通过靶向和非靶向代谢组学分析探索甲基苯丙胺自我给药大鼠模型中药物依赖的进展-动脉网

Exploring the progression of drug dependence in a methamphetamine self-administration rat model through targeted and non-targeted metabolomics analyses

Nature 等信源发布 2024-09-29 13:32

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AbstractPersistent neurochemical and biological disturbances resulting from repeated cycles of drug reward, withdrawal, and relapse contribute to drug dependence. Methamphetamine (MA) is a psychostimulant with substantial abuse potential and neurotoxic effects, primarily affecting monoamine neurotransmitter systems in the brain.

摘要由药物奖励，戒断和复发的重复周期引起的持续性神经化学和生物紊乱导致药物依赖。甲基苯丙胺（MA）是一种精神兴奋剂，具有很大的滥用潜力和神经毒性作用，主要影响大脑中的单胺类神经递质系统。

In this study, we aimed to explore the progression of drug dependence in rat models of MA self-administration, extinction, and reinstatement through targeted and non-targeted metabolomics analyses. Metabolic profiles were examined in rat plasma during the following phases: after 16 days of MA self-administration (Group M); after 16 days of self-administration followed by 14 days of extinction (Group MS); and after self-administration and extinction followed by a reinstatement injection of MA (Group MSM).

在这项研究中，我们旨在通过靶向和非靶向代谢组学分析探索MA自我给药，灭绝和恢复大鼠模型中药物依赖的进展。在以下阶段检查大鼠血浆中的代谢谱：MA自我给药16天后（M组）；自我给药16天后，灭绝14天（MS组）；自我管理和灭绝后，恢复注射MA（MSM组）。

Each group of MA self-administration, extinction, and reinstatement induces distinct changes in the metabolic pathways, particularly those related to the TCA cycle, arginine and proline metabolism, and arginine biosynthesis. Additionally, the downregulation of glycerophospholipids and sphingomyelins in Group MSM suggests their potential role in MA reinstatement.

MA的每组自我管理，灭绝和恢复都会引起代谢途径的明显变化，特别是与TCA循环，精氨酸和脯氨酸代谢以及精氨酸生物合成有关的代谢途径。此外，MSM组中甘油磷脂和鞘磷脂的下调表明它们在MA恢复中的潜在作用。

These alterations may signify the progressive deterioration of these metabolic pathways, possibly contributing to drug dependence following repeated cycles of drug reward, withdrawal, and relapse. These results provide valuable insights into the metabolic changes associated with MA use at various stages, potentially facilitating the discovery of early diagnostic biomarkers and therapeutic targets for MA use disorders..

这些改变可能意味着这些代谢途径的逐渐恶化，可能在药物奖励，戒断和复发的重复周期后导致药物依赖。这些结果为在不同阶段与MA使用相关的代谢变化提供了有价值的见解，可能有助于发现MA使用障碍的早期诊断生物标志物和治疗靶点。。

IntroductionAccording to the World Drug Report 2023, the number of drug users has progressively increased from an estimated 219 million in 2011 to 296 million in 2021, representing 5.8% of the global population aged 15–64 years. This signifies that one in every 17 individuals worldwide used drugs in 2021, 23% more than a decade earlier1.

引言根据《2023年世界毒品报告》，吸毒人数已从2011年的估计2.19亿逐渐增加到2021年的2.96亿，占全球15-64岁人口的5.8%。这意味着2021年全世界每17个人中就有一个人使用药物，比十年前多了23%1。

In particular, the number of individuals with drug use disorders was estimated at 39.5 million in 2021, reflecting a 45% increase from 10 years ago, with only 1 in 5 individuals receiving treatment1. The dysregulation of multiple neurotransmitter systems plays a key role in the development of drug use disorders.

