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
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.
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)
Bechara A Nature Neuroscience 8, 1458 - 1463 (2005).
Effects of Alcohol Intoxication on Brain Glucose
Metabolism (Marker of Brain Function)
Decreases
prefrontal cortex
cingulate gyrus
Increases
Amygdala, NAcc
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.
•
Chronic Drug Effects
– Disruption of Inhibitory Control
DA DA
DA D2 Receptors
DA
DA
DA
DA
DA
signal
Metabolism
Dopamine D2 Receptors are Lower in Addiction
DADA
Cocaine
DA
DA DA DA
DA
DA DA
DADA
DA
Reward Circuits
Non-Drug Abuser
Meth
DA
DA
DA
Alcohol
DA
DA
DA
Reward Circuits
Drug Abuser
Heroin
control
addicted
Adapted from Volkow et al.,
Neurobiology of Learning and
Memory 78:610-624, 2002.
Impulsivity (z-score)
In Methamphetamine Abusers Low Striatal DA D2/D3
Receptor Availability Is Associated with Impulsivity
-3
-2
-1
0
1
2
D2/D3 Receptors BP
(Z-score)
Lee, B. et al. J. Neurosci. 2009.
3
PreF
OFC
CG
Striatum
umol/100g/min
Correlations Between D2 Receptors in Striatum
and Brain Glucose Metabolism
r = 0.7, p < 0.001
35
OFC
cocaine abuser
umol/100gr/min
30
1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4
DA D2 Receptors (Ratio Index)
90
OFC
control
Cocaine
Abusers
65
60
55
50
45
40
METH
Abusers
80
70
60
50
40
r = 0.7, p < 0.005
30
2.9
3 3.1 3.2 3.3 3.4 3.5 3.6
DA D2 Receptors (Bmax/kd)
Volkow et al., AJP 158(3):377-382, 2001.
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
Some Psychoactive Drugs
Exacerbate Neurotoxic Effects of HIV
Chang et al., Neuroimage, 42:869-78, 2008.
Rate of Seroconversion (%)
Among IDUs the Most Effective HIV/AIDS
Prevention Strategy is Drug Abuse Treatment
HIV Seroconversion at 18 Months
By Receipt of Treatment
25
No treatment
Partial treatment
Continuous treatment
20
15
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.
Future Research
Long-Acting Injectable Medications (i.e., Depot Naltrexone)
Placebo: N=124
XR-NTX: N=126
IM Injection
every 4 weeks
for 24 weeks
Krupitzky et al.,
unpublished
Future Research
Immunotherapies for Addiction Treatment (i.e., Vaccines)
Antibodies Can Reduce Brain Concentrations
VACCINE
Binding Site
Antibodies
Capillary
Blood Flow
Brain
Targeting the drugs,
not the receptors
Capillary
Blood Flow
Brain
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
Addicted Brain
Non-Addicted Brain
Control
Control
CG
STOP
Saliency
Saliency
Saliency
NAc
Drive
OFC
Drive
Drive
GO
Memory
Memory
Memory
Amygdala
Adapted from: Volkow et al.,
J Clin Invest 111(10):1444-1451, 2003.
Medications for Relapse Prevention
Addicted
Brain
Non-Addicted Brain
Interfere with drug’s
reinforcing effects
Control
Control
Saliency
Saliency
GO
STOP
Drive
Drive
Memory
Memory
Vaccines
Enzymatic degredation
Naltrexone
DA D3 antagonists
CB1 antagonists
Executive function/
Inhibitory control
Biofeedback
Modafinil
Bupropion
Stimulants
Strengthen prefrontalstriatal communication
Adenosine
A2 antagonists
DA D3 antagonists
Interfere with conditioned
memories (craving)
Antiepileptic GVG
N-acetylcysteine
Teach new memories
Cycloserine
Counteract stress responses
that lead to relapse
CRF antagonists
Orexin antagonists
Naltrexone & Buprenorphine in the
Treatment of Cocaine Dependence
Rates (%) of Positive Urines for
Cocaine Metabolites
--Naltrexone Alone
40
--Naltrexone + Buprenorphine
41.67
36.67
33.33
18.18
9.09
Gerra G et al., J Psychopharmacol Online First January 9, 2006.
Impulsive Rats Have Lower D2R in Striatum
Dalley JW et al., Science 315, 1267 (2007).