Animal models of gambling. Catharine A. Winstanley University of British Columbia, Canada
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1 Animal models of gambling Catharine A. Winstanley University of British Columbia, Canada
2 Disclosures Advisory Board: Shire
3 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?
4 Impulsivity is a risk factor for addiction disorders ADHD Bipolar disorder Personality disorders IMPULSIVITY GAMBLING
5 Bechara et al Iowa Gambling Task (IGT)
6 Modeling the IGT: the rat gambling task (rgt) Food tray
7 Modeling the IGT: the rat gambling task (rgt) Food tray
8 Modeling the IGT: the rat gambling task (rgt) D OH! Food tray
9 Modeling the IGT: the rat gambling task (rgt) Food tray
10 Modeling the IGT: the rat gambling task (rgt) Food tray
11 Modeling the IGT: the rat gambling task (rgt) Food tray
12 Modeling the IGT: the rat gambling task (rgt) Food tray
13 Modeling the IGT: the rat gambling task (rgt) Food tray
14 Modeling the IGT: the rat gambling task (rgt) Food tray
15 Modeling the IGT: the rat gambling task (rgt) Food tray
16 Modeling the IGT: the rat gambling task (rgt) Food tray
17 Modeling the IGT: the rat gambling task (rgt) Pellets P(punishment) Duration of punishment s s s s 110 Maximum reward per session
18 Modeling the IGT: the rat gambling task (rgt) Pellets P(punishment) Duration of punishment s s s s 110 Maximum reward per session 100 rgt baseline Zeeb et al. 2009
19 Neural circuitry
20 Stacked vs Shuffled IGT Stacked (original) Shuffled Bechara et al, 1999 Fellows and Farah, 2005
21 Lesions to both the BLA and OFC slow learning of the task Sham BLA Lesion OFC Lesion Zeeb and Winstanley JN 2011
22 Post-training: BLA lesions, but not OFC lesions, increase risky choice Sham BLA Lesion OFC Lesion * * * Zeeb and Winstanley JN 2011
23 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?
24 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
25 High motor impulsivity is also linked to fast decision-making Meta-analysis of ~200 rats Barrus et al., J Psych Neuro 2014
26 High motor impulsivity is NOT linked to time taken to collect reward Meta-analysis of ~200 rats Barrus et al., J Psych Neuro 2014
27 Problem gambling and dopamine agonist therapy in Parkinson s Disease
28 No effect of ropinirole on choice in rgt, regardless of baseline choice preference
29 Transient increase in premature responses on rgt
30 Adding cues to the rgt nosepoke in any hole premature response 5 s time out: houselight on traylight on: nosepoke in food tray 5 s ITI (withhold from responding) stimulus lights on no response made omission nosepoke in lit hole Trial rewarded 1 pellet delivered (p = 0.9) 4 pellets delivered (p = 0.4) 2 pellets delivered (p = 0.8) 3 pellets delivered (p = 0.5) Uncued rgt: Cued rgt: OR Trial punished 5s time out (p = 0.1) 40s time out (p = 0.6) 10s time out (p = 0.2) 30s time out (p = 0.5) Maximum possible pellets available Barrus et al, in preparation
31 Adding cues to the rgt increases risky choice Barrus et al, in preparation
32 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 A increases choice of P2, decreases choice of P3
33 Choice on the uncued rgt is not sensitive to D3 ligands D3 agonist PD128,907- no effect D3 antagonist SB A no effect
34 Considerations for preclinical models Many different types of gambling behavior
35 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)
36 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
37
38 Can we model the near-miss effect? ROLL Food tray
39 Can we model the near miss effect? ROLL COLLECT
40 Can we model the near miss effect? ROLL COLLECT
41 Can we model the near-miss effect? 1,1,1 WIN COLLECT 1,1,0 1,0,1 0,1,1 0,1,1 0,1,0 0,0,1 0,0,0 LOSS LOSS LOSS LOSS LOSS LOSS LOSS DON T COLLECT
42 Can we model the near-miss effect? Cocker et al. 2014
43 Quinpirole increases erroneous expectation of reward on loss trials CLEAR WIN CLEAR LOSS CLEAR WIN CLEAR LOSS Winstanley et al. 2011
44 Quinpirole s effects cannot be attenuated by a mixed D2/3 receptor antagonist CLEAR WIN CLEAR LOSS Cocker et al. 2014
45 D4 agonist impairs performance; D 4 antagonist improves performance CLEAR WIN CLEAR LOSS CLEAR WIN CLEAR LOSS Cocker et al. 2014
46 Quinpirole s effects CAN be attenuated by a selective D4 receptor antagonist CLEAR WIN CLEAR LOSS Cocker et al. 2014
47 Anterior cingulate inactivations increase errors on rsmt Collect lever choice (%) Saline Bac-Mus Saline Bac-Mus 0 1,1,1 1,1,0 1,0,1 0,1,1 1,0,0 0,1,0 0,0,1 0,0, Trial type Lights illuminated Cocker et al. in preparation
48 Intra-ACC infusion of a D4 agonist selectively increases true near-miss errors? Collect lever choice (%) Saline 0.5 mg/kg Saline 0.5 mg/kg 0 1,1,1 1,1,0 1,0,1 0,1,1 1,0,0 0,1,0 0,0,1 0,0, Trial type Lights illuminated Cocker et al. in preparation
49 Chronic ropinirole doesn t significantly alter choice patterns on the rsmt Cocker, Tremblay et al. in preparation
50 ..but chronic ropinirole does increase total trials performed Cocker, Tremblay et al. in preparation
51 Increased number of trials performed is maintained even in extinction and reinstatement of play
52 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?
53 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
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