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.可卡因使用障碍是一场公共卫生危机，目前尚无美国食品药品监督管理局（FDA）批准的治疗药物。越来越多的研究揭示了大脑与肠道常驻细菌群体——肠道微生物组（gut microbiome）——在精神疾病模型中的重要关联。急性清除肠道细菌可增强小鼠可卡因位置偏好模型中的奖赏效应，而补充细菌源性短链脂肪酸（SCFA）代谢物则可逆转这一效应。 然而，在长期戒断后，肠道微生物组及其代谢物在调节可卡因寻求行为中的作用仍不明朗。鉴于预防复吸是物质使用障碍治疗中最具临床挑战性的问题，在与复吸相关的模型中探究微生物组调控手段的研究至关重要。 本研究中，斯普拉格-道利大鼠（Sprague-Dawley rats）分别接受未处理的饮水或抗生素以清除肠道微生物组及其代谢物。大鼠经训练完成可卡因自身给药行为后，或接受session内阈值测试以评估其对可卡因的动机需求，或经历21天戒断后开展线索诱导的可卡因寻求任务以模拟复吸行为。 肠道微生物组清除并未影响固定比率1（FR1）程序下的可卡因获得行为。但经微生物组清除的个体在session内阈值测试中，对低剂量可卡因的动机显著增强。类似地，长期戒断后，微生物组清除会提升线索诱导的可卡因寻求行为。 在正常微生物组缺失的情况下，补充细菌源性短链脂肪酸代谢物可逆转与微生物组清除相关的行为与转录组学改变。 上述研究结果表明，肠道细菌可通过其代谢物成为药物寻求行为的关键调控因子，这使微生物组成为潜在的转化研究靶点。