Dopamine D2-like receptor stimulation blocks negative feedback in visual and spatial reversal learning in the rat: behavioural and computational evidence.
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Phillips, Benjamin U
Nilsson, Simon RO
Calafat-Pla, Teresa C
Plumbridge, Jessica M
Mar, Adam C
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Alsiö, J., Phillips, B. U., Sala-Bayo, J., Nilsson, S. R., Calafat-Pla, T. C., Rizwand, A., Plumbridge, J. M., et al. (2019). Dopamine D2-like receptor stimulation blocks negative feedback in visual and spatial reversal learning in the rat: behavioural and computational evidence.. Psychopharmacology, 236 (8), 2307-2323. https://doi.org/10.1007/s00213-019-05296-y
ABSTRACT Rationale: Dopamine 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. Objectives: We 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. Methods: Male 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. Results: D2R 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. Conclusions: D2R stimulation impairs reversal learning by blocking the impact of negative feedback.
Animals, Rats, Dopamine, Receptors, Dopamine D1, Receptors, Dopamine D2, Dopamine Agonists, Dopamine Antagonists, Photic Stimulation, Reversal Learning, Space Perception, Visual Perception, Male, Feedback, Physiological, Dopamine D2 Receptor Antagonists
All experiments were conducted at the Behavioural and Clinical Neuroscience Institute, which was jointly funded by the Medical Research Council (MRC) and the Wellcome Trust. This research was also supported in part by the UK National Health Service (NHS) National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. An MRC Clinical Research Infrastructure award supported part of this work. J.S.B. was supported by a PhD scholarship from the La Caixa Foundation, Spain, and a studentship from Boehringer Ingelheim Pharma GmbH, Germany.
WELLCOME TRUST (104631/Z/14/Z)
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External DOI: https://doi.org/10.1007/s00213-019-05296-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293647
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