

DA DADA

DA DA

DA

DA

DA

Effects of Tx with an Adenovirus Carrying a DAD2 Receptor Gene into NAc in DA D2 Receptors


Compulsive overeating shares many of the samecharacteristics as drug addiction.

Obesity

Do obese subjects have abnormal levels of D2-receptor?10 severely obese subjects (BMI: 51±5 kg/m2)10 age-matched controls (BMI: 25±3 kg/m2)


Lower dopamine receptors in obese than in control subjects

2

0ml/gm

Control Subjects

Obese Subjects

[11C]raclopride

Wang et al, Lancet 2001

Bmax/Kd

BM

I

BMI

Control subjects

20

25

30

35

40

45

50

55

60

65

1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4 3.6 3.8

Obese subjects (n = 10)

Control subjects (n = 10)

BMI

Dopamine Receptor Concentration

P < 0.002

P < 0.3


Thanos et al 20053H-Spiperone

0.00100200300400500600700

Lean Obese

Wei

ght (

gram

s)

P < 0.05

Weight

0.00

100

200

300

400

500

600

Lean Obese

Loco

mot

or A

ctiv

ity(b

eam

cro

ssin

gs)

P < 0.05

Locomotion

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

rsSt

riatu

m/C

ereb

ellu

m

P < 0.05

D2-Receptors

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


Anatomy

DA

DA

DA

DA DA DA

DA

signal

Dopamine Cell

DA Receptors

Metabolism

What is the functional significance of low D2-R?


Striatum

CG

PreF

OFC3035404550556065

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

OFC

u

mol

/100

g/m

in

r = 0.7, p < 0.001

Cocaine Abusers

30

40

50

60

70

80

90

2.9 3 3.1 3.2 3.3 3.4 3.5 3.6

OFC

umol

/100

gr/m

in

DA D2 Receptors (Bmax/kd)

r = 0.7, p < 0.005

METHAbusers

Salience Attribution

Inhibitory Control

control cocaine abuser

Correlations Between D2 Receptors inStriatum and Brain Glucose Metabolism


MP

85

0

µmole/100g/min

Brain Activation with MethylphenidateInduced Cocaine Craving

Placebo

OrbitofrontalActivation

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 10m

icro

mol

/100

g/m

in(M

P - P

lace

bo)

Self Report Craving

r = 0.79, p < 0.0002


% M

eta

bo

lic C

han

ges

-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

OrbitofrontalActivation

Brain Activation with Food Stimuli


Activation of hippocampus during craving

Cocaine cravingBreiter et al, 1997

Food craving

Hippocampus

Pelchat et al, 2004

Hippocampus

DelParigi et al, 2004


Why do some people continue to eat when the stomach is full?

Implantable gastric stimulator: IGS

Wang et al, PNAS USA 2006

PET-FDG (IGS “on” vs IGS “off” in obese subjects)

• Higher metabolism in brain reward pathways when a"stomach stimulator" is turned “on” to simulatefullness vs. “off”.

• The same areas are also activated during drugcraving in addicted subjects, supporting similaritiesbetween compulsive overeating and drug addiction.

Em

oti

on

al

ea

tin

g

3

4

5

6

7

8

9

10

11

12

13

.6 .8 1 1.2 1.4 1.6 1.8 2 2.2 2.4

22

3

ON OFF


•What makes obese subjects differentfrom drug abusers?

ObesityVS

Drug Abuse


Regions that are More Active in Obese than Controls

Right Hemisphere Left Hemisphere

Wang et al, NeuroReport 2002

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


DriveSaliency

Memory

Control

Non-Addicted Brain

STOPDrive

Memory

Saliency

Control

Drive

Memory

Saliency

GO

AddictedBrain



L. Miller (biophysicist)M. Miura (chemist)L. Pena (neuroscience)M. Schueller (medical physics)D. Schlyer (chemistry)W. Schiffer (neurobiology)D. Smith (MRI physics)F. Telang (neurology)P. Thanos (neuroscience)D. Tomasi (MRI physics)P. Vaska (PET physics)G-J Wang (Chair, medicine)8 technicians and nurses13 graduate students and post-docs

D. Alexoff (engineering)H. Benveniste (medicine)A. Biegon (pharmacology)E. Caparelli (physics)S. Dewey (neuroanatomy)A. Dilmanian (physics)C. Du (medical physics)J. Dunn (microbiologist)R. Ferrieri (chemistry)J. Fowler (chemistry)A. Gifford (pharmacology)R. Goldstein (psychology)F. Henn (ALD, psychiatry)N. Klein (psychology)J. Logan (modeling)Y. Ma (image analysis)

Center for Translational Neuroimaging


Thank You!

Supported byDOE/OBERNIDA/NIAAA

Documents

Neuroimaging studies of obesity and drug addiction · 2016-08-09 · obesity and drug addiction. Brookhaven Science Associates U.S. Department of Energy VTA/SN nucleus accumbens frontal