Effects of COMT suppression in a randomized trial on the neural correlates of inhibitory processing among people with Alcohol Use Disorder.

Abstract

Background: Dysregulation of inhibitory control is a core feature of Alcohol Use Disorder (AUD), and is mediated, in part, by catechol-O-methyltransferase (COMT) regulation of cortical dopaminergic neurotransmission. Tolcapone, a brain-penetrant COMT inhibitor, potentiates evoked dopamine release, and may improve inhibitory control in AUD.

Methods: Non-treatment-seeking participants with AUD (n=64) were randomized to tolcapone (titrated to 200 mg t.i.d.) or placebo for 8 days and completed an fMRI stop-signal task on study Days 1 (prior to medication ingestion) and 7. Brain areas in which activation for the contrast of successful vs. unsuccessful stop trials (SS>SE) differed between medication groups on Day 7 relative to Day 1 were identified. Activation of these areas, and their functional connectivity with other areas, was tested for association with changes in drinking during the medication period and with stop-signal reaction time, a behavioral index of inhibitory control.

Results: The tolcapone group demonstrated greater SS>SE activation in the right dorsolateral prefrontal cortex and inferior frontal gyrus (iFG). In the tolcapone group, greater activation of both areas was associated with improved inhibitory control, and greater iFG activation was associated with reduced drinking. Increased connectivity between iFG and right anterior insula was associated with reduced drinking, and between iFG and anterior cingulate cortex with improved inhibitory control.

Conclusions: Tolcapone increased activation of cortical areas implicated in inhibitory control. The associations between increased iFG activation and connectivity, improved inhibitory control, and reduced drinking suggest that pharmacological interventions that increase cortical dopamine may rescue dysregulated inhibitory control among people with AUD.