Animal models of gambling
Catharine A. Winstanley
University of British Columbia, Canada
Disclosures
• Advisory Board: Shire
What questions can preclinical
research help to answer?
• Which brain areas are involved?
• What neurotransmitter systems mediate choice
(dopamine? noradrenaline?)
• How do putative therapeutics affect behaviour,
both acutely and chronically?
• Biomarkers for vulnerability to maladaptive
behavioral patterns?
• Factors influencing expression of key behaviors?
Impulsivity is a risk factor for addiction disorders
ADHD
Bipolar disorder
Personality
disorders
IMPULSIVITY
GAMBLING
Iowa Gambling Task (IGT)
Bechara et al. 1999
Modeling the IGT: the rat gambling task (rGT)
Food tray
Modeling the IGT: the rat gambling task (rGT)

Food tray
Modeling the IGT: the rat gambling task (rGT)

D’OH!
Food tray
Modeling the IGT: the rat gambling task (rGT)

Food tray
Modeling the IGT: the rat gambling task (rGT)
2
4
1
3
Food tray
Modeling the IGT: the rat gambling task (rGT)
Food tray
Modeling the IGT: the rat gambling task (rGT)
Food tray
Modeling the IGT: the rat gambling task (rGT)
Food tray
Modeling the IGT: the rat gambling task (rGT)
2
4
1
3
Food tray
Modeling the IGT: the rat gambling task (rGT)
Food tray
Modeling the IGT: the rat gambling task (rGT)
Food tray
Modeling the IGT: the rat gambling task (rGT)
Pellets
P(punishment)
Duration of
punishment
Maximum reward
per session
1
0.1
5s
324
2
0.2
10s
480
3
0.5
30s
154
4
0.6
40s
110
Modeling the IGT: the rat gambling task (rGT)
Pellets
P(punishment)
Duration of
punishment
Maximum reward
per session
1
0.1
5s
324
2
0.2
10s
480
3
0.5
30s
154
4
0.6
40s
110
rGT baseline
100
90
80
70
60
50
40
30
20
10
0
1
2
3
4
Zeeb et al. 2009
Neural circuitry
Stacked vs Shuffled IGT
Stacked (original)
Bechara et al, 1999
Shuffled
Fellows and Farah, 2005
Lesions to both the BLA and OFC slow
learning of the task
Sham
BLA Lesion
OFC Lesion
Zeeb and Winstanley
JN 2011
Post-training: BLA lesions, but not OFC
lesions, increase risky choice
Sham
BLA Lesion
OFC Lesion
*
*
*
Zeeb and Winstanley
JN 2011
Learning vs performing
• OFC and BLA required for
most effective acquisition of
task- functional
connectivity?
• Particular role for BLA in
suppressing maladaptive
choices- signalling potential
loss?
High motor impulsivity and poor decisionmaking DO correlate in a large sample size
Meta-analysis of ~200 rats
Barrus et al., J Psych Neuro 2014
High motor impulsivity is also linked to fast
decision-making
Meta-analysis of ~200 rats
Barrus et al., J Psych Neuro 2014
High motor impulsivity is NOT linked to time
taken to collect reward
Meta-analysis of ~200 rats
Barrus et al., J Psych Neuro 2014
Problem gambling and dopamine agonist
therapy in Parkinson’s Disease
No effect of ropinirole on choice in rGT,
regardless of baseline choice preference
Transient increase in premature responses
on rGT
Adding cues to the rGT…
traylight on: nosepoke in food
tray
nosepoke in
any hole
premature response
5 s time out:
houselight on
5 s ITI
(withhold from
responding)
stimulus
lights on
no response
made
omission
nosepoke in lit
hole
Trial
rewarded
1 pellet
delivered
4 pellets
delivered
2 pellets
delivered
3 pellets
delivered
(p = 0.9)
(p = 0.4)
(p = 0.8)
(p = 0.5)
Uncued rGT:
Cued rGT:
OR
Trial
punished
Maximum possible
pellets available
5s time out
(p = 0.1)
295
40s time out
(p = 0.6)
99
10s time out
(p = 0.2)
411
30s time
out (p = 0.5)
135
Barrus et al, in preparation
Adding cues to the rGT increases risky
choice
Barrus et al, in preparation
Choice on the cued rGT is sensitive to D3
ligands
D3 agonist PD128,907 decreases
choice of P2, increases choice of P3
D3 antagonist SB 277011A increases
choice of P2, decreases choice of P3
Choice on the uncued rGT is not sensitive
to D3 ligands
D3 agonist PD128,907- no effect
D3 antagonist SB 277011A – no effect
Considerations for preclinical models
Many different types of gambling behavior
Considerations for preclinical models
Many different types of gambling behavior
The concept of loss as compared to the failure to wincan rats “play the odds”?
Cognitive biases- subjective interpretations?
VALUE
LOSSES
GAINS
Based on Kahneman and
Tversky (1979)
Considerations for preclinical models
Many different types of gambling behavior
The concept of loss as compared to the failure to wincan rats “play the odds”?
Cognitive biases- subjective interpretations?
Gambling as an inherently enjoyable pursuit
Can we model the near-miss effect?
ROLL
Food tray
Can we model the near miss effect?
ROLL
COLLECT
Can we model the near miss effect?

