V. Vatsalya,1 J. L. Gowin,1 M. L. Schwandt,1 R. Momenan,1 M. Heilig,1 S. E. Bartlett,2 V. A. Ramchandani1; 1National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 2Queensland University of Technology, Brisbane, Australia

BACKGROUND: Pre-clinical and emerging clinical evidence suggest that varenicline, a nicotinic partial agonist approved for smoking cessation, attenuates alcohol seeking and consumption. This study examined the effects of varenicline in heavy drinkers using experimental models of motivation and consumption of alcohol including: (1) a novel Alcohol-Food Incentive Delay (AFID) functional magnetic resonance imaging (fMRI) task to examine brain activation associated with incentive salience of alcohol reward cues, and (2) an intravenous alcohol self-administration (IV-ASA) paradigm.
METHODS: In this double-blind, placebo-controlled, randomized trial, 29 participants, aged 21-60 years, received varenicline (2 mg/day) or placebo for 3 weeks. After 2 weeks of treatment, participants underwent an fMRI scan while performing the AFID task. At baseline and at 3 weeks of treatment, participants underwent IV-ASA sessions in the laboratory.
RESULTS: Cues signaling alcohol reward were associated with significant brain activation in the nucleus accumbens, amygdala and posterior insula in the placebo, but not in the varenicline group (all p<0.05). Varenicline also attenuated subjective feelings of happiness and excitement in response to alcohol cues compared to placebo. Participants with higher insula response to alcohol cues showed higher IV-ASA behavior across treatment groups (R2=0.26).
CONCLUSION: Varenicline decreased activation in striato-cortico-limbic regions associated with motivation and incentive salience of alcohol reward in heavy drinkers. Medication repurposing of varenicline could be targeted towards reward-drinkers seeking treatment for AUD. Human experimental models of alcohol seeking and consumption may facilitate development of pharmacotherapies for AUD.