Vulnerability to Addictions: Dopamine Studies in Humans - Marco Leyton

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

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. Bob Pihl, Ph.D. CIHR

Acute Drug Effects ��

Striatal Dopamine Release

3 t

7 4.5

t

7

3

Cocaine Amphetamine Alcohol

6.2

t 3.5

t

Boileau et al 2003 Synapse Cox et al 2009 Biol Psychiatry Leyton et al 2002 Neuropsychopharm

Drug-Induced [11C]Raclopride Response

Individual Differences Novelty Seeking 0

0.1

0.2

0.3

0.4

0.5

0.6

10 15 20 25 30

r = 0.75, p < 0.033

TPQ-Novelty Seeking

-0.4

-0.2

0

0.2

0.4

0.6

5.5 6 6.5 7 7.5 8 8.5

TPQ-Exploratory Excitability

r = 0.79, p < 0.021

0

0.1

0.2

0.3

0.4

0.5

0.6

5.5 6 6.5 7 7.5 8 8.5

r = 0.74, p = 0.037

-0.4

-0.2

0

0.2

0.4

0.6

10 15 20 25 30

r = 0.43, p = 0.29

Am

phet

amin

e-In

duce

d ∆

[11C

]Rac

lopr

ide

BP

VentralStriatum

T-Map

Leyton et al 2002 Neuropsychopharmacology

Individual Differences Novelty Seeking Novelty Seeking / Impulsivity

0

0.1

0.2

0.3

0.4

0.5

0.6

10 15 20 25 30

r = 0.75, p < 0.033

TPQ-Novelty Seeking

-0.4

-0.2

0

0.2

0.4

0.6

5.5 6 6.5 7 7.5 8 8.5

TPQ-Exploratory Excitability

r = 0.79, p < 0.021

0

0.1

0.2

0.3

0.4

0.5

0.6

5.5 6 6.5 7 7.5 8 8.5

r = 0.74, p = 0.037

-0.4

-0.2

0

0.2

0.4

0.6

10 15 20 25 30

r = 0.43, p = 0.29

Am

phet

amin

e-In

duce

d ∆

[11C

]Rac

lopr

ide

BP

VentralStriatum

T-Map

Leyton et al 2002 Buckholtz et al 2010 Science Neuropsychopharmacology

Cortical Thickness

!Thick cortex = small DA response

Casey et al In revision n=24

Cortical Thickness



Schilling et al NeuroImage 2012, n=32

Thick cortex = Less impulsivity

Cortical Thickness

Schilling et al Mol Psychiatry 2013, n=1620



Schilling et al NeuroImage 2012, n=32

Thick cortex = Less impulsivity Thick cortex = Less impulsivity

Behavioral Significance ��

Drug-Induced DA Response

Montgomery et al 2003 Am J Psychiatry

Acute Phenylalanine/Tyrosine Depletion (APTD)

r = -0.82, p < 0.025

Leyton et al 2004 Neuropsychopharmacology

APTD decreases amphetamine-induced change in BP

APTD changes resting BP

Phenylalanine

PH

Tyrosine

TH

L-DOPA

AAAD

Dopamine

APTD Decreases Frontostriatal Connectivity

Nagano-Saito et al 2008 J Neurosci

Seeds Regions x y z T-value

L APFC Putamen 32

12 8 3.48

L DLPFC Putamen -3 0

10 10 3.59

Putamen 22

10 8 3.34

Caudate -16

-8 26 3.26

R VLPFC Caudate 6 6 10 3.57

Areas with less frontostriatal connectivity after APTD

Pleasure

1

2

3

4

5

6

7

8V

AS

Eup

hori

a APTD+DOPAAPTDBAL

†††

†

Pre-AA 4 hrs Cue 0.2 mg/kg 0.5 mg/kg 1.0 mg/kg

†††

Cocaine Dose (mg/kg/line)

Cocaine Amphetamine Control APTD APTD+DOPA

Leyton et al, 2005 Leyton et al, 2007

1.5

3

4.5

"Hig

h" (m

ean±

SEM

)

Pre-AA Water Cue Alc Cue Alc Drink

APTD+DOPA

APTD

BAL

Barrett et al 2008

Control APTD APTD+DOPA

Alcohol Tobacco *

Control APTD APTD+DOPA

VAS

‘H

igh’

Casey et al 2006

Leyton et al 2007 JPN

Leyton et al 2000 Alc: Clin Exp Res Interpuff Interval

0

10

20

30

40

50

1st Cigarette 2nd Cigarette 3rd Cigarette 4th CigaretteAve

rage

Tim

e B

etw

een

Puffs

(s)

Casey et al, 2006 Eur Neuropsychopharm

Control APTD APTD + DOPA

0.1

0.15

0.2

0.25

0.3

Line

s / m

in

0.2 0.5 1.0

APTD+DOPA

APTD

BAL

Dose (mg/kg/line)

†††

Leyton et al, 2005 Behav Neuroscience

Cocaine Rate of Self-Administration Cigarette Inter-Puff Interval Leyton et al 2000 Alc:Clin Exp Res

