Nora D. Volkow, M.D.Director

National Institute on Drug AbuseNational Institutes of Health

Nora D. Volkow, M.D.Director

National Institute on Drug AbuseNational Institutes of Health

Healthy Heart Diseased Heart

Decreased Heart Metabolism in Heart Disease Patient

ADDICTION IS A DISEASE OF THE BRAINas other diseases it affects the tissue function

Control Cocaine Abuser

Decreased Brain Metabolism in Drug Abuse Patient

Sources: From the laboratories of Drs. N. Volkow and H. Schelbert

High

Low

ADDICTION INVOLVES MULTIPLE FACTORS

AddictionAddiction

DRUGDRUG

Brain MechanismsBrain Mechanisms

Biology/GenesBiology/GenesJo

hn S

mit

h

Jam

es S

mit

h

Ann

Jon

es

John

Jon

es

Mar

y H

ill

Wal

ter

Jone

s

Jam

es H

ill

Susa

n A

dam

s

Ali

ce P

rice

Tho

mas

Jon

es

Wil

liam

Pri

ce

Ric

hard

Hil

l

Stev

en

Ada

ms

All

ison

Fi

elds

Mar

y W

alte

rs

Ali

ce B

enso

n

Reb

ecca

Wil

son

Tho

mas

Smit

h

John

Sm

ithE

dwar

dSm

ith

Ann

eCoo

k

Jane

Wal

kerJo

hn W

alke

r

Jane

Jone

s

Susa

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dwar

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Jam

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ook

Bet

h B

ryso

nJona

than

Coo

k

Edw

ard

Bry

son

Am

y M

ason

Bet

h C

arte

r

EnvironmentEnvironment

Anatomy DA

DA

DA

DA DA DA

DA

signal

Dopamine Cell

DA Transporters

DA Receptors

Metabolism

Brain Dopamine System

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

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

HeroinHeroin

MethMeth

controlcontrol addictedaddicted

Adapted from Volkow et al., Neurobiology of Learning andMemory 78:610-624, 2002.

2nd

D2R

Vec

tor

0

10

20

30

40

50

60

Per

cen

t C

han

ge in

D2R

4 6 8 10 24

p < 0.0005p < 0.0005

p < 0.005

p < 0.10

p < 0.005

1st

D2R

Vec

tor

0

Nu

ll V

ecto

r

-100

-80

-60

-40

-20

0

Time (days)4 6 8 10 24

p < 0.001% C

han

ge 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

Overexpression of DA D2 receptors reduces alcoholself-administration

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

DA DADA

DADA

DA

DA

DA

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

Becomes SubordinateStress remains

IndividuallyHoused

GroupHoused

Morgan, D. et al. Nature Neuroscience, 5: 169-174, 2002.

**

S .003 .01 .03 .1

0

10

20

30

40

50

Rei

nfo

rcer

s (p

er s

essi

on)

Cocaine (mg/kg/injection)

Dominant

Subordinate

Becomes DominantNo longer stressed

Isolation Can Change NeurobiologyIsolation Can Change Neurobiology

Effects of a Social Stressor on Brain DA D2 Receptors and Propensity to Administer Drugs

ADDICTION CONTRIBUTES TO MANY SERIOUS MEDICAL CONSEQUENCES

• Mental Illness• Cancer• Infectious Diseases (HIV, HCV)• Cardiac• Pulmonary• Learning Disorders• Obesity• Cerebrovascular (strokes)• Trauma (accidents)

Partial Recovery of Brain Dopamine Transportersin Methamphetamine (METH)

Abuser After Protracted Abstinence

Normal Control METH Abuser(1 month detox)

METH Abuser(14 months detox)

0

3

ml/gm

Source: Volkow, ND et al., Journal of Neuroscience 21, 9414-9418, 2001.

ADDICTION CAN BE TREATED

HIV Seroconversion at 18 MonthsBy Receipt of Treatment

HIV Seroconversion at 18 MonthsBy Receipt of Treatment

00

55

1010

1515

2020

2525

Rat

e of

Ser

ocon

vers

ion

(%

)R

ate

of S

eroc

onve

rsio

n (

%)

Treatment StatusTreatment Status

No treatmentNo treatment

Partial treatmentPartial treatment

Continuous treatmentContinuous treatment

Source: Metzger, D. S., Woody, G. E., McLellan, A. T., O’Brien, C. P., Druley, P., Navaline, H., De Philipps, D., Stolley, P., & Abrutyn, E. (1993). Human immunodeficiency virus seroconversion among intravenous drug users in- and out-of-treatment: An 18-month prospective follow-up. Journal of Acquired Immune Deficiency Syndromes, 6, 1049-1056.

Among IDUs the Most Effective HIV/AIDSPrevention Strategy is Drug Abuse Treatment

Medications for Relapse Prevention

Addicted Brain

Drive

Control

Saliency

Memory

GO Strengthen prefrontal-striatal communicationStrengthen prefrontal-striatal communication

Executive function/Inhibitory controlExecutive function/Inhibitory control

Interfere with conditioned memories (craving)Interfere with conditioned memories (craving)

Teach new memoriesTeach new memories

Counteract stress responsesthat lead to relapseCounteract stress responsesthat lead to relapse

Interfere with drug’sreinforcing effectsInterfere with drug’sreinforcing effects

VaccinesEnzymatic degredationNaltrexoneDA D3 antagonistsCB1 antagonists

VaccinesEnzymatic degredationNaltrexoneDA D3 antagonistsCB1 antagonists

BiofeedbackModafinilBupropionStimulants

BiofeedbackModafinilBupropionStimulants

Antiepileptic GVGN-acetylcysteineAntiepileptic GVGN-acetylcysteine

CycloserineCycloserine

CRF antagonistsOrexin antagonistsCRF antagonistsOrexin antagonists

STOP Drive

Control

Memory

Non-Addicted Brain

Saliency AdenosineA2 antagonistsDA D3 antagonists

AdenosineA2 antagonistsDA D3 antagonists

DriveOFCDriveOFC

Saliency NAcSaliency NAc

MemoryAmygdalaMemoryAmygdala

Control CG Control CG

Non-Addicted Brain Addicted Brain

STOP STOP

GOGODriveDrive

MemoryMemory

Saliency Saliency

ControlControl

DriveDrive

MemoryMemory

Saliency Saliency

Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003. Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.

Cocaine abusers, when directed, can inhibit cue-induced craving and decrease limbic activity

No-Inhibition (NI)

2

4

6

8

10

NI CI

Sel

f-re

por

t C

ravi

ng

(1-1

0)

*** Before After

pu < 0.001

Cognitive-Inhibition (CI)

ACGACG

OFCOFCSCCSCC

HippHipp

NAccNAccVPVP

AmygAmyg

REWARDREWARD

INHIBITORY CONTROL

INHIBITORY CONTROL

MEMORY/LEARNING MEMORY/

LEARNING

EXECUTIVEFUNCTIONEXECUTIVEFUNCTION

PFCPFC

MOTIVATION/DRIVE

MOTIVATION/DRIVE

MULTIPLE BRAIN CIRCUITS ARE INVOLVED IN ADDICTION

Mapping Drug Risk Factors in a Community

John A. Pollard, Ph.D. Developmental Research and Programs

No studentsin this area.

Insufficient number ofstudents in this area.

Neighborhood #2

Neighborhood #3 Neighborhood #1

• Poor family support• Drug availability• Poverty• Crime

What are the neurobiological factors that mediate social stressors as a risk factor for drug abuse?