Summary: A randomized study shows that tolcapone, a drug that increases cortical dopamine, strengthens brain circuits involved in self-control and correspondingly reduces alcohol consumption in people with alcohol use disorder (AUD). The medication enhanced activity in the inferior frontal gyrus, a key part of the prefrontal cortex that supports inhibitory control.
Participants who received tolcapone demonstrated improved performance on a laboratory response-inhibition task and reported less drinking during the treatment period. These results point to prefrontal dopamine modulation as a promising strategy for developing new, mechanism-based treatments for AUD.
Key Facts
- New therapeutic focus: Tolcapone targets impaired inhibitory control rather than primarily addressing cravings or withdrawal, offering a different pathway for AUD treatment.
- Brain mechanism: By inhibiting catechol-O-methyltransferase (COMT) and raising dopamine in the prefrontal cortex, tolcapone strengthens neural circuits that mediate response inhibition.
- Clinical potential: The findings support further development of cortical dopamine–modulating medications to reduce problematic alcohol use more effectively.
Source: Elsevier
Overview
Researchers report a clear neural and behavioral effect of tolcapone in people with Alcohol Use Disorder (AUD). In a double-blind randomized trial, tolcapone increased activation in prefrontal cortical regions during a stop-signal task, a well-established probe of inhibitory control. Greater activation in the inferior frontal gyrus (iFG) and dorsolateral prefrontal cortex (dlPFC) correlated with better stopping performance and with reductions in drinking over the medication period.
Published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, the study suggests that medications which selectively increase dopamine signaling in the prefrontal cortex may “rescue” impaired inhibitory control, a core deficit that contributes to compulsive drinking and relapse in AUD.
Current pharmacotherapies for AUD mostly target craving or withdrawal and show limited effectiveness for many patients. By contrast, tolcapone directly targets the neural circuitry responsible for stopping unwanted actions and resisting alcohol-related impulses—functions that are typically compromised in AUD.
“We urgently need new, mechanism-driven treatments for AUD,” says senior author Joseph P. Schacht, PhD, Department of Psychiatry, University of Colorado School of Medicine. “This study shifts the therapeutic focus toward restoring impaired inhibitory control through increased prefrontal dopamine.”
The trial enrolled 64 non-treatment-seeking adults diagnosed with AUD who were randomized to receive either tolcapone (titrated to 200 mg three times daily) or a placebo for eight days. Participants completed a stop-signal task while undergoing functional MRI scans on Day 1 (before medication) and Day 7. The stop-signal task requires participants to interrupt an initiated response on a subset of trials, reliably activating PFC regions that mediate response inhibition.
Compared with placebo, tolcapone increased the fMRI blood-oxygen-level-dependent response for successful versus unsuccessful stops in the right dorsolateral prefrontal cortex and inferior frontal gyrus. In the tolcapone group, larger increases in activation in these regions were associated with faster stop-signal reaction times (improved inhibitory control), and greater iFG activation specifically correlated with reduced alcohol consumption during the medication period.
Functional connectivity analyses showed that increased coupling between the iFG and right anterior insula tracked with decreased drinking, while enhanced connectivity between iFG and anterior cingulate cortex was linked to better inhibitory control. These brain–behavior relationships strengthen the interpretation that tolcapone’s clinical effects operate through modulation of prefrontal control networks.
Lead author Drew E. Winters, PhD, notes that while stronger iFG activation was expected to relate to better stopping ability, the observed association with reduced drinking was an important and unanticipated validation of the role of impaired control in AUD.
Cameron S. Carter, MD, Editor-in-Chief of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, emphasizes that dopamine plays a central role in reward, motivation, decision-making, and cognitive control. The study highlights the value of targeting specific cortical circuits that govern self-control as a path to reduce problematic alcohol use. He recommends further research into tolcapone and other cortical dopamine modulators to refine dosing, safety, and clinical utility for AUD populations.
About this neuroscience and alcohol use disorder research news
Author: Eileen Leahy
Source: Elsevier
Contact: Eileen Leahy – Elsevier
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Effects of COMT Suppression in a Randomized Trial on the Neural Correlates of Inhibitory Processing Among People with Alcohol Use Disorder” by Joseph P. Schacht et al., Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Abstract
Effects of COMT Suppression in a Randomized Trial on the Neural Correlates of Inhibitory Processing Among People with Alcohol Use Disorder
Background
Impaired inhibitory control is a hallmark of Alcohol Use Disorder and is partly regulated by catechol-O-methyltransferase (COMT), an enzyme that influences cortical dopamine levels. Tolcapone is a brain-penetrant COMT inhibitor that potentiates cortical dopamine and may therefore improve inhibitory control in people with AUD.
Methods
Sixty-four non-treatment-seeking participants with AUD were randomized to receive tolcapone (titrated to 200 mg three times daily) or placebo for eight days. Participants completed an fMRI stop-signal task on Day 1 (pre-medication) and Day 7. Researchers identified brain regions where the contrast of successful versus unsuccessful stop trials (SS>SE) changed differentially between medication groups over time. The study examined whether activation and connectivity in those regions were associated with changes in drinking and with stop-signal reaction time, a behavioral measure of inhibitory control.
Results
Compared with placebo, tolcapone increased SS>SE activation in the right dorsolateral prefrontal cortex and inferior frontal gyrus. In the tolcapone group, greater activation in these regions correlated with improved inhibitory control; greater iFG activation correlated with reduced drinking. Increased functional connectivity between iFG and right anterior insula was linked to reduced drinking, while increased connectivity between iFG and anterior cingulate cortex related to better inhibitory control.
Conclusions
Tolcapone enhanced activation of cortical regions that support inhibitory control. The observed links between increased iFG activation and connectivity, improved stopping performance, and reduced alcohol use suggest that pharmacological strategies to raise cortical dopamine may help restore dysregulated inhibitory control in individuals with AUD, offering a promising direction for future treatment development.