Microbial short-chain fatty acids regulate drug seeking and transcriptional control in a model of cocaine seeking.

Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an FR1 schedule. However, microbiome-depleted subjects exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target. Overall design: Comparative gene expression profiling analysis of cocaine self-administering Sprague-Dawley rats with normal microbiomes (control), depleted microbiomes, supplemented with short-chain fatty acids, or depleted microbiome with short-chain fatty acids.

可卡因使用障碍（Cocaine use disorder）是一项公共卫生危机，目前尚无美国食品药品监督管理局（Food and Drug Administration, FDA）批准的治疗药物。越来越多的研究阐明了大脑与肠道微生物组（gut microbiome）——即肠道常驻细菌——在精神疾病模型中的重要关联。既往研究显示，在小鼠可卡因位置偏好模型（place preference model）中，急性耗竭肠道细菌可增强奖赏效应，而补充细菌来源的短链脂肪酸（short-chain fatty acid, SCFA）代谢物则可逆转该效应。然而，长期戒断（abstinence）后，肠道微生物组及其代谢物在调控可卡因觅药行为（cocaine-seeking behavior）中的作用仍不明确。鉴于复吸（relapse）预防是物质使用障碍治疗中最具临床挑战性的难题，在复吸相关模型中探究微生物组操控效应的研究至关重要。本研究中，研究人员向斯普拉格-道利大鼠（Sprague-Dawley rats）提供未处理的饮水或抗生素，以耗竭其肠道微生物组及其代谢物。随后对大鼠进行可卡因自身给药（cocaine self-administration）训练，并分别开展两类实验：一是进行session内阈值测试以评估可卡因寻求动机，二是先进行21天戒断，随后开展线索诱导的可卡因觅药任务（cue-induced cocaine-seeking task）以模拟复吸行为。微生物组耗竭并未影响固定比率1（FR1）程序下的可卡因获得行为。但在session内阈值测试中，微生物组耗竭的大鼠对低剂量可卡因的寻求动机显著增强。类似地，长期戒断后，微生物组耗竭可增强线索诱导的可卡因觅药行为。在正常微生物组缺失的情况下，补充细菌来源的SCFA代谢物可逆转微生物组耗竭相关的行为与转录变化（transcriptional changes）。上述研究结果表明，肠道细菌可通过其代谢物成为药物觅药行为的关键调控因子，提示微生物组是一项具有潜力的转化研究靶点。总体实验设计：对具有正常微生物组（对照组）、微生物组耗竭、补充短链脂肪酸，或微生物组耗竭且补充短链脂肪酸的可卡因自身给药斯普拉格-道利大鼠进行比较基因表达谱分析（comparative gene expression profiling analysis）。