Effects of dopamine D2/D3 receptor antagonism on human planning and spatial working memory

Psychopharmacological studies in humans suggest important roles for dopamine (DA) D2 receptors in human executive functions, such as cognitive planning and spatial working memory. However, studies that investigate an impairment of such functions using the selective DA D2/3 receptor antagonist sulpiride have yielded inconsistent results, perhaps because relatively low doses were used. We report, for the first time, the effects of a higher (800mg p.o.) single dose of sulpiride as well as of genetic variation in the DA receptor D2 gene (DA receptor D2 Taq1A polymorphism), on planning and working memory. With 78 healthy male volunteers, we apply a between-groups, placebo controlled design. We measure outcomes in the difficult versions of the CANTAB One-Touch Stockings of Cambridge (OTSOC) and the self-ordered Spatial Working Memory (SWM) task. Volunteers in the sulpiride group showed significant impairments in planning accuracy and, for the more difficult problems, in spatial working memory. Sulpiride administration speeded response latencies in the planning task on the most difficult problems. Volunteers with at least one copy of the minor allele (A1+) of the DA receptor D2 Taq1A polymorphism showed better spatial working memory capacity, regardless of whether they received sulpiride or placebo. There were no effects on blood pressure, heart rate or subjective sedation. In sum, a higher single dose of sulpiride impairs spatial working memory and executive planning functions, in a manner independent of the DA receptor D2 Taq1A polymorphism.