This is a presentation that was given at the Lost in Translation 2013: Exploring the Origins of Addiction conference, that took place on March 25 - 26, 2013 in Vancouver, British Columbia, Canada

1. Vulnerability to Addictions
Dopamine Studies in Humans
Marco Leyton, Ph.D.
Professor William Dawson Chair
Departments of Psychiatry, Psychology, and Neurology Neurosurgery
McGill University
Montreal, Quebec, Canada

2. Acknowledgements
Psychiatry Dept, McGill Univ.
Neurology Neurosurgery, MNI
Marije aan het Rot, Ph.D.
Isabelle Boileau, Ph.D.
Chawki Benkelfat, M.D., DERBH
Alain Dagher, M.D.
Linda Booij, Ph.D.
Mirko Diksic, Ph.D.
Kevin Casey, M.Sc.
Elaine Setiawan, Ph.D.
Elizabeth Cawley, M.Sc.
Viswanath Venugopalan, Ph.D.
Sylvia Cox, Ph.D.
Krzysztof Welfeld, B.Sc.
Aryan Fotros, M.D.
Roberta Palmour, Ph.D.
Psychiatry Dept, U. Alberta
Simon Young, Ph.D.
Glen Baker, Ph.D., D.Sc.
Psychology Dept, McGill Univ
Sean Barrett, Ph.D.
Mariya Cherkasova, Ph.D.
CIHR
Bob Pihl, Ph.D.

3. Acute Drug Effects
Striatal Dopamine Release

4. Drug-Induced [11C]Raclopride Response
t
3
Cocaine Amphetamine Alcohol
6.2
7
7
t
t
t
3.5
3
4.5
Cox et al 2009 Biol Psychiatry
Leyton et al 2002 Neuropsychopharm
Boileau et al 2003 Synapse

5. 0.4
0.3
0.2
0.1
Individual Differences
0
5.5 Novelty7Seeking
6 6.5 7.5 8 8.5
0.6
r = 0.79, p 0.021
0.4
0.2
0
-0.2
-0.4
5.5 6 6.5 7 7.5 8 8.5
Leyton et al 2002
Neuropsychopharmacology

6. 0.4
0.3
0.2
0.1
Individual Differences
0
5.5 Novelty7Seeking
6 6.5 7.5 8 8.5 Novelty Seeking / Impulsivity
0.6
r = 0.79, p 0.021
0.4
0.2
0
-0.2
-0.4
5.5 6 6.5 7 7.5 8 8.5
Leyton et al 2002
Buckholtz et al 2010 Science
Neuropsychopharmacology

7. Cortical Thickness
Casey et al In revision
n=24
Thick cortex = small DA response
!

8. Cortical Thickness
Casey et al In revision
n=24
Thick cortex = small DA response
!
Thick cortex = Less impulsivity
Schilling et al NeuroImage 2012, n=32

9. Cortical Thickness
Casey et al In revision
n=24
Thick cortex = small DA response
!
Thick cortex = Less impulsivity
Thick cortex = Less impulsivity
Schilling et al NeuroImage 2012, n=32
Schilling et al Mol Psychiatry 2013, n=1620

10. Behavioral Significance
Drug-Induced DA Response

11. Acute Phenylalanine/Tyrosine Depletion
Phenylalanine
(APTD)
PH
Tyrosine
TH
r = -0.82, p 0.025
L-DOPA
AAAD
Dopamine
APTD decreases amphetamine-induced
APTD changes resting BP
change in BP
Leyton et al 2004
Montgomery et al 2003
Neuropsychopharmacology
Am J Psychiatry

12. APTD Decreases Frontostriatal Connectivity
Areas with less frontostriatal connectivity after APTD
Seeds
Regions
x
y
z
T-value
L APFC
Putamen
3 12
8
3.48
2
L DLPFC
Putamen
-3 10
10
3.59
0
Putamen
2 10
8
3.34
2
Caudate
-1 -8
26
3.26
6
R VLPFC
Caudate
6
6
10
3.57
Nagano-Saito et al 2008 J Neurosci

13. Pleasure
8
Cocaine
Amphetamine
7 †††
BAL
Control
Control
APTD
APTD
APTD
6
VAS Euphoria
APTD+DOPA
APTD+DOPA ††† APTD+DOPA
5
4
†
3
2
1
Pre-AA 4 hrs Cue 0.2 mg/kg 0.5 mg/kg 1.0 mg/kg
Leyton et al, 2005
Cocaine Dose (mg/kg/line)
Leyton et al, 2007
Alcohol
Tobacco
BAL
Control
4.5 APTD
APTD
APTD+DOPA
APTD+DOPA
*
VAS ‘High’
High (mean±SEM)
3
1.5
Barrett et al 2008
Pre-AA Water Cue Alc Cue Alc Drink Casey et al 2006

