Dissociable fronto-striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility

Abstract

Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor (DRD2) in flexible behavioral adaptation, mostly shown in reward-based learning paradigms. Recent evidence from imaging genetics indicates that also intentional cognitive flexibility, associated with lateral frontal cortex, is affected by variations in DRD2 signaling. In the present functional magnetic resonance imaging (MRI) study, we tested the effects of a direct pharmacological manipulation of DRD2 stimulation on intentional flexibility in a task-switching context, requiring switches between cognitive task rules and between response hands. In a double blind, counterbalanced design, participants received either a low dose of the DRD2 agonist bromocriptine or a placebo in two separate sessions. Bromocriptine modulated the blood-oxygen-level-dependent (BOLD) signal during rule switching: rule-switching-related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo, at comparable performance levels. Fronto-striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions. Hand-switching-related activity, in contrast, was reduced under bromocriptine in sensorimotor regions. Our results provide converging evidence for an involvement of DRD2 signaling in fronto-striatal mechanisms underlying intentional flexibility, and indicate that the neural mechanisms underlying different types of flexibility (cognitive vs motor) are affected differently by increased dopaminergic stimulation.

Keywords: Bromocriptine; Functional magnetic resonance imaging (fMRI); Intentional flexibility; Psychopharmacology.

Figure 1

Task-switching paradigm. Depending on task cues (i.e., square vs. diamond), participants performed two different tasks on visually presented number stimuli (i.e., odd/even vs. smaller/larger five decisions). Task rules and response hands were either repeated or switched from trial to trial, according to a pseudorandomly determined sequence.

Figure 2

(A) Rule-switching-related activity (red transparent) and interaction effects with drug (placebo vs. bromocriptine, red). Bar graph illustrates mean parameter estimates for IFJ interaction region, demonstrating increased rule-switching effects under bromocriptine. (B) Hand-switching-related activity (red transparent) and interaction effects with drug (placebo vs. bromocriptine, red). Bar graphs illustrate mean parameter estimates for SMA and postcentral interaction regions, demonstrating decreased rule-switching effects under bromocriptine. All thresholded at p < .005, uncorrected, k > 20 voxel. Error bars represent standard error of the mean.

Figure 3

(A) Main effects of bromocriptine in anatomical striatum mask for the rule-switching analysis. Bar graphs illustrate mean parameter estimates for each region. (B) Interaction effects of drug x rule switching in anatomical striatum mask. (C) Psychophysiological interaction effects in anatomical striatum mask with drug x rule-switching IFJ cluster as seed region, rule switch vs. rule repetition as psychological factor. All thresholded at p < .005, uncorrected, k > 5.