Right inferior frontal cortex activity correlates with tolcapone responsivity in problem and pathological gamblers

Neuroimage Clin. 2016 Dec 20:13:339-348. doi: 10.1016/j.nicl.2016.12.022. eCollection 2017.

Abstract

Failures of self-regulation in problem and pathological gambling (PPG) are thought to emerge from failures of top-down control, reflected neurophysiologically in a reduced capacity of prefrontal cortex to influence activity within subcortical structures. In patients with addictions, these impairments have been argued to alter evaluation of reward within dopaminergic neuromodulatory systems. Previously we demonstrated that augmenting dopamine tone in frontal cortex via use of tolcapone, an inhibitor of the dopamine-degrading enzyme catechol-O-methyltransferase (COMT), reduced delay discounting, a measure of impulsivity, in healthy subjects. To evaluate this potentially translational approach to augmenting prefrontal inhibitory control, here we hypothesized that increasing cortical dopamine tone would reduce delay discounting in PPG subjects in proportion to its ability to augment top-down control. To causally test this hypothesis, we administered the COMT inhibitor tolcapone in a randomized, double-blind, placebo-controlled, within-subject study of 17 PPG subjects who performed a delay discounting task while functional MRI images were obtained. In this subject population, we found that greater BOLD activity during the placebo condition within the right inferior frontal cortex (RIFC), a region thought to be important for inhibitory control, correlated with greater declines in impulsivity on tolcapone versus placebo. Intriguingly, connectivity between RIFC and the right striatum, and not the level of activity within RIFC itself, increased on tolcapone versus placebo. Together, these findings support the hypothesis that tolcapone-mediated increases in top-down control may reduce impulsivity in PPG subjects, a finding with potential translational relevance for gambling disorders, and for behavioral addictions in general.

Trial registration: ClinicalTrials.gov NCT02772978.

Keywords: Dopamine; Frontostriatal; Gambling; Prefrontal cortex; Tolcapone; Ventral striatum.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Benzophenones / administration & dosage
  • Benzophenones / pharmacology*
  • Catechol O-Methyltransferase Inhibitors / administration & dosage
  • Catechol O-Methyltransferase Inhibitors / pharmacology*
  • Connectome / methods*
  • Delay Discounting / drug effects
  • Delay Discounting / physiology*
  • Double-Blind Method
  • Female
  • Gambling / diagnostic imaging
  • Gambling / drug therapy*
  • Gambling / physiopathology
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Nitrophenols / administration & dosage
  • Nitrophenols / pharmacology*
  • Prefrontal Cortex* / diagnostic imaging
  • Prefrontal Cortex* / drug effects
  • Prefrontal Cortex* / physiopathology
  • Tolcapone
  • Ventral Striatum* / diagnostic imaging
  • Ventral Striatum* / drug effects
  • Ventral Striatum* / physiopathology
  • Young Adult

Substances

  • Benzophenones
  • Catechol O-Methyltransferase Inhibitors
  • Nitrophenols
  • Tolcapone

Associated data

  • ClinicalTrials.gov/NCT02772978