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.

Dopamine and Gambling Disorder: Prospects for Personalized Treatment

“…This form of control is thought to be instantiated by prefrontal and other higher-order cortical influences over subcortical brain regions including the striatum (e.g. (66,(81)(82)(83)). By this hypothesis, augmenting prefrontal control by whatever means should improve goal-oriented behaviors.…”

Dopamine, time perception, and future time perspective

“…Subjects were administered either 200 mg tolcapone or placebo in a randomized, double-blind, counterbalanced, crossover design. This dose of tolcapone was selected based on our previously published findings indicating that a single 200 mg tolcapone dose produces reliable behavioral results without significant or consistent side effects (Cameron et al 2018;Kayser et al 2012;Kayser et al 2015;Kayser et al 2017;Saez et al 2015). Order was assigned using standard random allocation sequence-generating software by a study investigator who did not otherwise have contact with subjects.…”

“…These studies suggest that increasing dopamine in prefrontal cortex may correspondingly improve time perception, and that this improvement may be mediated by changes in top-down control over behavior (i.e., via altered connectivity between relevant prefrontal regions and the striatum). Because the FDAapproved COMT inhibitor tolcapone acts to preferentially augment dopamine tone in frontal regions of the brain (Doudet et al 1997), this medication may be useful in assessing this hypothesis, especially as previous work has shown that tolcapone can improve behavioral self-regulation and, correspondingly, alter the magnitude of correlations between frontal and striatal brain areas (Kayser et al 2012;Kayser et al 2017).…”

Dopamine, time perception, and future time perspective

“…Subjects were administered either 200 mg tolcapone or placebo in a randomized, double-blind, counterbalanced, crossover design. This dose of tolcapone was selected based on our previously published findings indicating that a single 200 mg tolcapone dose produces reliable behavioral results without significant or consistent side effects (Cameron et al 2018 ; Kayser et al 2012 ; Kayser et al 2015 ; Kayser et al 2017 ;Saez et al 2015 ). Order was assigned using standard random allocation sequence-generating software by a study investigator who did not otherwise have contact with subjects.…”

“…These studies suggest that increasing dopamine in prefrontal cortex may correspondingly improve time perception, and that this improvement may be mediated by changes in top-down control over behavior (i.e., via altered connectivity between relevant prefrontal regions and the striatum). Because the FDA-approved COMT inhibitor tolcapone acts to preferentially augment dopamine tone in frontal regions of the brain (Doudet et al 1997 ), this medication may be useful in assessing this hypothesis, especially as previous work has shown that tolcapone can improve behavioral self-regulation and, correspondingly, alter the magnitude of correlations between frontal and striatal brain areas (Kayser et al 2012 ; Kayser et al 2017 ).…”