Influence of gut microbiome metabolites on cocaine demand and cocaine-seeking behavior.
Influence of gut microbiome metabolites on cocaine demand and cocaine-seeking behavior.
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肠道微生物代谢物对可卡因需求和可卡因寻求行为的影响。
DOI：
10.1038/s41386-023-01743-9
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Olive,MFoster
中科院分区：
文献类型：
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作者：
Acuña,AmandaM;Olive,MFoster
胃肠道内的细菌可以调节几种脑细胞的细胞和转录活动，进而影响认知和大脑功能的各个方面。因此，有很大程度的猜测认为，肠道-大脑信号的异常可能导致神经精神障碍的症状，包括毒瘾[1]。肠道-大脑沟通发生的机制尚不完全清楚，但可能涉及肠道微生物区系分泌的代谢物的作用，这些代谢物进入体循环并最终进入大脑。这类分子的一个潜在类别是短链脂肪酸(SFCA，主要是丙酸、丁酸盐和醋酸酯)，它是由膳食纤维的代谢分解产生的。在早期的一项研究中，Kiraly等人[2]报告说，给小鼠注射不可吸收的抗生素(ABX)来耗尽肠道微生物群会增加小鼠对可卡因的运动敏感度，以及可卡因诱导的条件位置偏爱。这些影响被微生物单链脂肪酸的再补充所逆转。为了扩展这些观察，Meckel等人[3]现在研究了肠道微生物群枯竭和SFCA补充或不补充对自身静脉注射可卡因的获取和需求的影响，以及在强制戒断3周后线索诱导的可卡因寻求的影响。雄性SD大鼠在饮水中加入不可吸收的抗生素新霉素、万古霉素、杆菌素和匹马利星的混合物，耗尽肠道微生物菌群2周。ABX处理组的大鼠也接受了单链脂肪酸的补充，而对照组大鼠只接受了单链脂肪酸或水。大鼠限食(18g/d)以增加手术反应的动力，然后进行静脉导管植入，连续7d，每天3h，以0.8 mg/kg/次的剂量测试可卡因的自我给药。提示提示伴随着每次药物输注。微生物组的枯竭对可卡因自身给药的获得没有明显的影响，补充SCFA也没有明显的影响。在获得对可卡因的稳定反应后，Meckel等人[3]使用Zittel-Lazarini等人之前开发的会话内剂量下降行为经济学程序测试了大鼠的可卡因需求。与对照组相比，服用ABX的大鼠在更高的行为价格(每接受一毫克可卡因产生的反应)下对可卡因的需求增加，但没有观察到可卡因需求弹性(α，提高价格[反应要求]减少可卡因摄入量的比率)的变化，也没有观察到最低限制价格(Q0)的可卡因摄入量。
The resident bacteria of the gastrointestinal tract modulate the cellular and transcriptional activity of several brain cell types, which in turn affect various aspects of cognition and brain function. As a result, there is a great degree of speculation that aberrant gut-brain signaling may contribute to symptoms of neuropsychiatric disorders, including drug addiction [1]. The mechanisms by which gut-brain communication occurs are not fully understood, but may involve actions of metabolites secreted by gut microbiota, which enter systemic circulation and ultimately the brain. One potential class of such molecules are short-chain fatty acids (SFCAs, mainly propionate, butyrate, and acetate), which are produced by metabolic breakdown of dietary fiber. In an earlier study, Kiraly et al.[2] reported that administration of non-absorbable antibiotics (Abx) to mice to deplete the gut microbiome increased locomotor sensitization to cocaine and cocaine-induced conditioned place preference. These effects were reversed by repletion of microbial SCFAs. To expand on these observations, Meckel et al.[3] now examined the effects of gut microbiome depletion with or without repletion of SFCAs on acquisition of and demand for intravenously self-administered cocaine, as well as cue-induced cocaine seeking after 3 weeks forced abstinence. Male Sprague-Dawley rats underwent depletion of the gut microbiome via administration of a mixture of the non-absorbable antibiotics neomycin, vancomycin, bacitracin and pimaricin in the drinking water for 2 weeks. Subsets of Abx-treated rats also received supplementation of SCFAs, and control rats received only SFCAs or water. Rats were food restricted (18 g/day) to increase motivation for operant responding, then underwent intravenous catheter implantation and tested for acquisition of self-administration of cocaine at a dose of 0.8 mg/kg/infusion in 3-h daily sessions across 7 days. Cue presentation accompanied each drug infusion. Microbiome depletion had no observable effects on acquisition of cocaine self-administration, nor did supplementation with SCFAs.After acquisition of stable responding for cocaine, Meckel et al.[3] tested the rats for cocaine demand using a within-session descending dose behavioral economics procedure previously developed by Zittel-Lazarini et al.[4]. Abx-treated rats showed increased demand for cocaine at higher behavioral prices (responses exerted per mg cocaine received) as compared to control rats, but no change in cocaine demand elasticity (α, the rate at which increasing the price [response requirement] reduces cocaine intake) was observed, nor was cocaine intake at a minimally constraining price (Q0).