Nora D. Volkow, M.D.Director

National Institute on Drug AbuseNational Institutes of Health

Overlapping Neuronal Circuits In

Signals that Control:

Homeostatic factorsLeptin, Insulin, Ghrelin, PYY

RewardDopamine, Cannabinoids,

Serotonin, Opioids

Hypothalamus

Ventral tegmental area(Reward)

(Nutritional need)

Hypothalamus

Ventral tegmental area(Reward)

RewardDopamine, Cannabinoids,

Serotonin, Opioids

Drug Consumption Food Consumption

0100200300400500600700800900

10001100

0 1 2 3 4 5 hrTime After Amphetamine

% o

f B

asal

Rel

ease

AMPHETAMINE

0

50

100

150

200

0 60 120 180Time (min)

% o

f B

asal

Rel

ease

EmptyBox Feeding

Di Chiara et al.

FOOD

VTA/SNVTA/SNnucleus accumbensnucleus accumbens

frontalcortexfrontalcortex

Dopamine Neurotransmission

TYROSINE

DA

DOPA

DA

DA

DA

DA

TYROSINE

DA

DOPA

DA

DA

DA

DADA DA DA

DADADA

RRRRRR

-10 0 10 20 30 40-202468

10

Sel

f-R

epor

ts(0

-10)

Change in DopamineBmax/kd (Placebo - MP)

“High”

Reward Circuit in Addictionand in Obesity

racloprideraclopride

DA DA

Volkow et al., JPET 291(1):409-415, 1999.

NAccNAccVPVP

REWARDREWARD

methylphenidate

High-BMI participants showed decreased response in caudate in response to consummatory food rewardcompared with low-BMI participants

Striatal Activation to Food Reward

in Obese and Lean Ss

Stice et al., J Abnormal Psychology 2008.

Reactivity of Dopamine System to Drug Consumption in

Actively Using Addicted Subjects

Active cocaine abusers showed a marked reduction in MPH-induced DA increases and in its reinforcing effects

Cocaine abuser246810

Self

-rep

ort H

igh

(1-10)

P < 0.001

Control Abuser

Placebo MPH

High

Low

Control subject 0

5

10

15

20

25

Control Abuser% C

hang

e B

max

/Kd

14%

3%

P < .001

HippHipp

AmygAmyg MEMORY/LEARNING MEMORY/

LEARNING

Philipps et al Nature 422, 614-618.

In training the cue was paired with cocaine

In training the cue was not paired with cocaine

Memory Circuit in AddictionMemory Circuit in Addiction and in Obesityand in Obesity

• In rats when a neutral stimuli is repeatedly paired with the drug (conditioned), it elicits DA increases and reinstates drug self- administration

Here we tested if conditioned stimuli increase DA in addicted subjects and its relationship to drug craving Here we tested if conditioned stimuli increase DA in addicted subjects and its relationship to drug craving

DA

Rel

ease

NA

c

Auditory cue

[11C]Raclopride Binding In Cocaine Abusers Viewing a

Neutral and a Cocaine-Cue Video

Viewing a video of cocaine scenes decreased specific binding of [11C]raclopride presumably from DA increases

Neutral video

Volkow et al J Neuroscience 2006.

[11C]Raclopride Binding in Food Deprived Controls (n=16)

During Neutral and Food Cues

Volkow, et al., Synapse 2002.

Food Cue:

1.5

0

ml/g

Subjects were asked to

describe their family genealogy

Neutral:

Bmax/Kd decreased with exposure to food-cues

DA

DA

DA

DA DA DA

DA

signal

Motivation & Executive Control Circuits ACGACG

OFCOFCSCCSCC

INHIBITORY CONTROL

INHIBITORY CONTROL

EXECUTIVEFUNCTIONEXECUTIVEFUNCTION

PFCPFC

MOTIVATION/DRIVE

MOTIVATION/DRIVE

• In addicted subjects or in obese subjects, are the changes in DA function linked with disruption of frontal activity?

• Used multiple tracers to evaluated in the same subject DA D2 receptors and brain glucose metabolism (marker of brain function).

DA D2 Receptors

Metabolism

Dopamine D2 Receptors are Lower in Addiction

DA

D2

Rec

epto

r A

vaila

bili

tyD

A D

2 R

ecep

tor

Ava

ilab

ility

CocaineCocaine

AlcoholAlcohol

HeroinHeroin

MethMeth

controlcontrol addictedaddicted Volkow et al., Neurob Learning Memory 2002.

1.5

2

2.5

3

3.5

4

4.5

15 20 25 30 35 40 45 50

DA

D2

Rec

epto

rs(R

atio

Ind

ex)

20 25 30 35 40 45 50

1.6

1.8

2

2.2

2.4

2.6

2.8

3

3.2

Bm

ax/K

d

Normal ControlsNormal ControlsCocaine AbusersCocaine Abusers

Compulsive overeating shares many ofthe same characteristics as drug addiction

Obesity

Control Subjects2.99 (Sd 0.41)

2

0ml/gmObese Subjects

2.47 (Sd 0.36)

Dopamine D2 Receptors [11C]raclopride

Wang et al, Lancet 2001.

P < 0.008

DA D2 Receptors and BMI in Controls

and Obese Subjects

2025

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

p < 0.002

• Obese subjects

• Control subjects

Bmax/Kd

BM

Ip = 0.3

Correlations Between D2 Receptors in Striatum

& Brain Glucose Metabolism

Striatum

CGPreF

OFC

OF

C

3035404550556065

u

mol

/100

g/m

in

r = 0.7, p < 0.001

Cocaine Abusers

DA D2 Receptors (Ratio Index)

2.2 2.4 2.6 2.8 3 3.2 3.41.8 230

40

50

60

70

80

90

2.9 3 3.1 3.2 3.3 3.4 3.5 3.6

OF

Cum

ol/1

00gr

/min

DA D2 Receptors(Bmax/kd)

r = 0.7, p < 0.005

METHAbusers

Volkow et al., AJP 158(3):377-382, 2001.

Relationship Between DAD2Receptors (D2R) & Brain

Metabolism in Obese Subjects

p < 0.005 3.0 3.5 4.0 4.5 5.040455055606570

D2R (Bmax/Kd)

Medial Orbitofrontal

3.0 3.5 4.0 4.5 5.040455055606570 Cingulate

Gyrus

Mol

/100

g/m

in

Low D2R in obese subjects is associated in with reduced metabolism in cingulate gyrus and medial orbitofrontal cortex

workfamilyfriendscommunitynature

foodSexsportsmusicDanceArt

drugs

GlucosePeptidesNeurohormonesAmino acidsFatty acids

OrgansTissuesCellsMolecules

food intake

HYP

Source: Volkow ND et al., in review, 2012. (Modified with permission from an unpublished presentation,

courtesy of Dr. John Doyle)

Dopamine mediates behavioral responses in the Brain

workfamilyfriendscommunitynature foodSexsportsMusicdanceartdrugs

VTA/SN

DOPAMINE

PFCNAcAmygdalaHippocampusDorsal StriatumMotor Complex

Reward Motivation Action System (incentive, salience, learning, perseverance)

workfamilyfriendscommunitynature

foodsextool-makingsportsmusicdancecraftsart

drugs