PROJECT SUMMARY Alcohol use disorder (AUD) is a devastating disease characterized by loss of control over drinking. Behavioral control is mediated, in part, by dopamine (DA) signaling in the prefrontal cortex (PFC), and the relationship between cortical DA and control is believed to be inverted-U-shaped, with both excessively high and low cortical DA tone associated with poor control. Thus, loss of control over drinking might be remediated through modulation of cortical DA. In the PFC, DA inactivation is primarily regulated by the enzyme catechol-O- methyltransferase (COMT). The val allele of a common single nucleotide polymorphism (SNP) in COMT, val158met, is associated with a four-fold increase in COMT efficacy, leading to relatively lower cortical DA tone among individuals harboring the val-allele homozygote genotype. The selective, reversible COMT inhibitor tolcapone, which is FDA-approved for the treatment of Parkinson's disease, acutely increases cortical DA, and has been reported to reduce alcohol consumption in animal models of heavy drinking. Among healthy human subjects, tolcapone has been reported to increase inhibitory control, with greater effects among COMT val-allele homozygotes. Importantly, tolcapone has not shown adverse effects when tested among individuals with other addictive behaviors/disorders who are also active drinkers. Therefore, COMT inhibition may represent a “druggable target” for AUD, and COMT val-allele homozygotes, who have relatively reduced cortical DA tone, might particularly benefit from tolcapone. This proposal will test the effects of tolcapone on alcohol consumption among 90 non-treatment-seeking individuals with AUD who have been prospectively genotyped for the COMT val158met SNP and randomized to active or placebo medication on the basis of this genotype. Additionally, the proposal will examine several mechanisms of action for tolcapone's potential effect on drinking. There are two specific aims and one exploratory aim: (1) evaluate the interactive effects of tolcapone and COMT val158met variation on drinking in the natural environment and on alcohol self-administration in a bar-lab paradigm; (2) test, using fMRI, whether changes in cortical activation related to alcohol cue reactivity and cognitive control mediate the moderating effects of COMT genotype on tolcapone effects; and (3) explore tolcapone and COMT val158met effects on corticostriatal connectivity during alcohol cue exposure. Understanding whether cortical DA regulation can reduce drinking among some individuals, and the mechanism by which such an effect might operate, may ultimately lead to the development of more personalized treatment options for AUD.