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Impaired set-shifting and dissociable effects on tests of spatial working memory following the dopamine D2 receptor antagonist sulpiride in human volunteers

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Abstract

Rationale

Dopamine (DA) D2 receptor antagonists have been shown to produce similar impairments to those seen in Parkinson’s disease. These include working memory and set-shifting deficits. Theories of DA function have predicted that distraction or impaired switching may be important determinants of such deficits.

Objectives

In order to test these hypotheses, we have followed up our previous findings with more refined tests (1) that allow measurement of spatial working memory (SWM) and distraction, (2) that allow separation of executive and mnemonic components of SWM and (3) that allow isolation of set-shifting from learning deficits.

Methods

Thirty-six young healthy male volunteers were tested on two occasions after oral administration of either 400 mg sulpiride or placebo. All participants performed the delayed response task. Sixteen participants received task-irrelevant distractors during this task, and were also given a self-ordered SWM test. The remaining participants were given delayed response tasks with task-relevant distractors, and tests of attentional and task set-shifting.

Results

Sulpiride impaired performance of the delayed-response task both without distraction and with task-relevant distraction. By contrast, the drug protected against deficits from task-irrelevant distraction seen in the placebo group. Task set-switching was also impaired by sulpiride, with participants being slower to respond on switch trials compared with non-switch trials. There was also a trend for attentional set-shifting to be impaired following sulpiride. In contrast, self-ordered SWM performance was enhanced by sulpiride on the second test session only.

Conclusions

These results support models of central DA function that postulate a role in switching behaviour, and in certain aspects of working memory.

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Acknowledgements

We thank the volunteers for their participation in this study and Dr. Ulrich Müller for his comments on a draft of this manuscript. This work was supported by a Wellcome Trust Programme Grant awarded to T.W.R., B.J.S., B.J. Everitt and A.C. Roberts and was completed within the MRC Centre for Behavioural and Clinical Neuroscience. M.A.M. was supported by a MRC research studentship.

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  1. Mitul A. Mehta

    Present address: Neuroimaging Research (PO89), Institute of Psychiatry, King’s College, Denmark Hill, London, SE5 8AF, UK

  2. Facundo F. Manes

    Present address: Cognitive Neurology Section, Institute of Neurology (FLENI), Buenos Aires, Argentina

Authors and Affiliations

  1. Department of Psychiatry, Level E4, Addenbrooke’s Hospital, University of Cambridge, Cambridge, CB2 2QQ, UK

    Mitul A. Mehta, Facundo F. Manes, Gianna Magnolfi & Barbara J. Sahakian

  2. Department of Experimental Psychology, University of Cambridge, Cambridge, CB2 3EB, UK

    Trevor W. Robbins

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  1. Mitul A. Mehta
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Correspondence to Mitul A. Mehta.

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Mehta, M.A., Manes, F.F., Magnolfi, G. et al. Impaired set-shifting and dissociable effects on tests of spatial working memory following the dopamine D2 receptor antagonist sulpiride in human volunteers. Psychopharmacology 176, 331–342 (2004). https://doi.org/10.1007/s00213-004-1899-2

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