Elsevier

Neuroscience

Volume 162, Issue 1, 4 August 2009, Pages 118-127
Neuroscience

Molecular Neuroscience
Research Paper
A role for dopamine D2 receptors in reversal learning

https://doi.org/10.1016/j.neuroscience.2009.04.052Get rights and content

Abstract

Reversal learning has been shown to require intact serotonergic innervation of the forebrain neocortex. Whether dopamine acting through D2 receptors plays a complementary role in this anatomic area is still unclear. Here we show that mice lacking dopamine D2 receptors exhibited significantly impaired performance in the reversal learning phase of an attention-set-shifting task (ASST) and that wild type mice treated chronically with the D2-like receptor antagonist haloperidol exhibited the same cognitive deficit. The test-phase-specific deficits of D2 mutants and haloperidol-treated mice were also accompanied by deficits in the induction of expression of early growth response gene 2 (egr-2), a regulatory transcription factor previously shown to be selectively induced in the ventrolateral orbital frontal cortex and the pre- and infralimbic medial prefrontal cortex of ASST-tested mice. D2-receptor knockout mice and haloperidol-treated wild type, however, exhibited lower egr-2 expression in these anatomic regions after completion of an ASST-test phase that required reversal learning but not after completion of set-shifting phases without rule reversals. In contrast, mice treated chronically with clozapine, an atypical neuroleptic drug with lower D2-receptor affinity and broader pharmacological effects, had deficits in compound discrimination phases of the ASST, but also these deficits were accompanied by lower egr-2 expression in the same anatomic subregions. Thus, the findings indicate that egr-2 expression is a sensitive indicator of test-phase-specific performance in the ASST and that normal function of D2 receptors in subregions of the orbital frontal and the medial prefrontal cortex is required for cognitive flexibility in tests involving rule reversals.

Section snippets

Animals

All procedures involving animals were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee at Columbia University and the New York State Psychiatric Institute. During the course of the study, the number of animals was kept to a minimum to ensure statistical validity and no procedures were performed that caused pain or severe discomfort. Adult male congenic C57BL/6J

ASST performance of D2 mutants and haloperidol- or clozapine-treated wild type

Fig. 1 illustrates the response accuracy (number of trials to criterion) of wild type, D2 mutants, and haloperidol-treated wild type. In wild type mice, a repeated measures ANOVA revealed significant differences when the number of trials to criterion was compared between test phases (F(4,40)=3.276; P=0.02). A post hoc Tukey–Kramer multiple comparisons test revealed that the number of trials to criterion needed to complete the EDS phase was significantly higher than that needed for either SD or

Discussion

The present study illustrates that knockout mice lacking dopamine D2 receptors and wild type mice treated chronically with the D2-like receptor blocker haloperidol have a deficit in the reversal phase of the ASST. In addition, both groups of mice exhibited decreased test-evoked expression of the transcription factor egr-2 in the vlOFC and IL/PrL subregions of the mPFC.

We show here that the reversal learning deficits of D2 mutants, their higher basal levels of egr-2 expression, and their

Acknowledgments

This work was supported by grants from the National Institutes of Health MH56123 and MH062185.

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