特别是，2021年，患有药物使用障碍的人数估计为3950万，比10年前增加了45%，只有五分之一的人接受了治疗1。多种神经递质系统的失调在药物使用障碍的发展中起着关键作用。

The initial or recreational administration of psychostimulants, such as methamphetamine (MA), immediately releases monoamines and reduces their reuptake, provoking a marked increase in their levels in extracellular spaces and excessive stimulation of the sympathetic nervous system. However, in rodents and non-human primates, repeated administration of increasing MA doses has been found to decrease striatal concentrations of dopamine and its metabolites.

精神兴奋剂（如甲基苯丙胺（MA））的初始或娱乐性给药会立即释放单胺并减少其再摄取，从而引起细胞外空间水平的显着增加和交感神经系统的过度刺激。然而，在啮齿动物和非人灵长类动物中，已发现重复施用增加的MA剂量可降低多巴胺及其代谢物的纹状体浓度。

In human stimulant users, both the presynaptic and postsynaptic functions of the dopamine system in the striatum are downregulated2,3,4. These findings suggest that persistent neurochemical and biological disturbances, resulting from repeated positive and negative reinforcements associated with ongoing cycles of drug reward, withdrawal, and reinstatement, contribute to the development of drug use disorders.

在人类兴奋剂使用者中，纹状体多巴胺系统的突触前和突触后功能均被下调2,3,4。。

In previous animal studies, metabolic disruptions in amino acid metabolism, lipid metabolism, and the TCA cycle have been reported following exposure of morphine5 and heroin5,6. Hair or blood samples obtained from individuals with a history of MA addiction or abuse have been e.

在以前的动物研究中，已经报道了吗啡5和海洛因5,6暴露后氨基酸代谢，脂质代谢和TCA循环的代谢破坏。从有MA成瘾或滥用史的个体获得的头发或血液样本已被e。

Formic acid, 2-aminoanthracene, and 2,3,4,5,6-pentafluorobenzoic acid were purchased from Sigma Aldrich (St. Louis, MO). The AbsoluteIDQ p180 kit used for targeted analysis was purchased from Biocrates Life Sciences AG (Innsbruck, Austria). All solvents were of high-performance liquid chromatography (HPLC) grade.

甲酸，2-氨基蒽和2,3,4,5,6-五氟苯甲酸购自Sigma-Aldrich（密苏里州圣路易斯）。用于靶向分析的AbsoluteIDQ p180试剂盒购自Biocrates Life Sciences AG（奥地利因斯布鲁克）。所有溶剂均为高效液相色谱（HPLC）级。

All other chemicals were of reagent grade..

所有其他化学品均为试剂级。。

Animals

动物

Male Sprague-Dawley rats (Daehan Animal, Seoul, Republic of Korea), 7 weeks old (weighing 260–280 g) at the start of the study, were housed individually in cages in the laboratory animal facility under controlled temperature (22 ± 2 °C) and humidity (60 ± 2%) and with a 12 h light/dark cycle. Animals had ad libitum access to food and water.

在研究开始时，将7周龄（体重260-280克）的雄性Sprague-Dawley大鼠（Daehan Animal，Seoul，Republic of Korea）在受控温度（22±2°C）和湿度（60±2%）下分别饲养在实验动物设施的笼子中，并进行12小时光照/黑暗循环。动物可以随意获得食物和水。

All experimental procedures were approved by the Institutional Animal Care and Use Committee of the Korea Institute of Toxicology, Daejeon, Republic of Korea (No. KIT-1802-0074). All methods involving animals are reported in accordance with ARRIVE guidelines. Euthanasia was done at the end of the study using carbon dioxide in accordance with the scientific research guidelines and regulations of the Korea Institute of Toxicology..

。所有涉及动物的方法均根据ARRIVE指南报告。根据韩国毒理学研究所的科学研究指南和规定，在研究结束时使用二氧化碳进行安乐死。。

Animal behavior study

动物行为研究

The procedures used for food training, surgical implantation of the jugular catheter, self-administration of MA or saline (SAL), extinction training, and MA-priming-induced reinstatement were conducted as described previously24,25, with minor modifications. Rats were anesthetized with pentobarbital (50 mg/kg, intraperitoneal) and an intravenous catheter was inserted into the right jugular vein that exited the body on the dorsal surface of the scapulae.