14. Incentive Salience / Reward Seeking
Leyton et al 2007 JPN
Leyton et al 2000 Alc:Clin Exp Res
Cocaine Rate of Self-Administration
Cigarette Inter-Puff Interval
Interpuff Interval
Leyton et al 2000 Alc: Clin Exp Res
Average Time Between Puffs (s)
† 50
0.3 ††
40
0.25 30
Lines / min
20
0.2
10
BAL
0.15
APTD 0
APTD+DOPA 1st Cigarette 2nd Cigarette 3rd Cigarette 4th Cigarette
0.1 Control
Leyton et al, 2005
0.2 0.5 1.0 APTD
Casey et al, 2006
Behav Neuroscience
Eur Neuropsychopharm
Dose (mg/kg/line) APTD + DOPA

15. Cigarette PR Breakpoint
Early
‘Chippers’ (n=16)
**
Sustained
‘Chippers’ (n=15)
Dependent
Smokers (n=16)
Barrett et al 2008 Eur Neuropsychopharm
BAL APTD
Venugopalan et al 2011
Neuropsychopharmacology
Money PR Breakpoint
Control
APTD
p = 0.031
Cawley et al, JPN in press

16. Repeated Drug Effects

17. Sensitization
Context-Dependent DA Sensitization
1st or 6th time (10-day abstinence)
Duvauchelle et al 2000
Lorrain et al 2000
Pre-exposure
Pre-exposure
Saline
AMPH
Behavioral
Repeat cocaine (5 days)
activity
followed by a 15 mg /
kg challenge 2 wks later
Willingness
to work for
drug
Kalivas Duffy
1993
Mendrek et al 1998
Test Sessions
Time (min)

18. Sensitization in Humans?
Authors
# of Doses
Amphetamine Sensitization?
Dose
Johanson Uhlenhuth 1981
5 doses
5.0 mg, p.o.
No - mood,
drug tablets chosen
Kelly et al 1991
6 doses
10.0 mg, p.o.
No - speech rate, smoking,
stimulant effects, liking
Healthy
Subjects
Cocaine
Dependent
Subjects
Martinez et al 2007
Am J Psychiatry
Volkow et al 1997 Nature

19. Behavioral Sensitization in Humans?
Authors # of Doses Amphetamine Sensitization?
Dose
Johanson Uhlenhuth 1981 5 doses 5.0 mg, p.o. No - mood,
drug tablets chosen
Kelly et al 1991 6 doses 10.0 mg, p.o. No - speech rate, smoking,
stimulant effects, liking
Wachtel de Wit 1999 2 doses 20.0 mg, p.o. No - subjective and
psychomotor effects
Strakowski et al 1996 2 doses ~ 20 mg, p.o. (0.25 mg / kg) Yes - energy, eye-blink,
mood, speech rate
Strakowski Sax 1998 3 doses ~ 20 mg, p.o. (0.25 mg / kg) Yes - energy, eye-blink
Strakowski et al 2001 3 doses ~ 20 mg, p.o. (0.25 mg / kg) Yes - energy, euphoria
Boileau et al 2006 4 doses ~ 20 mg, p.o. (0.30 mg / kg) Yes - energy, eye-blink
O’Daly et al 2011 4 doses ~ 20 mg, p.o. (0.30 mg / kg) Yes - energy, euphoria
Childs de Wit 2011 2 doses 20 mg, p.o. Yes - stimulation, craving
Leyton 2007 PNPBP
Leyton Vezina 2013 NBR

20. Behavioral Sensitization in Humans?
Authors # of Doses Amphetamine Sensitization?
Dose
Johanson Uhlenhuth 1981 5 doses 5.0 mg, p.o. No - mood,
drug tablets chosen
Kelly et al 1991 6 doses 10.0 mg, p.o. No - speech rate, smoking,
stimulant effects, liking
Wachtel de Wit 1999 2 doses 20.0 mg, p.o. No - subjective and
psychomotor effects
Strakowski et al 1996 2 doses ~ 20 mg, p.o. (0.25 mg / kg) Yes - energy, eye-blink,
mood, speech rate
Strakowski Sax 1998 3 doses ~ 20 mg, p.o. (0.25 mg / kg) Yes - energy, eye-blink
Strakowski et al 2001 3 doses ~ 20 mg, p.o. (0.25 mg / kg) Yes - energy, euphoria
Boileau et al 2006 4 doses ~ 20 mg, p.o. (0.30 mg / kg) Yes - energy, eye-blink
O’Daly et al 2011 4 doses ~ 20 mg, p.o. (0.30 mg / kg) Yes - energy, euphoria
Childs de Wit 2011 2 doses 20 mg, p.o. Yes - stimulation, craving
Leyton 2007 PNPBP
Leyton Vezina 2013 NBR

