THE PARTIAL DOPAMINE D2 RECEPTOR AGONIST ARIPIPRAZOLE IMPAIRS REVERSAL LEARNING IN RATS: BEHAVIOURAL AND COMPUTATIONAL EVIDENCE

Cognitive flexibility is the ability to adapt behaviour to changes in the environment. Impairment is reflected in poor performance on reversal learning tasks, observed in schizophrenia and Parkinsons patients, and has been associated with stimulation of the dopamine D2 receptor (D2R). Computational analysis of data from healthy volunteers and animal studies using reinforcement learning models reveals a specific effect of D2R agonism on learning from negative feedback. Partial D2R agonists such as aripiprazole are increasingly used in the treatment of schizophrenia but effects on cognitive flexibility are poorly characterised. Here, thirty-nine male Lister-hooded rats were trained to discriminate between two visual stimuli (CS+, CS-) in a touchscreen reversal learning task. Responses yielded a sucrose pellet or no reward and upon reaching criteria reward contingencies were reversed. A probe stimulus, probabilistically rewarded at a 50% rate, was intermittently presented with either CS+ or CS-. Before each session of the reversal phase rats were injected with the partial dopamine D1 receptor agonist SKF38393 (0,1,3mg/kg). The protocol was repeated with new visual stimuli for aripiprazole (0,0.3,0.7mg/kg). SKF did not affect accuracy overall, but increased errors during the mid and late phases of reversal learning. In contrast, aripiprazole impaired accuracy on standard trials and a specific impairment on positive probe trials implied reduced sensitivity to positive feedback. Hierarchical multivariate Bayesian models were used to explore how latent variables including learning rates and reinforcement sensitivity were affected by the drug treatments. These results suggest that partial D2 agonism by aripiprazole can impair cognitive flexibility.