如前所述[24,25]，进行了用于食物训练，颈静脉导管手术植入，MA或盐水（SAL）自我给药，灭绝训练和MA引发诱导恢复的程序，并进行了一些小的修改。用戊巴比妥（50 mg/kg，腹膜内）麻醉大鼠，并将静脉导管插入右侧颈静脉，该静脉在肩胛骨背表面离开身体。

Each rat was administered Ketoprofen (0.5 mL/kg, subcutaneous) as a post-operative analgesic immediately following surgery and allowed to recover for 5 days prior to the beginning of behavioral testing13,26. Figure 1A illustrates the timeline of the animal behavior study, experimental sessions, and treatment groups.

每只大鼠在手术后立即给予酮洛芬（0.5 mL/kg，皮下）作为术后镇痛药，并在行为测试开始前恢复5天13,26。图1A说明了动物行为研究，实验阶段和治疗组的时间表。

After passing the food pellet test, 34 rats underwent consecutive experimental sessions involving drug self-administration, extinction, and reinstatement in the same operating chamber. Rats were subjected to predetermined experimental sessions and classified accordingly. After a 5-day recovery period from chronic indwelling jugular catheter implantation surgery, 10 and 24 rats were exposed to self-administered SAL (Group S) and MA (0.05 mg/kg/infusion; Group M), respectively, under a fixed-ratio 1 (FR-1) 20-s time-out reinforcement schedule for 2 h/day for 16 days.

通过食物颗粒测试后，34只大鼠在同一手术室中进行了连续的实验，包括药物自我给药，灭绝和恢复。对大鼠进行预定的实验并进行相应分类。在慢性留置颈静脉导管植入手术恢复5天后，将10只和24只大鼠分别暴露于自我给药的SAL（S组）和MA（0.05 mg/kg/输注；M组），固定比例1（FR-1）20-S超时强化时间表，每天2小时，持续16天。

Immediately after the last self-administration session, four (Group S) and six (Group M) of the 10 and 24 rats, respectively, were sacrificed for plasma collection; the remaining 6 and 18 rats were used to continue extinction to diminish the previously learned drug-seeking behavior of MA self-administered rats for 14 days (Group SS and Group MS, respectively), following the same protocol as SAL self-administration.

在最后一次自我管理会议后，分别处死10只和24只大鼠中的4只（S组）和6只（M组）进行血浆采集；其余6只和18只大鼠用于继续灭绝，以减少MA自我给药大鼠先前学习的药物寻求行为14天（分别为SS组和MS组），遵循与SAL自我给药相同的方案。

Immediately after the last extinct.

就在最后一次灭绝之后。

Fig. 1Summary of animal behavior experiments. (A) Timeline, experimental sessions, and animal groups for behavioral assessment. Gray circle represents the day of blood collection. (B) Numbers of infusions and lever presses during the self-administration period (1–16 days) of Groups S and M. (C) Numbers of infusions and lever presses during self-administration (1–16 days) and extinction period (17–30 days) of Groups SS and MS.

图1动物行为实验总结。（A）时间表，实验课程和动物组进行行为评估。灰色圆圈代表采血的日子。（B） S组和M组自我管理期间（1-16天）的输液和杠杆按压次数。（C）SS组和MS组自我管理期间（1-16天）和灭绝期间（17-30天）的输液和杠杆按压次数。

(D) Numbers of infusions and lever presses during self-administration (1–16 days), extinction (17–30 days), and reinstatement period (31 day) of Groups MSS and MSM. Statistical analyses were performed using the two-way ANOVA test, followed by Bonferroni’s multiple comparison post hoc test. The data are presented as mean ± standard error of the mean (SEM).

