Specific effect of a dopamine partial agonist on counterfactual learning: evidence from Gilles de la Tourette syndrome

Alexandre Salvador,Stefano Palminteri,Andreas Hartmann,Yulia Worbe,Cécile Delorme,Giorgio Coricelli,Raphaël Gaillard,Trevor W Robbins

doi:10.1038/s41598-017-06547-8

Abstract

The dopamine partial agonist aripiprazole is increasingly used to treat pathologies for which other antipsychotics are indicated because it displays fewer side effects, such as sedation and depression-like symptoms, than other dopamine receptor antagonists. Previously, we showed that aripiprazole may protect motivational function by preserving reinforcement-related signals used to sustain reward-maximization. However, the effect of aripiprazole on more cognitive facets of human reinforcement learning, such as learning from the forgone outcomes of alternative courses of action (i.e., counterfactual learning), is unknown. To test the influence of aripiprazole on counterfactual learning, we administered a reinforcement learning task that involves both direct learning from obtained outcomes and indirect learning from forgone outcomes to two groups of Gilles de la Tourette (GTS) patients, one consisting of patients who were completely unmedicated and the other consisting of patients who were receiving aripiprazole monotherapy, and to healthy subjects. We found that whereas learning performance improved in the presence of counterfactual feedback in both healthy controls and unmedicated GTS patients, this was not the case in aripiprazole-medicated GTS patients. Our results suggest that whereas aripiprazole preserves direct learning of action-outcome associations, it may impair more complex inferential processes, such as counterfactual learning from forgone outcomes, in GTS patients treated with this medication.

Highlights

The dopamine partial agonist aripiprazole is increasingly used to treat pathologies for which other antipsychotics are indicated because it displays fewer side effects, such as sedation and depression-like symptoms, than other dopamine receptor antagonists
All patients consulting at the Gilles de la Tourette syndrome (GTS) Reference Centre in Paris and meeting inclusion and exclusion criteria were screened for inclusion and offered participation in this study until we reached a figure of 40 patients (20 per treatment) giving consent to be included
Using a probabilistic learning paradigm with factual and counterfactual feedback information conditions in healthy controls and aripiprazole-medicated and unmedicated GTS

Summary

Introduction

The dopamine partial agonist aripiprazole is increasingly used to treat pathologies for which other antipsychotics are indicated because it displays fewer side effects, such as sedation and depression-like symptoms, than other dopamine receptor antagonists. Our results suggest that whereas aripiprazole preserves direct learning of action-outcome associations, it may impair more complex inferential processes, such as counterfactual learning from forgone outcomes, in GTS patients treated with this medication. In GTS, aripiprazole is effective for suppressing tics while displaying a less severe side effect profile than dopamine receptor antagonists with regard to motivational deficits such as sedation and depressive reactions[8] Due to this advantageous cost-benefit trade-off, aripiprazole has become a widely prescribed treatment for schizophrenia and GTS. Reward-seeking behaviour and reward prediction errors encoded in the ventral striatum were reduced by haloperidol administration in healthy volunteers[11] Both functions were preserved in GTS patients medicated with aripiprazole[12]. A recent study that investigated counterfactual learning under a regimen of dietary depletion of serotonin and dopamine/noradrenalin precursors indicated that brain tracking of fictive prediction error might be sensitive to both dopamine and serotonin manipulation[21]

Methods

Results

Conclusion