Increased vulnerability to alcohol abuse after gastric bypass: Neural mechanisms

 描述（由申请人提供）：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）手术是一种常用且非常有效的方法，可实现显著的长期体重减轻并治疗相关合并症。然而，与RYGB后改善的食物偏好和减少的食物渴望相反，临床报告显示了对患者饮酒风险增加的担忧。然而，我们的研究小组和其他人最近发现，接受RYGB的饮食肥胖雄性大鼠的酒精偏好和摄入量增加，这表明了生物病因学（即，不受人类特有的心理社会和共病因素的混淆），没有明确的证据表明这些影响最终会导致酒精成瘾风险增加。此外，RYGB如何增加和维持饮酒动机的最终神经机制以及潜在的影响因素（如术后饮食依从性，体重减轻史和激素/代谢改善）值得研究。此外，尽管超过80%的RYGB患者是女性，但还没有研究调查酒精对雌性大鼠的影响。因此，该高风险高增益、概念验证R21应用将使用高脂肪饮食诱导的肥胖、非酒精偏好的Sprague-Dawley雌性大鼠，其被认为捕获了肥胖的最常见环境病因学和多基因特征，并且是大多数减肥手术中心的重度饮酒者排除标准的代表。测试的中心假设是，RYGB基于其增加的奖励效应增加了对酒精的偏好和摄入量，从而增加了成瘾发展的风险。关于潜在的机制，我们认为这种作用是由于减轻了大脑多巴胺系统中与肥胖相关的缺陷，这是由于手术的未知独特作用，即，与体重减轻或术后饮食变化无关。目的1将使用一组全面的行为测试来调查RYGB增加酒精寻求和服用行为并导致独立于体重减轻和饮食变化的酒精成瘾易感性增加的假设。将使用体内脑成像（正电子发射断层扫描，µPET）评估RYGB与限制热量摄入条件性酒精提示后脑活动的功能变化。目标2将通过测试手术对多巴胺信号传导的功能和静态测量的影响来扩展对潜在机制的调查，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R 01的应用提供初始数据，重点关注多巴胺奖赏系统上游的特定途径和药理学靶点。这项临床前转化研究具有很高的影响力，因为它将帮助临床医生为酒精使用障碍风险增加的患者制定个性化的术后治疗计划，并防止成瘾的发展。

 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.