D1- versus D2-receptor modulation of visuospatial working memory in humans

Abstract

The effects of pergolide, a mixed D1/D2 receptor agonist, and bromocriptine, a selective D2 receptor agonist, were assessed in a visual delay task to further investigate the "dopamine link" of working memory in humans and to look for differential D1 versus D2 receptor contributions. Two groups of 32 healthy young adults (16 female) received either 0.1 mg of pergolide or 2.5 mg of bromocriptine in a placebo-controlled cross-over design. A pretreatment with domperidone, a peripherally active D2 antagonist, was performed in both groups to reduce side effects. Interindividual differences in pharmacokinetics were controlled by the time course of serum prolactin inhibition. The working memory paradigm was a visuospatial delayed matching task; the location of a randomly generated seven-point pattern had to be memorized and compared after 2, 8, or 16 sec with a second pattern that was either identical or slightly shifted within a reference frame. The task was designed with the intention to present unique stimuli at each trial and to require minimal motor demands. Practice effects between the two pharmacological test days were minimized by training sessions that preceded the tests. The paradigm showed significant error and reaction time increases with longer delays. After comparable doses, only pergolide, but not bromocriptine, facilitated visuospatial working memory performance as demonstrated by a significant drug-by-delay interaction. These findings are in accordance with the monkey literature as well as with neuroanatomical findings, and they confirm a preferential role of prefrontal D1 receptors for working memory modulation in humans.

Fig. 1.

Time course of an experimental day (1 = training session; 2 = main session; 0 min = drug administration).

Fig. 2.

A, Location of frame and dot pattern on the screen. B, Visuospatial delayed matching task; time course of a single trial.

Fig. 3.

A, Practice effects in the pergolide study: total error rates in the training sessions of the 3 test days (A1, B1, C1). There was no significant difference between the two pharmacological test days (B1and C1). B, Practice effects in the bromocriptine study: total error rates in the training sessions of the 3 test days (A1, B1, C1). There was no significant difference between the 2 pharmacological test days (B1and C1).

Fig. 4.

A, Error rates after placebo and pergolide (0.1 mg/80 kg body weight) adjusted for the performance in the 2 sec delay control condition (error rate_{8 or 16 sec} − error rate_{2 sec}) in young adults. The D1/D2 agonist pergolide significantly improved delayed matching performance in the 16 sec delay condition. B, Error rates after placebo and bromocriptine (2.5 mg/80 kg) adjusted for the performance in the 2 sec delay control condition (error rate_{8 or 16 sec} − error rate_{2 sec}) in young adults. There was no significant effect of the D2 agonist bromocriptine in either the 8 sec or the 16 sec delay condition.

Fig. 5.

A, Time course of prolactin responses to pergolide (0.1 mg/80 kg body weight) and placebo after pretreatment with 3 × 10 mg of domperidone. There was a significant drug × time interaction. B, Time course of prolactin responses to bromocriptine (2.5 mg/80 kg) and placebo after pretreatment with 3 × 10 mg of domperidone. There was a significant drug × time interaction.