（D） MSS和MSM组在自我管理（1-16天），灭绝（17-30天）和恢复期（31天）期间的输液和杠杆按压次数。使用双向ANOVA检验进行统计分析，然后进行Bonferroni的多重比较事后检验。数据表示为平均值的平均值±标准误差（SEM）。

*p < 0.05, **p < 0.01, ***p < 0.001 for daily comparison between groups; ##p < 0.01, ###p < 0.001 for total comparison between groups. NS, not significant; SAL, saline; MA, methamphetamine; Ac, active lever; InA, inactive lever.Full size imagePlasma sampling.

*组间每日比较p<0.05，**p<0.01，***p<0.001##组间总比较p<0.01，p<0.001。NS，不显着；SAL，盐水；MA，甲基苯丙胺；Ac，主动杆；InA，无效操纵杆。全尺寸图像等离子体采样。

Rats were anesthetized with pentobarbital (50 mg/kg, intraperitoneal) and sacrificed to obtain blood samples. Blood was collected through the abdominal vena cava (approximately 5 mL), and aliquots were transferred to EDTA tubes (BD Vacutainer® K2E (EDTA) 18.0 mg, BD Biosciences, Franklin Lakes, NJ, USA).

用戊巴比妥（50 mg/kg，腹膜内）麻醉大鼠并处死以获得血样。通过腹腔腔静脉收集血液（约5 mL），并将等分试样转移至EDTA管（BD Vacutainer®K2E（EDTA）18.0 mg，BD Biosciences，Franklin Lakes，NJ，USA）。

After a brief mixing period, the tubes were allowed to stand at room temperature for 30 min. Following centrifugation at 1624×g for 10 min at 4 °C, the supernatant (plasma) was transferred to a 1.5 mL microfuge tube and stored at − 80 °C before analysis13..

短暂混合后，使试管在室温下静置30分钟。在4°C下以1624×g离心10分钟后，将上清液（血浆）转移到1.5 mL微量离心管中，并在分析前保存在-80°C 13。。

Targeted and non-targeted metabolomics analysis

靶向和非靶向代谢组学分析

All sample preparation and instrumental analyses for targeted and non-targeted metabolomic analyses were conducted following the procedures outlined in our previous study13, with the exception of the analysis of tricarboxylic acid (TCA) metabolites, which were investigated using our validated in-house method.

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For targeted metabolomic analysis of 40 acylcarnitines, 42 amino acids and biogenic amines, 90 glycerophospholipids, 15 sphingolipids, and 1 monosaccharide, samples were prepared using the AbsoluteIDQ p180 kit (Biocrates Life Sciences AG) according to the manufacturer’s instructions and analyzed using flow injection analysis (FIA)-tandem mass spectrometry (MS/MS) and HPLC-MS/MS (AB Sciex 4000 QTrap mass spectrometer, Sciex, Framingham, MA, USA).

为了对40种酰基肉碱，42种氨基酸和生物胺，90种甘油磷脂，15种鞘脂和1种单糖进行靶向代谢组学分析，使用AbsoluteIDQ p180试剂盒（Biocrates Life Sciences AG）根据制造商的说明制备样品，并使用流动注射分析（FIA）-串联质谱（MS/MS）和HPLC-MS/MS（AB Sciex 4000 QTrap质谱仪，Sciex，Framingham，MA，USA）进行分析。

The kit was validated using MetValTM (Biocrates Life Sciences AG) software, and the analytical results were processed using AnalystTM (Sciex) and MetValTM software..

使用MetValTM（Biocrates Life Sciences AG）软件对试剂盒进行了验证，并使用AnalystTM（Sciex）和MetValTM软件对分析结果进行了处理。。

For analyzing 10 TCA metabolites, rat plasma samples were protein-precipitated using ice-cold acetone and then centrifuged at 19,274×g for 10 min at 4 °C. The supernatants were filtered using a 0.45 μm polyvinylidenefluoride microporous membrane and filtered sample was analyzed by HPLC–MS/MS. LC-MS/MS analysis was conducted using a reverse-phase column coupled with a 1260 Infinity LC system and 6460 Triple Quadrupole MS/MS (Agilent Technologies, Santa Clara, CA, USA).

