Dave Yesha A, Koperska Marta, Lucerne Kelsey E, Shipman Ava L, Zeldin Sharon M, Osman Aya, Hofford Rebecca S, Kiraly Drew D
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
Department of Translational Neuroscience, Wake Forest University School of Medicine, Atrium Wake Forest Baptist Health, Winston-Salem, NC 27101, United States; Wake Forest Center for Addiction Research, Wake Forest University School of Medicine, Atrium Wake Forest Baptist Health, Winston-Salem, NC 27101, United States.
J Neuroimmunol. 2025 Jun 15;403:578609. doi: 10.1016/j.jneuroim.2025.578609. Epub 2025 Apr 7.
Cocaine use disorder is a chronic relapsing condition with no FDA-approved biological treatments. The gut microbiome has emerged as a key modulator of neurobehavioral responses to drugs of abuse, yet its role in female animals has been under studied. Here, we investigated the effects of gut microbiome depletion on cocaine-induced behavioral and transcriptional responses in female mice. Adult female C57BL/6 J mice were treated with a non-absorbable oral antibiotic (Abx) cocktail for two weeks to deplete the gut microbiome, followed by behavioral assays assessing locomotor sensitization and conditioned place preference (CPP) to cocaine. Abx-treated females displayed reduced locomotor sensitization and a shifted CPP dose-response curve, characterized by attenuated preference at higher cocaine doses. Transcriptional analysis of the nucleus accumbens (NAc) revealed that microbiome depletion suppressed cocaine-induced expression of immediate early genes (c-Fos, FosB, Nr4a1, Egr4) and altered dopamine-related (Drd1) and microglial (Cx3cr1) markers. These findings contrast with prior studies in males, where microbiome depletion enhanced cocaine-induced behavioral plasticity. The observed effects suggest distinct gut-brain signaling as an important contributor to cocaine reinforcement and neuroadaptations in females. This study provides novel insights into microbiome regulation of addiction-relevant behaviors and highlights the necessity of sex-specific investigations in neuropsychiatric disorders. Further research is needed to elucidate the molecular pathways linking gut dysbiosis to substance use vulnerability in females.
可卡因使用障碍是一种慢性复发性疾病，目前尚无美国食品药品监督管理局（FDA）批准的生物治疗方法。肠道微生物群已成为对滥用药物产生神经行为反应的关键调节因子，但其在雌性动物中的作用尚未得到充分研究。在此，我们研究了肠道微生物群耗竭对雌性小鼠可卡因诱导的行为和转录反应的影响。成年雌性C57BL/6 J小鼠接受不可吸收的口服抗生素（Abx）鸡尾酒治疗两周以耗尽肠道微生物群，随后进行行为试验，评估对可卡因的运动致敏和条件性位置偏爱（CPP）。接受Abx治疗的雌性小鼠表现出运动致敏降低和CPP剂量反应曲线的改变，其特征是在较高可卡因剂量下偏爱减弱。伏隔核（NAc）的转录分析表明，微生物群耗竭抑制了可卡因诱导的即刻早期基因（c-Fos、FosB、Nr4a1、Egr4）的表达，并改变了多巴胺相关（Drd1）和小胶质细胞（Cx3cr1）标志物。这些发现与之前在雄性动物中的研究形成对比，在雄性动物中，微生物群耗竭增强了可卡因诱导的行为可塑性。观察到的效应表明，独特的肠-脑信号传导是雌性可卡因强化和神经适应的重要因素。本研究为微生物群对成瘾相关行为的调节提供了新的见解，并强调了在神经精神疾病中进行性别特异性研究的必要性。需要进一步研究以阐明将肠道菌群失调与女性物质使用易感性联系起来的分子途径。
