Abstract
RationaleDopamine D2-like receptors (D2R) are important drug targets in schizophrenia and Parkinson’s disease, but D2R ligands also cause cognitive inflexibility such as poor reversal learning. The specific role of D2R in reversal learning remains unclear.ObjectivesWe tested the hypotheses that D2R agonism impairs reversal learning by blocking negative feedback and that antagonism of D1-like receptors (D1R) impairs learning from positive feedback.MethodsMale Lister Hooded rats were trained on a novel visual reversal learning task. Performance on “probe trials”, during which the correct or incorrect stimulus was presented with a third, probabilistically rewarded (50% of trials) and therefore intermediate stimulus, revealed individual learning curves for the processes of positive and negative feedback. The effects of D2R and D1R agonists and antagonists were evaluated. A separate cohort was tested on a spatial probabilistic reversal learning (PRL) task after D2R agonism. Computational reinforcement learning modelling was applied to choice data from the PRL task to evaluate the contribution of latent factors.ResultsD2R agonism with quinpirole dose-dependently impaired both visual reversal and PRL. Analysis of the probe trials on the visual task revealed a complete blockade of learning from negative feedback at the 0.25 mg/kg dose, while learning from positive feedback was intact. Estimated parameters from the model that best described the PRL choice data revealed a steep and selective decrease in learning rate from losses. D1R antagonism had a transient effect on the positive probe trials.ConclusionsD2R stimulation impairs reversal learning by blocking the impact of negative feedback.
Highlights
Cognitive flexibility is required to navigate in a changing environment and requires both new associative learning and the ability to disregard rules when they become obsolete
The valence-probe visual discrimination (VPVD) task was optimised with regard to probe stimulus exemplar and probe trial frequency (Fig. 1a, b), so that rats displayed below-chance performance in probe trials for learning from both negative feedback (A− < C50/50) and positive feedback (B+ > C50/50) immediately following reversal (Fig. 1c)
To test the a priori hypothesis that dopamine D1-receptor antagonism impairs learning from positive feedback, we investigated the effects of SCH39166 and raclopride on positive and negative probe trials separately
Summary
Cognitive flexibility is required to navigate in a changing environment and requires both new associative learning and the ability to disregard rules when they become obsolete. The causal link between this neuronal activity and reinforcement learning has been demonstrated using optogenetic approaches in rats, from the perspectives of both positive (Steinberg et al 2013) and negative prediction errors (Chang et al 2016). In agreement with these studies, DA activity provides a prediction error signal during reversal learning, transiently declining in response to errors after a shift in response-outcome contingencies and increasing after unexpected rewards, as the subjects begin to interact with the previously non-rewarded, rewarded response option (Klanker et al 2015; Verharen et al 2018)
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