Post on 14-Dec-2015
DRUG ADDICTION: A Brain Disease Associated with
High Risk Behavior
DRUG ADDICTION: A Brain Disease Associated with
High Risk Behavior
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
Drug Use Has Played A Major Role in HIV Transmission
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.
Convergence of HIV Seroprevalence Among IDU and Non-IDU among Selected Cities
a p < 0.05b p < 0.005c p < 0.001
Intravenous Methylphenidate Increased Sexual Desirein Cocaine Abusers and Controls
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).
Alcohol decreased activity of areas involved with control and increased activity of areas involved with impulsivity
Decreasesprefrontal cortexcingulate gyrus
IncreasesAmygdala, NAcc
Zhu et al., Alcohol Alcohol 39: 53-58 2004.
Effects of Alcohol Intoxication on Brain Glucose Metabolism (Marker of Brain Function)
• Chronic Drug Effects – Disruption of Inhibitory Control
DA
DA
DA
DA DA DA
DA
signal
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
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.
In Methamphetamine Abusers Low Striatal DA D2/D3 Receptor Availability Is Associated with Impulsivity
Lee, B. et al. J. Neurosci. 2009.
Imp
uls
ivit
y (z
-sco
re)
D2/D3 Receptors BP (Z-score)
-3 -2 -1 0 1 2 3
Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism
Striatum
CG
PreF
OFC3035404550556065
1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4DA D2 Receptors (Ratio Index)
OF
C
um
ol/1
00g/
min
r = 0.7, p < 0.001
30
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)
Cocaine Abusers
r = 0.7, p < 0.005
METHAbusers
control cocaine abuserVolkow et al., AJP 158(3):377-382, 2001.
What are the Mechanisms Underlying theRelationship 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
Chang et al., Neuroimage, 42:869-78, 2008.
Some Psychoactive DrugsExacerbate Neurotoxic Effects of HIV
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
Krupitzky et al.,unpublished
Placebo: N=124XR-NTX: N=126
IM Injectionevery 4 weeksfor 24 weeks
Future Research
Long-Acting Injectable Medications (i.e., Depot Naltrexone)
Binding Site
CapillaryBlood Flow
Brain
Antibodies
VACCINE
Antibodies Can Reduce Brain Concentrations
Future Research Immunotherapies for Addiction Treatment (i.e., Vaccines)
CapillaryBlood Flow
Brain
Targeting the drugs, not the receptors
##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
Heroin 1 mg/kg, s.c.
30 min
Hot Plate Test
The Vaccine(s)O
RO
RO
NH
R = Acetyl = HeroinR = H = Morphine
KLH
KLH = Keyhole Limpet Hemocyanin
LINKER
New Heroin Vaccine(s) K.D. Janda & G.F. Koob Laboratories at TSRI
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.
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
Rat
es (
%)
of P
osit
ive
Uri
nes
for
C
ocai
ne
Met
abol
ites
Gerra G et al., J Psychopharmacol Online First January 9, 2006.
36.6740
41.67
18.18
33.33
9.09
--Naltrexone Alone --Naltrexone + Buprenorphine
Naltrexone & Buprenorphine in the Treatment of Cocaine Dependence
Dalley JW et al., Science 315, 1267 (2007).
Impulsive Rats Have Lower D2R in Striatum