Impaired set-shifting and dissociable effects on tests of spatial working memory following the dopamine D2 receptor antagonist sulpiride in human volunteers.
BACKGROUND
Dopamine (DA) D(2) 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.


OBJECTIVE
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.
Mehta
Mitul A
MA
Department of Psychiatry, Level E4, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 2QQ, UK. m.mehta@iop.kcl.ac.uk
Manes
Facundo F
FF
Magnolfi
Gianna
G
Sahakian
Barbara J
BJ
Robbins
Trevor W
TW
D000328:Adult; D000339:Affect / Q000187:drug effects; D001288:Attention / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D011597:Psychomotor Performance / Q000187:drug effects*; D011930:Reaction Time / Q000187:drug effects; D012727:Sex Characteristics; D013028:Space Perception / Q000187:drug effects*; D013469:Sulpiride / Q000494:pharmacology*
D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D013469:Sulpiride