Incentive Salience / Reward Seeking

Early ‘Chippers’ (n=16) Sustained ‘Chippers’ (n=15) Dependent Smokers (n=16)

Barrett et al 2008 Eur Neuropsychopharm

**

Control APTD

p = 0.031

Cawley et al, JPN in press

Money PR Breakpoint

Cigarette PR Breakpoint

BAL APTD Venugopalan et al 2011 Neuropsychopharmacology

Repeated Drug Effects

Lorrain et al 2000

1st or 6th time (10-day abstinence)

Kalivas & Duffy 1993

Repeat cocaine (5 days) followed by a 15 mg / kg challenge 2 wks later

Time (min) Mendrek et al 1998

Duvauchelle et al 2000

Context-Dependent DA Sensitization Sensitization

Pre-exposure

Pre-exposure Saline AMPH

Test Sessions

Behavioral activity

Willingness to work for drug

Sensitization in Humans? Authors # of Doses Amphetamine

Dose Sensitization?

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

Volkow et al 1997 Nature

Martinez et al 2007 Am J Psychiatry

Leyton 2007 PNPBP Leyton & Vezina 2013 NBR

Behavioral Sensitization in Humans? Authors # of Doses Amphetamine

Dose Sensitization?



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


Dose Sensitization?












Dose Sensitization?












Dose Sensitization?











Repeat Amphetamine Administration Dopamine Sensitization

Boileau et al, 2006 Arch Gen Psychiatry

Conditioned Dopamine Release

Amphetamine

CS+

Boileau et al 2007 J Neuroscience

Repeated Drug Effects ��

Effects in Substance Abusers?

Cue-Induced DA Release: Cocaine Dependence

20

25

30

35

40

45

1 2 3

Series1

Series2

20

25

30

35

40

45

1 2 3

Series1

Series2

Neutral Cues Cocaine Cues


*!*!

**!

Limbic Associative Sensorimotor Limbic Associative Sensorimotor

BPN

D (m

ean+

SEM

)

BPN

D (m

ean+

SEM

)

Striatum: Low Cravers Striatum: High Cravers


Fotros et al, In Press, Neuropsychopharmacology

20

25

30

35

40

45

1 2 3

Series1

Series2

20

25

30

35

40

45

1 2 3

Series1

Series2



*!*!

**!


BPN

D (m

ean+

SEM

)

BPN

D (m

ean+

SEM

)


BPN

D (m

ean+

SEM

)

0.5

1

1.5

2

2.5

3

3.5

1 2

Amygdala: Low Amygdala: High

*!



20

25

30

35

40

45

1 2 3

Series1

Series2

20

25

30

35

40

45

1 2 3

Series1

Series2



*!*!

**!


BPN

D (m

ean+

SEM

)

BPN

D (m

ean+

SEM

)


BPN

D (m

ean+

SEM

)

0.5

1

1.5

2

2.5

3

3.5

1 2

Amygdala: Low Amygdala: High Rt. Hipp: Low Rt. Hipp: High

*!

0.5

0.6

0.7

0.8

0.9

1

1.1

1 2

*!BP

ND (m

ean+

SEM

)



Effect of Past Drug Use

Absence of drug cues: Nondescript capsule

Drug cues: Mirror Cocaine powder Razor blade Straw

Lifetime Stimulant Drug Use Lifetime Stimulant Drug Use

Cox et al 2009 Biol Psychiatry

Casey et al 2010 ACNP

-30

-25

-20

-15

-10

-5

0

5

10

0 20 40 60 80 100 120 140

Total Stimulant Uses

% C

han

ge B

PN

D W

ho

le S

tria

tum

Cocaine Study Amphetamine Study

0

Dopamine: A Dimensional Model

High DA In the presence of drug cues

Low DA In the absence of drug cues

Sustained drive to obtain rewards Premature responding / behavioral disinhibition

Inability to sustain focused goal-directed behavior Prefer small rewards if immediately available

Normal DA Healthy novelty seeking

Healthy exploratory behavior Healthy reward processing

Well regulated goal-directed behavior

Leyton 2007 Prog Neuropsychopharm & Biol Psychiatr

Risk for Substance Use Disorders ��

Family History

Subject Characteristics Healthy Ctl

n=17 FH- n=15

FH+ 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

Amphetamine (no cues) Induced Dopamine Release


4

14.9

t

Ctrl

FH-

FH+

Amphetamine (no cues) Induced Dopamine Release


Risk for Alcohol Use Disorders ��

Behavioral Response to Alcohol��(cues present) ��

��

Low Risk (13 {3F})

High Risk (13 {5F})

P

SHAS7 (alcohol response) 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†

Subject Characteristics

Setiawan et al, in revision

High-Risk


Alcohol-Induced (cues present) DA Release

t!

3.1!

7.3!

High-Risk Low-Risk


Alcohol-Induced (cues present) DA Release

t!

3.1!

7.3!

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.

Date post:	05-Dec-2014
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Vulnerability to Addictions: Dopamine Studies in Humans - Marco Leyton

Health & Medicine