21. Behavioral Sensitization in Humans?
Authors # of Doses Amphetamine Sensitization?
Dose
Johanson Uhlenhuth 1981 5 doses 5.0 mg, p.o. No - mood,
drug tablets chosen
Kelly et al 1991 6 doses 10.0 mg, p.o. No - speech rate, smoking,
stimulant effects, liking
Wachtel de Wit 1999 2 doses 20.0 mg, p.o. No - subjective and
psychomotor effects
Strakowski et al 1996 2 doses ~ 20 mg, p.o. (0.25 mg / kg) Yes - energy, eye-blink,
mood, speech rate
Strakowski Sax 1998 3 doses ~ 20 mg, p.o. (0.25 mg / kg) Yes - energy, eye-blink
Strakowski et al 2001 3 doses ~ 20 mg, p.o. (0.25 mg / kg) Yes - energy, euphoria
Boileau et al 2006 4 doses ~ 20 mg, p.o. (0.30 mg / kg) Yes - energy, eye-blink
O’Daly et al 2011 4 doses ~ 20 mg, p.o. (0.30 mg / kg) Yes - energy, euphoria
Childs de Wit 2011 2 doses 20 mg, p.o. Yes - stimulation, craving
Leyton 2007 PNPBP
Leyton Vezina 2013 NBR

22. Behavioral Sensitization in Humans?
Authors # of Doses Amphetamine Sensitization?
Dose
Johanson Uhlenhuth 1981 5 doses 5.0 mg, p.o. No - mood,
drug tablets chosen
Kelly et al 1991 6 doses 10.0 mg, p.o. No - speech rate, smoking,
stimulant effects, liking
Wachtel de Wit 1999 2 doses 20.0 mg, p.o. No - subjective and
psychomotor effects
Strakowski et al 1996 2 doses ~ 20 mg, p.o. (0.25 mg / kg) Yes - energy, eye-blink,
mood, speech rate
Strakowski Sax 1998 3 doses ~ 20 mg, p.o. (0.25 mg / kg) Yes - energy, eye-blink
Strakowski et al 2001 3 doses ~ 20 mg, p.o. (0.25 mg / kg) Yes - energy, euphoria
Boileau et al 2006 4 doses ~ 20 mg, p.o. (0.30 mg / kg) Yes - energy, eye-blink
O’Daly et al 2011 4 doses ~ 20 mg, p.o. (0.30 mg / kg) Yes - energy, euphoria
Childs de Wit 2011 2 doses 20 mg, p.o. Yes - stimulation, craving
Leyton 2007 PNPBP
Leyton Vezina 2013 NBR

23. Repeat Amphetamine Administration
Dopamine Sensitization
Boileau et al, 2006
Arch Gen Psychiatry

24. Conditioned Dopamine Release
Amphetamine
CS+
Boileau et al 2007
J Neuroscience

25. Repeated Drug Effects
Effects in Substance Abusers?

26. Cue-Induced DA Release: Cocaine Dependence
Striatum: Low Cravers
Striatum: High Cravers
**!
45
45
Neutral Cues
Series1
Neutral Cues
Series1
Cocaine Cues
Cocaine Cues
Series2
Series2
BPND (mean+SEM)
BPND (mean+SEM)
40
40
*!
35
35
30
30
*!
25
25
20
20
1
2
3
1
2
3
Limbic
Associative Sensorimotor
Limbic Associative Sensorimotor
Neutral
Cues
Cocaine
Cues
Fotros et al, In Press, Neuropsychopharmacology

27. Cue-Induced DA Release: Cocaine Dependence
Striatum: Low Cravers
Striatum: High Cravers
**!
45
45
Neutral Cues
Series1
Neutral Cues
Series1
Cocaine Cues
Cocaine Cues
Series2
Series2
BPND (mean+SEM)
BPND (mean+SEM)
40
40
*!
35
35
30
30
*!
25
25
20
20
1
2
3
1
2
3
Limbic
Associative Sensorimotor
Limbic Associative Sensorimotor
3.5
Amygdala: Low Amygdala: High
*!
3
BPND (mean+SEM)
2.5
2
1.5
1
0.5
1
2
Fotros et al, In Press, Neuropsychopharmacology

