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DRUG ADDICTION: A Brain Disease Associated with High Risk Behavior. Nora D. Volkow, M.D. Director National Institute on Drug Abuse National Institutes of Health. Drug Use Has Played A Major Role in HIV Transmission. Convergence of HIV Seroprevalence Among IDU

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slide1

DRUG ADDICTION:

A Brain Disease Associated with

High Risk Behavior

Nora D. Volkow, M.D.

Director

National Institute on Drug Abuse

National Institutes of Health

slide3

Convergence of HIV Seroprevalence Among IDU

and Non-IDU among Selected Cities

Non-injecting drug use appears to be an important factor contributing to HIV infection due to their high-risk behaviors and overlapping social and sexual networks with IDUs

Strathdee and Stockman Curr HIV/AIDS Rep. 2010 7(2):99-106.

slide4

Intravenous Methylphenidate Increased Sexual Desire

in Cocaine Abusers and Controls

a p < 0.05

b p < 0.005

c p < 0.001

Volkow ND et al., AJP 2007 164: 157-160.

key brain structures of the impulsive red and the controlling systems blue

Key Brain Structures of the Impulsive (red) and the Controlling Systems (blue)

Bechara A Nature Neuroscience 8, 1458 - 1463 (2005).

slide6

Decreases

prefrontal cortex

cingulate gyrus

Increases

Amygdala, NAcc

Effects of Alcohol Intoxication on Brain Glucose Metabolism (Marker of Brain Function)

Alcohol decreased activity of areas involved with control

and increased activity of areas involved with impulsivity

Zhu et al., Alcohol Alcohol 39: 53-58 2004.

slide7

Chronic Drug Effects

  • – Disruption of Inhibitory Control

DA

DA

DA D2 Receptors

DA

DA

DA

DA

DA

signal

Metabolism

slide8

Dopamine D2 Receptors are Lower in Addiction

DA

DA

Cocaine

DA

DA

DA

DA

DA

DA

DA

DA

DA

DA

Reward Circuits

Non-Drug Abuser

Meth

DA D2 Receptor Availability

DA

DA

DA

Alcohol

DA

DA

DA

Reward Circuits

Drug Abuser

Heroin

Adapted from Volkow et al.,

Neurobiology of Learning and

Memory 78:610-624, 2002.

control

addicted

slide9

In Methamphetamine Abusers Low Striatal DA D2/D3

Receptor Availability Is Associated with Impulsivity

Impulsivity (z-score)

-3 -2 -1 0 1 2 3

D2/D3 Receptors BP

(Z-score)

Lee, B. et al. J. Neurosci. 2009.

slide10

90

80

70

60

50

40

30

2.9

3

3.1

3.2

3.3

3.4

3.5

3.6

Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism

Cocaine

Abusers

65

60

55

OFC

CG

50

umol/100g/min

45

PreF

Striatum

40

r = 0.7, p < 0.001

35

OFC

30

1.8

2

2.2

2.4

2.6

2.8

3

3.2

3.4

DA D2 Receptors (Ratio Index)

METH

Abusers

OFC

umol/100gr/min

r = 0.7, p < 0.005

control cocaine abuser

DA D2 Receptors

(Bmax/kd)

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

slide11

What are the Mechanisms Underlying the

Relationship Between Drug Use and HIV/AIDS?

  • Acute Drug Effects
  • – Drug Intoxication and Decision Making
  • Chronic Drug Effects
  • – Disruption of Inhibitory Control
  • Interaction of Drugs and HIV
slide12

Some Psychoactive Drugs

Exacerbate Neurotoxic Effects of HIV

Chang et al., Neuroimage, 42:869-78, 2008.

hiv seroconversion at 18 months by receipt of treatment

Among IDUs the Most Effective HIV/AIDS

Prevention Strategy is Drug Abuse Treatment

HIV Seroconversion at 18 MonthsBy Receipt of Treatment

25

No treatment

20

Partial treatment

15

Rate of Seroconversion (%)

Continuous treatment

10

5

0

Treatment Status

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.

slide14

Future Research

Long-Acting Injectable Medications (i.e., Depot Naltrexone)

IM Injection

every 4 weeks

for 24 weeks

Placebo: N=124

XR-NTX: N=126

Krupitzky et al.,

unpublished

slide15

Future Research

Immunotherapies for Addiction Treatment (i.e., Vaccines)

Antibodies Can Reduce Brain Concentrations

VACCINE

Binding Site

Antibodies

Targeting the drugs,

not the receptors

Capillary

Blood Flow

Capillary

Blood Flow

Brain

Brain

new heroin vaccine s k d janda g f koob laboratories at tsri
New Heroin Vaccine(s)K.D. Janda & G.F. Koob Laboratories at TSRI

The Vaccine(s)

Hot Plate Test

Heroin 1 mg/kg,

s.c.

30 min

##p<0.01, ###p<0.001, significant reduction of analgesia vs. Control/KLH group, ### p<0.001, significant reduction of analgesia vs. Control/KLH group

slide17

Control

Control

CG

STOP

Saliency

Saliency

Drive

Drive

Drive

OFC

Saliency

NAc

GO

Memory

Memory

Memory

Amygdala

Addicted Brain

Non-AddictedBrain

Adapted from: Volkow et al.,

J Clin Invest 111(10):1444-1451, 2003.

slide18

Non-Addicted Brain

Control

STOP

Saliency

Drive

Cycloserine

Memory

Medications for Relapse Prevention

Vaccines

Enzymatic degredation

Naltrexone

DA D3 antagonists

CB1 antagonists

AddictedBrain

Interfere with drug’s

reinforcing effects

Control

Biofeedback

Modafinil

Bupropion

Stimulants

Executive function/

Inhibitory control

GO

Adenosine

A2 antagonists

DA D3 antagonists

Strengthen prefrontal-

striatal communication

Drive

Saliency

Interfere with conditioned

memories (craving)

Antiepileptic GVG

N-acetylcysteine

Memory

Teach new memories

Counteract stress responsesthat lead to relapse

CRF antagonists

Orexin antagonists

slide19

Naltrexone & Buprenorphine in the

Treatment of Cocaine Dependence

41.67

--Naltrexone Alone

--Naltrexone + Buprenorphine

40

36.67

33.33

Rates (%) of Positive Urines for

Cocaine Metabolites

18.18

9.09

Gerra G et al., J Psychopharmacol Online First January 9, 2006.

slide20

Impulsive Rats Have Lower D2R in Striatum

Dalley JW et al., Science 315, 1267 (2007).