Increased vulnerability to alcohol abuse after gastric bypass: Neural mechanisms

胃绕道手术后更容易酗酒：神经机制

基本信息

批准号：
9217538
负责人：
ANDRAS HAJNAL
金额：
$ 18.41万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-05 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9217538
关键词：
2-Fluoro-2-deoxyglucose Acute Adverse effects Affect Alcohol abuse Alcohol consumption Alcohol dependence Alcoholic beverage heavy drinker Alcohols Animal Model Autoradiography Bariatrics Basic Science Behavior Behavioral Biological Body Weight Body Weight Changes Body Weight decreased Brain Brain imaging Caloric Restriction Cessation of life Characteristics Clinical Comorbidity Consumption DRD2 gene Data Development Diet Dopamine Dopamine Receptor Eating Behavior Ethanol Etiology Exclusion Criteria Fat-Restricted Diet Fatty acid glycerol esters Female Food Food Preferences Future Gastric Bypass Health High Fat Diet Histologic Hormonal Hormonal Change Human Intake Interdisciplinary Study Intestinal Absorption Intravenous Investigation Lead Life Malabsorption Syndromes Measures Metabolic Methods Modeling Morbid Obesity Motivation Neuropharmacology Non-Insulin-Dependent Diabetes Mellitus Obesity Operative Surgical Procedures Oral Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacology Study Play Positron-Emission Tomography Postoperative Care Postoperative Period Predisposition Procedures Proxy Raclopride Rattus Recording of previous events Relapse Reporting Research Rewards Risk Role Route Savings Scientist Secondary to Self Administration Signal Transduction Surgeon System Testing Weight Wit Woman addiction alcohol abuse therapy alcohol behavior alcohol cue alcohol effect alcohol risk alcohol seeking behavior alcohol use disorder bariatric surgery base behavior test behavioral pharmacology behavioral study bench to bedside cohort common treatment dopamine system effective therapy experience experimental study food craving glucose metabolism high risk histological studies human subject imaging modality imaging study improved in vivo in vivo imaging male neuromechanism pre-clinical preclinical study preference prevent programs psychosocial public health relevance receptor relating to nervous system response tool translational study treatment planning weight maintenance

项目摘要

DESCRIPTION (provided by applicant): Obesity and its associated health consequences are among the main causes of preventable death. At present, Roux-en-Y gastric bypass (RYGB) surgery is a commonly performed and very effective method to achieve significant, long-term weight loss and to treat associated comorbidities. However, in contrast to improved food preferences and reduced food cravings following RYGB, clinical reports have revealed a concern for patients developing an increased risk for alcohol consumption. Whereas our research group and others have recently found increased alcohol preference and intake in dietary obese male rats that received RYGB suggesting a biological etiology (i.e., not confounded by psycho-social, and co-morbidity factors specific to humans), there is no clear evidence that these effects would eventually lead to increased risk for development of alcohol addiction. In addition, the ultimate neural mechanisms underlying how RYGB may increase and sustain motivation for alcohol use and potential contributing factors (such as postoperative dietary compliance, weight loss history and hormonal/metabolic improvements) warrant investigation. Moreover, no study has yet investigated alcohol effects in female rats despite the fact that >80% of RYGB patients are women. Thus, this high-risk high-gain, proof-of-concept R21 application will use high fat diet-induced obese, non-alcohol- preferring Sprague-Dawley female rats, believed to capture the most common environmental etiology and multigenic characteristics of obesity, and a proxy for the exclusion criteria of heavy drinkers by most bariatric surgery centers. The central hypothesis at test is that RYGB increases preference for and intake of alcohol based on its increased rewarding effects, and in turn, poses an increased risk for development of addiction. Regarding the underlying mechanism, we propose that this effect is due to alleviated obesity-related deficits in the brain dopamine systems due to yet unknown unique effects of surgery, i.e., independent of weight loss or post-surgical change of diets. Aim 1 will use a comprehensive battery of behavioral tests to investigate the hypothesis that RYGB increases alcohol-seeking and -taking behaviors and results in increased vulnerability to alcohol addiction independent of weight loss and change in diet. Functional changes in brain activity after RYGB vs. caloric restriction to conditioned alcohol cues will be assessed using in-vivo brain imaging (positron emission tomography, µPET). Aim 2 will extend investigations to underlying mechanisms by testing the effects of surgery on functional and static measures of dopamine signaling, and vice versa: the effects of dopamine receptor manipulations on alcohol-related behaviors. These studies are expected to provide initial data for a future R01 application with a focus on specific pathways and pharmacological targets upstream to the dopamine reward system. This pre-clinical translational study is of high impact in that it will help clinicians to make personalized postoperative treatment plans for patients wit increased risk of alcohol use disorder and to prevent development of addiction.

描述（由适用提供）：肥胖及其相关的健康后果是可预防死亡的主要原因之一。目前，roux-en-y胃旁路（RYGB）手术是一种常见且非常有效的方法，可以实现重大的长期体重减轻并治疗相关的合并症。但是，与RYGB后的食物偏好改善和食物渴望减少相反，临床报告显示患者的饮酒风险增加了。尽管我们的研究小组和其他人最近发现接受RYGB的饮食肥胖男性大鼠的酒精偏好和摄入量增加，这些大鼠提出了生物学病因（即，并不是由心理社会社会和特定的人类症状因素混淆），但没有明确的证据最终会导致饮酒成瘾的发展风险增加。此外，RYGB如何增加酒精使用和潜在促成因素（例如潜在的饮食依从性，体重减轻史和骑马/代谢改善）警告调查的最终神经机制。此外，尚无研究调查雌性大鼠的酒精作用，这一事实是80％的RYGB患者是女性。这是这种高风险的高增益概念验证R21应用程序将使用高脂肪饮食引起的肥胖，非酒精饮料 - 偏爱Sprague-Dawley雌鼠，据信可以捕获肥胖症的最常见环境病因和多基因型特征，并且是大多数BariaTric Cergrey Cergrey Cermery by Broteric center the Beighteria of Broime of Broiper of Broterigen Center ofergery center ofer of Broteria center ofer tergrey ofere brougery center。测试中的中心假设是，RYGB根据其增加的奖励作用增加对酒精的偏好和摄入量，进而增加了成瘾发展的风险。关于基本机制，我们建议这种作用是由于脑多巴胺系统中与肥胖相关的缺陷引起的，这是由于手术的独特作用尚不清楚，即独立于体重减轻或饮食后手术后的变化。 AIM 1将使用一系列的行为测试来研究RYGB增加寻求酒精和获取行为的假设，并导致增加对酒精成瘾的脆弱性，而不是体重减轻和饮食变化。 RYGB与热量限制到条件性酒精提示后的大脑活动的功能变化将使用体内脑成像（正电子发射断层扫描，µPET）评估。 AIM 2通过测试手术对多巴胺信号传导功能和静态测量的影响，将研究扩展到潜在机制，反之亦然：多巴胺受体操纵对酒精相关行为的影响。这些研究有望为未来的R01应用提供初始数据，重点是在多巴胺奖励系统上游的特定途径和药物目标上。这项临床前的翻译研究具有很大的影响，因为它将帮助临床医生制定个性化的术后治疗计划，以增加患者的饮酒风险并防止成瘾的发展。