Pramipexole Enhances Reward Learning by Preserving Value Estimates

Abstract

Background: Dopamine D2-like receptor agonists show promise as treatments for depression. They are thought to act by altering how individuals learn from rewarding experiences. However, the nature of these reward learning alterations, and the mechanisms by which they are produced is not clear. Reinforcement learning accounts describe three distinct processes that may produce similar changes in reward learning behaviour; increased reward sensitivity, increased inverse decision temperature and decreased value decay. As these processes produce equivalent effects on behaviour, arbitrating between them requires measurement of how expectations and prediction errors are altered. In the present study, we characterised the behavioural effects of a sustained 2-week course of the D2/3/4 receptor agonist pramipexole on reward learning and used fMRI measures of expectation and prediction error to assess which of these three mechanistic processes were responsible for the behavioural effects. Methods: 40 healthy volunteers (Age: 18-43, 50% female) were randomly allocated to receive either two weeks of pramipexole (titrated to 1mg/day) or placebo in a double-blind, between subject design. Participants completed a probabilistic instrumental learning task, in which stimuli were associated with either rewards or losses, before the pharmacological intervention and twice between days 12-15 of the intervention (once with and once without fMRI). Both asymptotic choice accuracy, and a reinforcement learning model, were used to assess reward learning. Results: Behaviourally, pramipexole specifically increased choice accuracy in the reward condition, with no effect in the loss condition. Pramipexole increased the BOLD response in the orbital frontal cortex during the expectation of win trials but decreased the BOLD response to reward prediction errors in the ventromedial prefrontal cortex. This pattern of results indicates that pramipexole enhances choice accuracy by reducing the decay of estimated values during reward learning. Conclusions: The D2-like receptor agonist pramipexole enhances reward learning by preserving learned values. This is a plausible candidate mechanism for pramipexole’s observed anti-depressant effect.