Research in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging shows dopamine-boosting drug tolcapone increases brain activation during behavioral control

Philadelphia, August 13, 2025 – Researchers have identified a promising new strategy for treating alcohol use disorder (AUD). A novel study found that the dopamine-boosting drug tolcapone increases activity in the prefrontal cortex (PFC) during self-control tasks. Greater activation of the inferior frontal gyrus, part of the PFC, was associated with better behavioral control and reduced alcohol consumption. The findings from this new study in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier, indicate that medications with a similar mechanism could one day be used to treat AUD.

AUD is a devastating disorder characterized by loss of control over alcohol consumption, for which existing pharmacological treatments are modestly effective. Most approved and off-label pharmacological treatments for AUD target alcohol craving and/or alcohol withdrawal symptoms.

“We desperately need new pharmacological treatments for AUD. Our study shifts the focus to ‘rescuing’ impaired inhibitory control, which is the brain's ability to stop unwanted thoughts or actions, a function often compromised in AUD,“ says senior author Joseph P. Schacht, PhD, Department of Psychiatry, University of Colorado School of Medicine. “Our study suggests that medications that increase prefrontal dopamine are an important lead to pursue.”

The study involved 64 participants with AUD who were randomly assigned to receive either tolcapone, an FDA-approved medication that increases dopamine in the PFC by suppressing catechol-O-methyltransferase (COMT), an enzyme that degrades dopamine, or a placebo for eight days. Participants completed a behavioral control task called a “stop signal” task while undergoing functional neuroimaging (fMRI), during which they had to try to stop themselves from pressing a button on certain trials. This task reliably elicits activation of regions of the PFC that underlie response inhibition. Analysis showed that tolcapone increased activation of cortical areas implicated in inhibitory control, as assessed by the fMRI blood oxygenation response.

Lead author Drew E. Winters, PhD, Department of Psychiatry, University of Colorado School of Medicine, notes, “Based on previous studies, we anticipated that greater inferior frontal gyrus activation would be associated with better behavioral control, but we were pleasantly surprised to find that it was also associated with reduced alcohol consumption. This association validates the importance of impaired control in the pathophysiology of AUD.“

Editor-in-Chief of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Cameron S. Carter, MD, University of California Irvine School of Medicine, concludes, “Dopamine is a crucial neurotransmitter involved in pleasure, motivation, reward, and control and decision-making. The findings of this study underscore the importance of targeting specific brain circuits that govern self-control to reduce problematic drinking. Future research should continue to investigate the neurobiological mechanisms of tolcapone and other cortical dopamine modulators to develop more effective treatments for AUD.”