Effects of tolcapone and bromocriptine on cognitive stability and flexibility

Ian G. M. Cameron,Ahmad Al-Zughoul,Andrew S. Kayser,Deanna L. Wallace,Mark D’Esposito

doi:10.1007/s00213-018-4845-4

Abstract

RationaleThe prefrontal cortex (PFC) and basal ganglia (BG) have been associated with cognitive stability and cognitive flexibility, respectively. We hypothesized that increasing PFC dopamine tone by administering tolcapone (a catechol-O-methyltransferase (COMT) inhibitor) to human subjects should promote stability; conversely, increasing BG dopamine tone by administering bromocriptine (a D2 receptor agonist) should promote flexibility.ObjectiveWe assessed these hypotheses by administering tolcapone, bromocriptine, and a placebo to healthy subjects who performed a saccadic eye movement task requiring stability and flexibility.MethodsWe used a randomized, double-blind, within-subject design that was counterbalanced across drug administration sessions. In each session, subjects were cued to prepare for a pro-saccade (look towards a visual stimulus) or anti-saccade (look away) on every trial. On 60% of the trials, subjects were instructed to switch the response already in preparation. We hypothesized that flexibility would be required on switch trials, whereas stability would be required on non-switch trials. The primary measure of performance was efficiency (the percentage correct divided by reaction time for each trial type).ResultsSubjects were significantly less efficient across all trial types under tolcapone, and there were no significant effects of bromocriptine. After grouping subjects based on Val158Met COMT polymorphism, we found that Met/Met and Val/Met subjects (greater PFC dopamine) were less efficient compared to Val/Val subjects.ConclusionsOptimal behavior was based on obeying the environmental stimuli, and we found reduced efficiency with greater PFC dopamine tone. We suggest that greater PFC dopamine interfered with the ability to flexibly follow the environment.

Highlights

Among the myriad of processes that constitute Bcognitive control^ (Miller and Cohen 2001; Fuster 2001; Cools and D’Esposito 2011; Stuss 2011), two opposing processes governing behavior have been described: cognitive stability and cognitive flexibility
Cognitive flexibility refers to the ability to override a task set in order to perform an alternative behavior (Robbins 2007), and this ability is thought to be mediated by Psychopharmacology (2018) 235:1295–1305 circuits involving the basal ganglia (BG) and the prefrontal cortex (PFC) (Cools and D’Esposito 2011)
22.67, P < 0.001), but no other interactions were significant. These results demonstrate that drug influenced performance efficiency across all trial types (Fig. 2), such that tolcapone reduced efficiency as compared to placebo (z = − 2.85, P < 0.05), but efficiency did not differ between bromocriptine and placebo (z = − 1.42, P = 0.32)

Summary

Introduction

Among the myriad of processes that constitute Bcognitive control^ (Miller and Cohen 2001; Fuster 2001; Cools and D’Esposito 2011; Stuss 2011), two opposing processes governing behavior have been described: cognitive stability and cognitive flexibility. Cognitive stability refers to the ability to establish and maintain a Btask set,^ so that goal-directed behaviors can be executed despite interference from conflicting alternative behaviors (Sakai 2008) This ability is thought to be critically dependent upon the function of the prefrontal cortex (PFC), which is known to be important to working memory, rule representation, and resistance to distraction (Miller and Cohen 2001; Fuster 2001; Cools and D’Esposito 2011). D1 receptors are thought to be more dominant than D2 receptors in the PFC, (Cools 2006; Cools and D’Esposito 2011), suggesting that if dopamine tone is increased in PFC, there would be a net increase in stability

Methods

Results

Conclusion