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

Abstract

Psychopharmacological studies in humans suggest important roles for dopamine (DA) D2 receptors in human executive functions, such as cognitive planning and spatial working memory (SWM). 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 believe we report for the first time, the effects of a higher (800 mg 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 Cambridge Neuropsychological Test Automated Battery One-Touch Stockings of Cambridge and the self-ordered SWM task. Volunteers in the sulpiride group showed significant impairments in planning accuracy and, for the more difficult problems, in SWM. 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 SWM 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 SWM and executive planning functions, in a manner independent of the DA receptor D2 Taq1A polymorphism.

Figure 1

Effects of sulpiride (800 mg) on the number of between-search errors (a) and relative use of the inefficient strategy against task difficulty level (b) in the spatial working memory (SWM) task. Plotted are means±error bars of two standard errors (corrected for repeated observations).

Figure 2

The effects of the dopamine (DA) receptor D2 Taq1A genotype on between-error searches (a and b) and relative use of the inefficient strategy against task difficulty level (c and d) in the spatial working memory (SWM) task. The left column (a and c) shows theses effects for the placebo group and the right column (b and d) for the sulpiride group only. Plotted are means±error bars of two standard errors (corrected for repeated observations).

Figure 3

Sulpiride (800 mg) effects on the mean number of moves required to correctly solve the task (accuracy) (a) and the mean log response latency taken for the first response to be made against task difficulty level (b) in the OTSOC task. Plotted are means±error bars of 2 standard errors (corrected for repeated observations). OTSOC, one-touch stockings of Cambridge.

Figure 4

Sulpiride (800 mg) effects on the relationship between response latency and accuracy. (a) In this figure, the relationship is shown for the easy problems (level 1–4). (b) In this figure, the relationship is shown for the hardest problem (level 6). We have added a fitted line to illustrate the strength of the relationship. OTSOC, one-touch stockings of Cambridge.

Figure 5

The effects of the dopamine (DA) receptor D2 Taq1A genotype on the mean number of moves required to correctly solve the task (accuracy) (a and b) and the mean log response latency taken for the first response to be made against task difficulty level (c and d) in the OTSOC task. The left column (a and c) shows theses effects for the placebo group and the right column (b and d) for the sulpiride group only. Plotted are means±error bars of two standard errors (corrected for repeated observations). OTSOC, one-touch stockings of Cambridge.