PHARMACOKINETICS AND SUBJECTIVE RESPONSES TO ALCOHOL AFTER BARIATRIC SURGERY

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 DESCRIPTION (provided by applicant): More than one million Americans have undergone bariatric surgery over the last decade and, given the obesity epidemic, it is anticipated that this number will continue to rise. Bariatric surgery procedures (including Roux-en-Y gastric bypass [RYGB] and sleeve gastrectomy [SG], and the purely restrictive laparoscopic adjustable gastric banding [LAGB] procedure) provide the most successful long-term treatment for obesity. However, there is an increased risk of alcohol use disorders (AUD) after surgeries that remove part of the stomach. The precise mechanism(s) underlying this association is uncertain but we hypothesize is due to gastric resection surgery-induced changes in both 1) alcohol pharmacokinetics and 2) gut-brain peptides that play a role in food- and drug-induced reward (e.g., ghrelin, glucagon-like peptide-1 (GLP-1)). Changes in both alcohol pharmacokinetics and central sensitivity to reward could affect how people feel after they drink alcohol (i.e., subjectie responses to alcohol) and increase their risk of developing an AUD. However, to date the effect of surgery-induced changes on subjective responses to alcohol within the same subject before and after surgery using validated questionnaires has not been determined, and it is unknown whether some surgery-induced changes in alcohol's subjective effects are centrally mediated, that is independent of changes in alcohol absorption, as recently shown in a rodent model of RYGB. Therefore, the primary aims of this proposed longitudinal study are to determine the effects of RYGB, SG, and LAGB on i) alcohol's pharmacokinetics (Aim 1) and ii) subjective responses to alcohol after alcohol is ingested (Aim 2), or intravenously clamped at identical BAC among groups (Aim 3). We will use the clamp approach to control for surgery-induced changes in alcohol absorption and validated questionnaires to assess changes in subjective responses to alcohol known to be associated with increased risk of developing AUD. As a secondary, exploratory, aim, we will determine the effects of RYGB, SG, and LAGB on gut peptide release (e.g. ghrelin, GLP-1) after alcohol is consumed and explore relationships between changes in peptide concentrations and subjective responses to alcohol. We hypothesize that RYGB and SG, but not LAGB, will 1) accelerate alcohol absorption, such that peak BAC will be reached faster and will be higher after than before surgery, and 2) increase sensitivity to positive subjective effects of alcohol even when alcohol is clamped such that all groups have equivalent brain BACs. This project will answer the question of whether SG and RYGB affect alcohol pharmacokinetics, and whether in addition they increase sensitivity to rewarding effects of alcohol independently of changes in alcohol absorption. This information could influence clinical practice guidelines for patients, both in the choice of bariatric surgery for specific high risk people (e.g. personal or family history of addiction) and appropriate counselling and monitoring postsurgery. In addition, our findings may further implicate the role of gut peptides in alcohol reward, potentially leading to the study of new treatment approaches for AUD.