tolcapone and Gambling

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.

Topics: Adult; Benzophenones; Catechol O-Methyltransferase Inhibitors; Connectome; Delay Discounting; Double-Blind Method; Female; Gambling; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Nitrophenols; Prefrontal Cortex; Tolcapone; Ventral Striatum; Young Adult

Pathological gambling (PG) is a disabling disorder experienced by 1-3% of adults, and empirically validated treatments are lacking. Perturbations of prefrontal-dependent cognitive functions are implicated in the pathophysiology of PG. The enzyme catechol-O-methyl-transferase (COMT) is responsible for degradation of dopamine in the cortices and thereby is known to regulate such cognitive functions and their neural substrates. The objective of this study was to determine whether tolcapone, a COMT inhibitor, improves symptoms of PG and to explore whether such effects are dependent on COMT val-158-met polymorphism status and relate to concomitant changes in fronto-parietal activation. Twenty-four individuals with PG were enrolled in an 8-week trial of oral tolcapone (100mg/day titrated to 100mg thrice/day) and 12 undertook pre- and post-treatment fMRI to examine brain activation during an executive planning task in a pre-defined fronto-parietal network. At baseline, patients with PG showed fronto-parietal under-activation versus controls during executive planning. Treatment was associated with statistically significant reductions on PG-Yale Brown Obsessive Compulsive Scale (PG-YBOCS), the extent of which correlated significantly with augmentation of planning-related fronto-parietal activation. Symptom improvement was also significantly more pronounced in subjects with the val/val COMT polymorphism. Tolcapone improved PG symptoms, and the extent of symptomatic improvement was significantly related to augmentation of fronto-parietal activation (fMRI probe) and COMT status. Objective genetic and fMRI markers hold promise in the search for targeting treatment and elucidating brain mechanisms associated with optimal clinical outcomes.

Topics: Adult; Aged; Benzophenones; Brain Mapping; Case-Control Studies; Catechol O-Methyltransferase; Enzyme Inhibitors; Female; Frontal Lobe; Gambling; Genotype; Humans; Male; Middle Aged; Nitrophenols; Parietal Lobe; Pilot Projects; Polymorphism, Single Nucleotide; Psychomotor Performance; Tolcapone; Treatment Outcome

Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val(158)Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype.. Thirty-four COMT Met(158)Met (Met-COMT) and 33 COMT Val(158)Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task.. In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences.. Depending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders.

Topics: Adolescent; Adult; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Cognition; Double-Blind Method; Gambling; Humans; Male; Memory, Short-Term; Methionine; Middle Aged; Neural Inhibition; Neuropsychological Tests; Nitrophenols; Polymorphism, Genetic; Task Performance and Analysis; Tolcapone; Valine; Young Adult

The course of pathological gambling (PG) in women has been described as having a later age of initiation but a shorter time to problematic gambling ("telescoped"). This study examined evidence for telescoping and its relationship with comorbidities. Seventy-one treatment-seeking individuals with PG underwent a diagnostic interview to examine gambling behaviors, age at initiation of gambling, and time from initiation to meeting criteria for PG. The women had a higher mean age at gambling initiation compared with that of the men (mean [SD] age, 31.3 [13.0] years, compared with 22.4 [7.9] years; p = 0.0003) and a significantly shorter time from initiation of gambling to meeting the criteria for PG (8.33 [8.7] years compared with 11.97 [9.1] years; p = 0.0476) after controlling for demographic and clinical variables. This study presents evidence for a gender-specific course of PG unrelated to psychiatric comorbidities and suggests a need for greater clinical focus on the gender differences of gambling behavior.

Topics: Acetylcysteine; Adult; Age of Onset; Aged; Benzophenones; Cognitive Behavioral Therapy; Combined Modality Therapy; Comorbidity; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Female; Free Radical Scavengers; Gambling; Humans; Interview, Psychological; Male; Memantine; Middle Aged; Nitrophenols; Risk Factors; Sex Factors; Tolcapone; Young Adult