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Dopamine D2/D3 receptor agonist quinpirole impairs spatial reversal learning in rats: investigation of D3 receptor involvement in persistent behavior

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Abstract

Rationale

Dopamine is strongly implicated in the ability to shift behavior in response to changing stimulus-reward contingencies.

Objectives

We investigated the effects of systemic administration of the D2/D3 receptor agonist quinpirole (0.1, 0.3 mg/kg), the D2/D3 receptor antagonist raclopride (0.1, 0.3 mg/kg), the selective D3 antagonist nafadotride (0.3, 1.0 mg/kg), and combined administration of raclopride (0.1 mg/kg) or nafadotride (1.0 mg/kg) with quinpirole (0.3 mg/kg) on spatial discrimination and reversal learning.

Materials and methods

Rats were trained on an instrumental two-lever spatial discrimination and reversal learning task. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a reversal was introduced.

Results

None of the drugs altered performance during retention of the previously reinforced contingencies. Quinpirole (0.3 mg/kg) significantly impaired reversal learning by increasing both trials and incorrect responses to criterion in reversal phase, a pattern of behavior manifested as increased perseverative responding on the previously reinforced lever. In contrast, neither raclopride nor nafadotride when administered alone altered reversal performance. However, raclopride blocked the quinpirole-induced reversal deficit, whereas combined administration of nafadotride and quinpirole affected not only performance during the reversal but also the retention phase. The reversal impairment resulting from co-administration of nafadotride and quinpirole was associated with both perseverative and learning errors.

Conclusions

Our data indicate distinct roles for D2 and D3 receptors in the capacity to modify behavior flexibly in the face of environmental change.

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Acknowledgments

This work was supported by a Programme Grant from the Wellcome Trust (no. 076274/4/Z/04/Z) to TWR. The BCNI is funded by a joint award from the Medical Research Council and the Wellcome Trust. VB is supported by the Domestic Research Studentship, the Cambridge European Trusts, the Bakalas Foundation Scholarship, and the Oon Khye Beng Ch’ia Tsio Studentship from Downing College. AC is recipient of a postdoctoral fellowship from FIS-ISCIII. We thank David Theobald for preparing the drugs.

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Authors and Affiliations

  1. Department of Experimental Psychology, Behavioral and Clinical Neuroscience Institute (BCNI), University of Cambridge, Downing Street, CB2 3EB, Cambridge, UK

    Vasileios Boulougouris, Anna Castañé & Trevor W. Robbins

  2. Department of Neurochemistry and Neuropharmacology, Institut d’Investigacions Biomediques de Barcelona (CSIC), IDIBAPS, Rosselló, 161, 08036, Barcelona, Spain

    Anna Castañé

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  1. Vasileios Boulougouris
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Correspondence to Vasileios Boulougouris.

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Boulougouris, V., Castañé, A. & Robbins, T.W. Dopamine D2/D3 receptor agonist quinpirole impairs spatial reversal learning in rats: investigation of D3 receptor involvement in persistent behavior. Psychopharmacology 202, 611–620 (2009). https://doi.org/10.1007/s00213-008-1341-2

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