Animal models of gambling
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
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