ROLL
COLLECT
Can we model the “near-miss” effect?
1,1,1
WIN
1,1,0
1,0,1
0,1,1
LOSS
LOSS
LOSS
0,1,1
0,1,0
0,0,1
0,0,0
LOSS
LOSS
LOSS
LOSS
COLLECT
DON’T
COLLECT
Can we model the “near-miss” effect?
Cocker et al. 2014
Quinpirole increases erroneous expectation of reward
on loss trials
CLEAR WIN
CLEAR LOSS
CLEAR WIN
CLEAR LOSS
Winstanley et al. 2011
Quinpirole’s effects cannot be attenuated by a mixed
D2/3 receptor antagonist
CLEAR WIN
CLEAR LOSS
Cocker et al. 2014
D4 agonist impairs performance; D4 antagonist
improves performance
CLEAR WIN
CLEAR LOSS
CLEAR WIN
CLEAR LOSS
Cocker et al. 2014
Quinpirole’s effects CAN be attenuated by a selective
D4 receptor antagonist
CLEAR WIN
CLEAR LOSS
Cocker et al. 2014
Anterior cingulate inactivations increase
errors on rSMT
100
Collect lever choice (%)
100
Saline
Bac-Mus
Saline
Bac-Mus
80
80
60
60
40
40
20
20
0
0
1,1,1 1,1,0 1,0,1 0,1,1 1,0,0 0,1,0 0,0,1 0,0,0
Trial type
3
2
1
0
Lights illuminated
Cocker et al. in preparation
Intra-ACC infusion of a D4 agonist selectively
increases “true” near-miss errors?
100
Collect lever choice (%)
100
Saline
0.5 mg/kg
Saline
0.5 mg/kg
80
80
60
60
40
40
20
20
0
0
1,1,1 1,1,0 1,0,1 0,1,1 1,0,0 0,1,0 0,0,1 0,0,0
Trial type
3
2
1
0
Lights illuminated
Cocker et al. in preparation
Chronic ropinirole doesn’t significantly alter
choice patterns on the rSMT
Cocker, Tremblay et al. in preparation
..but chronic ropinirole does increase total
trials performed
Cocker, Tremblay et al. in preparation
Increased number of trials performed is
maintained even in “extinction” and
reinstatement of play
Summary
Different gambling-related cognitions are
differentially susceptible to negative effects of DA
agonist therapy
 Bigger effects on biases rather than strategies?
 Less impact when losses are explicitly signaled i.e.
timeouts rather than simple reward omission?
 Impact of repeated performance of task itself on
DA system?
 Individual differences pre-drug do not predict
behavioural change following ropinirole treatment
 ex vivo analysis of DA receptor density/ signaling
proteins?

Acknowledgements

Winstanley lab: Jacqueline-Marie Ferland, Michael Barrus, Cole
Vonder-Haar, Fred Lam, Mason Silveria, Jacob Sussman, Melanie
Tremblay, Paul Cocker, Jay Hosking, Wendy Adams, Sukhbir Kaur