PHARMACOKINETICS AND SUBJECTIVE RESPONSES TO ALCOHOL AFTER BARIATRIC SURGERY

 描述（由申请人提供）：在过去十年中，超过一百万美国人接受了减肥手术，考虑到肥胖症的流行，预计这将导致肥胖症的发生。 数字将继续上升。减肥手术（包括Roux-en-Y胃旁路术[RYGB]和袖状胃切除术[SG]，以及纯粹限制性腹腔镜可调节胃束带术[LAGB]）为肥胖提供了最成功的长期治疗。然而，在切除部分胃的手术后，酒精使用障碍（AUD）的风险增加。这种关联背后的确切机制尚不确定，但我们假设是由于胃切除术引起的1）酒精药代动力学和2）肠脑肽的变化，这些肽在食物和药物诱导的奖励中发挥作用（例如，生长素释放肽，胰高血糖素样肽-1（GLP-1））。酒精药代动力学和中枢对奖励敏感性的变化可能会影响人们饮酒后的感受（即，受试者对酒精的反应），并增加他们患AUD的风险。然而，到目前为止，尚未确定手术诱导的变化对同一受试者在手术前后使用有效问卷对酒精的主观反应的影响，并且尚不清楚某些手术诱导的酒精主观效应变化是否是中枢介导的，即独立于酒精吸收的变化，如最近在RYGB的啮齿动物模型中所示。因此，这项拟议的纵向研究的主要目的是确定RYGB、SG和LAGB对i）酒精的药代动力学（目的1）和ii）摄入酒精后（目的2）或在组间以相同BAC静脉钳夹（目的3）对酒精的主观反应的影响。我们将使用钳夹方法控制手术引起的酒精吸收变化，并使用经验证的问卷评估已知与发生AUD风险增加相关的酒精主观反应变化。作为次要的探索性目的，我们将确定RYGB、SG和LAGB对饮酒后肠道肽释放（例如生长激素释放肽、GLP-1）的影响，并探索肽浓度变化与对酒精的主观反应之间的关系。我们假设，RYGB和SG（而非LAGB）将1）加速酒精吸收，从而使BAC峰值更快达到，并且术后比术前更高，以及2）增加对酒精积极主观影响的敏感性，即使酒精被钳夹，从而所有组具有相等的脑BAC。该项目将回答SG和RYGB是否会影响酒精药代动力学的问题，以及它们是否会增加对酒精奖励效应的敏感性，而不依赖于酒精吸收的变化。这些信息可能会影响患者的临床实践指南，包括针对特定高危人群（例如个人或家族成瘾史）的减肥手术选择以及术后适当的咨询和监测。此外，我们的研究结果可能进一步暗示肠道肽在酒精奖励中的作用，可能导致对AUD新治疗方法的研究。

 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.