The gut-brain axis is increasingly recognized as an important pathway involved in cocaine use disorder. Microbial products of the murine gut have been shown to affect striatal gene expression, and depletion of the microbiome by antibiotic treatment alters cocaine-induced behavioral sensitization in C57BL/6J male mice. Some reports suggest that cocaine-induced behavioral sensitization is correlated with drug self-administration behavior in mice. Here, we profile the composition of the naïve microbiome and its response to cocaine sensitization in two collaborative cross (CC) strains. These strains display extremely divergent behavioral responses to cocaine sensitization. A high-responding strain, CC004/TauUncJ (CC04), has a gut microbiome that contains a greater amount of Lactobacillus than the cocaine-nonresponsive strain CC041/TauUncJ (CC41). The gut microbiome of CC41 is characterized by an abundance of Eisenbergella, Robinsonella and Ruminococcus. In response to cocaine, CC04 has an increased Barnsiella population, while the gut microbiome of CC41 displays no significant changes. PICRUSt functional analysis of the functional potential of the gut microbiome in CC04 shows a significant number of potential gut-brain modules altered after exposure to cocaine, specifically those encoding for tryptophan synthesis, glutamine metabolism, and menaquinone synthesis (vitamin K2). Depletion of the microbiome by antibiotic treatment revealed an altered cocaine-sensitization response following antibiotics in female CC04 mice. Depleting the microbiome by antibiotic treatment in males revealed increased infusions for CC04 during a cocaine intravenous self-administration dose–response curve. Together these data suggest that genetic differences in cocaine-related behaviors may involve the microbiome.

中文翻译：

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两种行为不同的协作杂交小鼠品系对可卡因致敏的微生物群落动态

肠-脑轴越来越被认为是涉及可卡因使用障碍的重要途径。小鼠肠道的微生物产物已被证明会影响纹状体基因表达，并且通过抗生素治疗消除微生物组会改变 C57BL/6J 雄性小鼠中可卡因诱导的行为敏感性。一些报告表明，可卡因诱导的行为敏化与小鼠的药物自我给药行为相关。在这里，我们分析了两种协作交叉（CC）菌株中幼稚微生物组的组成及其对可卡因致敏的反应。这些菌株对可卡因致敏表现出极其不同的行为反应。高反应菌株 CC004/TauUncJ (CC04) 的肠道微生物组含有大量乳酸菌比可卡因无反应菌株 CC041/TauUncJ (CC41) 更有效。CC41 的肠道微生物群的特点是富含艾森伯格菌、罗宾逊菌和瘤胃球菌。响应可卡因，CC04 的巴恩氏菌数量增加人群，而 CC41 的肠道微生物组没有表现出显着变化。对 CC04 中肠道微生物组功能潜力的 PICRUSt 功能分析显示，接触可卡因后，大量潜在的肠脑模块发生了改变，特别是那些编码色氨酸合成、谷氨酰胺代谢和甲基萘醌合成（维生素 K2）的模块。通过抗生素治疗消除微生物群，揭示了雌性 CC04 小鼠在使用抗生素后可卡因致敏反应的改变。通过对男性进行抗生素治疗来消耗微生物组，结果显示在可卡因静脉自我给药剂量反应曲线期间 CC04 的输注量增加。这些数据共同表明，可卡因相关行为的遗传差异可能与微生物组有关。