28. Cue-Induced DA Release: Cocaine Dependence
Striatum: Low Cravers
Striatum: High Cravers
**!
45
45
Neutral Cues
Series1
Neutral Cues
Series1
Cocaine Cues
Cocaine Cues
Series2
Series2
BPND (mean+SEM)
BPND (mean+SEM)
40
40
*!
35
35
30
30
*!
25
25
20
20
1
2
3
1
2
3
Limbic
Associative Sensorimotor
Limbic Associative Sensorimotor
3.5
Amygdala: Low Amygdala: High
Rt. Hipp: Low Rt. Hipp: High
*!
3
BPND (mean+SEM)
1.1
*!
BPND (mean+SEM)
1
2.5
0.9
2
0.8
1.5
0.7
1
0.6
0.5
0.5
1
2
1
2
Fotros et al, In Press, Neuropsychopharmacology

29. Effect of Past Drug Use
Cocaine Study
Amphetamine Study
Lifetime Stimulant Drug Use Lifetime Stimulant Drug Use
-30
-25
% Change BPND Whole Striatum
-20
-15
-10
-5 0
0
5
10
0 20 40 60 80 100 120 140
Total Stimulant Uses
Drug cues:
Absence of drug cues:
Cox et al 2009
Mirror
Cocaine powder
Casey et al 2010
Nondescript capsule
Biol Psychiatry
Razor blade
Straw
ACNP

30. Dopamine: A Dimensional Model
Low DA
High DA
In the absence of drug cues
In the presence of drug cues
Inability to sustain focused goal-directed behavior
Sustained drive to obtain rewards
Prefer small rewards if immediately available
Premature responding / behavioral disinhibition
Normal DA
Healthy novelty seeking
Healthy exploratory behavior
Healthy reward processing
Well regulated goal-directed behavior
Leyton 2007
Prog Neuropsychopharm Biol Psychiatr

31. Risk for Substance Use Disorders
Family History

32. Subject Characteristics
Healthy Ctl
FH-
FH+
n=17
n=15
n=16
Age
20.5 ± 2.1
22.1 ± 1.8
21.3 ± 2.4
Amphetamine
0 ± 0
16.7 ± 23.8*
11.1 ± 13.1*
Cocaine
0 ± 0
12.5 ± 15.1*
30.4 ± 46.9*
Alcohol Intox
138.1 ± 134.1
401.2 ± 358.2*
417.9 ± 300.7*
Novelty Seeking
17.8 ± 3.7
21.6 ± 2.5*
22.5 ± 5.1*
Impulsivity
2.8 ± 1.8
3.6 ± 1.7
4.7 ± 2.1*
Casey et al, in revision

33. Amphetamine (no cues) Induced Dopamine Release
Casey et al, in revision

34. Amphetamine (no cues) Induced Dopamine Release
Ctrl
14.9
FH-
t
FH+
4
Casey et al, in revision

35. Risk for Alcohol Use Disorders
Behavioral Response to Alcohol
(cues present)

36. Subject Characteristics
Low Risk High Risk P
(13 {3F}) (13 {5F})
SHAS7 (alcohol respo n s e ) 37.7±3.4 11.4±3.6 0.001
Age 21.5±0.9 21.1±0.8 0.75
Age first intoxication 15.5±0.6 15.2±0.6 0.78
Current Avg. Drinks/wk 8.4±2.4 13.0±2.4 0.19
Current Drinking Episodes/wk 1.5±0.4 2.7±0.3 0.026*
Current Heavy Episodes/wk 1.0±0.3 1.7±0.4 0.14
Lifetime Alcohol Intoxications 198±60 300±131 0.48
MAST 0.8±0.2 2.2±0.6 0.044*
FH+ (alcohol on l y ) 3 8 0.055†
OCDS 3.8±0.6 6.1±1.1 0.076†
TPQ Impulsivity 1.6±0.4 2.9±0.6 0.08†
Setiawan et al, in revision

37. Alcohol-Induced (cues present) DA Release
High-Risk
7.3!
t!
3.1!
Setiawan et al, in revision

38. Alcohol-Induced (cues present) DA Release
High-Risk
Low-Risk
7.3!
t!
3.1!
Setiawan et al, in revision

39. Summary Conclusions
1. In healthy subjects, abused drugs, across pharmacological
classes, increase striatal DA release.
2. Following repeated substance use, conditioned and sensitized
DA responses can develop. Both exaggerated and diminished
DA responses are seen.
3. Individuals at risk for substance use disorders exhibit altered
DA responses. Again, both increases and decreases are seen.
4. The differential direction of effect might be related to:
1. Vulnerability to alcoholism specifically vs. broad spectrum of substance
abuse,
2. Effects of ethanol (cell body) vs. amphetamine (terminal region), or
3. The presence vs. absence of drug cues (cortically regulated?).
5. Together, these results raise the possibility that a biological
vulnerability trait (possible endophenotype?) for addiction is not
increased or decreased DA, per se, but rather susceptibility to
labile DAergic and appetitive responses to cues.