title: Right inferior frontal cortex activity correlates with tolcapone responsivity in problem and pathological gamblers.
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.
authors.affiliation: Department of Neurology, University of California, San Francisco, United States; Department of Neurology, VA Northern California Health Care System, United States.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Kayser
authors.affiliation: Department of Neurology, VA Northern California Health Care System, United States.
authors.forename: Taylor
authors.initials: T
authors.lastname: Vega
authors.affiliation: Department of Neurology, University of California, San Francisco, United States.
authors.forename: Dawn
authors.initials: D
authors.lastname: Weinstein
authors.affiliation: Department of Psychology, University of Cologne, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Peters
authors.affiliation: Department of Neurology, University of California, San Francisco, United States; Department of Psychiatry, University of California, San Francisco, United States.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Mitchell
mesh_terms: D000328:Adult; D001577:Benzophenones / Q000008:administration & dosage / Q000494:pharmacology*; D065098:Catechol O-Methyltransferase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D063132:Connectome / Q000379:methods*; D065786:Delay Discounting / Q000187:drug effects / Q000502:physiology*; D004311:Double-Blind Method; D005260:Female; D005715:Gambling / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D000077867:Tolcapone; D066328:Ventral Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D055815:Young Adult
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D009596:Nitrophenols; D000077867:Tolcapone
keywords: Dopamine; Frontostriatal; Gambling; Prefrontal cortex; Tolcapone; Ventral striatum