Differential Effects of Pergolide and Bromocriptine on Working Memory Performance and Brain Activation after Mild Traumatic Brain Injury

Abstract

Dopamine D1 and D2 receptors differ with respect to patterns of regional brain distribution and behavioral effects. Pre-clinical work suggests that D1 agonists enhance working memory, but the absence of selective D1 agonists has constrained using this approach in humans. This study examines working memory performance in mild traumatic brain injury (mTBI) patients when given pergolide, a mixed D1/D2 agonist, compared with bromocriptine, a selective D2 agonist. Fifteen individuals were studied 1 month after mTBI and compared with 17 healthy controls. At separate visits, participants were administered 1.25 mg bromocriptine or 0.05 mg pergolide prior to functional magnetic resonance imaging (MRI) using a working memory task (visual-verbal n-back). Results indicated a significant group-by-drug interaction for mean performance across n-back task conditions, where the mTBI group showed better performance on pergolide relative to bromocriptine, whereas controls showed the opposite pattern. There was also a significant effect of diagnosis, where mTBI patients performed worse than controls, particularly while on bromocriptine, as shown in our prior work. Functional MRI activation during the most challenging task condition (3-back > 0-back contrast) showed a significant group-by-drug interaction, with the mTBI group showing increased activation relative to controls in working memory circuitry while on pergolide, including in the left inferior frontal gyrus. Across participants there was a positive correlation between change in activation in this region and change in performance between drug conditions. Results suggest that activation of the D1 receptor may improve working memory performance after mTBI. This has implications for the development of pharmacological strategies to treat cognitive deficits after mTBI.

Keywords: dopamine agonists; functional magnetic resonance imaging; mild traumatic brain injury; working memory.

FIG. 1.

(A) Average activation during the visual-verbal n-back task for both groups for both study visits (3-back > 0-back contrast, p = 0.05), used as an explicit mask for statistical analyses. (B) Increased activation in working memory circuitry during the visual-verbal n-back task (3-back > 0-back contrast) for mild traumatic brain injury relative to the healthy control group on pergolide relative to bromocriptine (p_crit = 0.01, cluster-level p_uncorrected < 0.05). (C) Correlation of change in left inferior frontal gyrus activation with change in 3-back performance across all participants.

FIG. 2.

Prolactin time trends by drug condition (placebo, bromocriptine, pergolide) and participant group (mild traumatic brain injury = MTBI, healthy control = Control). The targeted times for beginning magnetic resonance imaging (MRI) and neuropsychological (NP) testing are noted. Prolactin suppression is evident during the scan and cognitive assessment time periods for both bromocriptine and pergolide relative to placebo, but does not differ by drug or group (see text for statistics).