Increased vulnerability to alcohol abuse after gastric bypass: Neural mechanisms

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 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.