为了分析10种TCA代谢物，使用冰冷的丙酮对大鼠血浆样品进行蛋白质沉淀，然后在4°C下以19274×g离心10分钟。使用0.45μm聚偏二氟乙烯微孔膜过滤上清液，并通过HPLC-MS/MS分析过滤后的样品。使用反相柱结合1260 Infinity LC系统和6460三重四极杆MS/MS（美国加利福尼亚州圣克拉拉的安捷伦科技公司）进行LC-MS/MS分析。

Data were processed using MassHunter software (B. 08. 00; Agilent Technologies)..

使用MassHunter软件（B.08）处理数据。00；安捷伦科技公司）。。

For non-targeted metabolomic analysis, samples were prepared by protein precipitation using acetonitrile and ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight electrospray ionization (ESI) mass spectrometry (UPLC-QTOF-ESI-MS) was conducted in both positive and negative ionization modes.

对于非靶向代谢组学分析，使用乙腈和超高效液相色谱结合四极杆飞行时间电喷雾电离（ESI）质谱（UPLC-QTOF-ESI-MS）通过蛋白质沉淀制备样品。正离子和负离子模式。

Analyses were performed using an Agilent 6530 Accurate-Mass Q-TOF LC/MS System with an Agilent 1290 Infinity LC (Agilent Technologies, Palo Alto, CA, USA). Pooled quality control samples, prepared by mixing aliquots from each sample, were analyzed every six sample analyses. Triplicate samples were analyzed for both targeted and non-targeted metabolomics..

使用具有Agilent 1290 Infinity LC（Agilent Technologies，Palo Alto，CA，USA）的Agilent 6530精确质量Q-TOF LC/MS系统进行分析。通过混合每个样品的等分试样制备的合并质量控制样品每六次样品分析进行一次分析。对一式三份的样品进行了靶向和非靶向代谢组学分析。。

Data processing and statistical analysis

数据处理和统计分析

Considering the UPLC-QTOF-ESI-MS data, data processing and statistical analyses were performed using MassHunter Profinder (version 10.0) and Mass Profiler Professional (MPP, version B.15.1) software (Agilent Technologies) as described in our previous study13, with minor modifications. The parameters for feature extraction in Profinders were as follows: peak height > 300 counts; ion species, [M + H]+ and [M + Na]+, for positive ions, and [M-H]− for negative ions; isotope peak spacing tolerance, 0.0025 m/z and 7.0 ppm; and charge state, a maximum of 1.

考虑到UPLC-QTOF-ESI-MS数据，使用MassHunter Profinder（版本10.0）和Mass Profiler Professional（MPP，版本B.15.1）软件（Agilent Technologies）进行数据处理和统计分析，如我们之前的研究13所述，稍作修改。Profinders中特征提取的参数如下：峰高>300计数；离子种类，[M + H]+和[M + Na]+，对于正离子，[M-H]-对于负离子；同位素峰间距公差，0.0025 m/z和7.0 ppm；和充电状态，最大值为1。

Ion features were aligned and extracted based on particular masses (mass window of 10 ppm + 2.00 mDa) and retention times (retention time window of 0.5 min). The peak abundances of internal standards in the quality control and experimental samples were inspected to reduce false-negative and false-positive features.

根据特定质量（质量窗口为10 ppm+ 2.00 mDa）和保留时间（保留时间窗口为0.5分钟）对离子特征进行比对和提取。检查质量控制和实验样品中内标的峰丰度，以减少假阴性和假阳性特征。

The CEF files were exported to MPP for metabolic investigation using an in-house database24 and MassHunter METLIN Metabolite PCDL (Demo version, summer, 2014)..

使用内部数据库24和MassHunter METLIN代谢物PCDL（演示版，2014年夏季），将CEF文件导出到MPP进行代谢调查。。

For statistical evaluation of data from both targeted and non-targeted metabolomic analyses, metabolic differences between groups were evaluated by principal component analysis (PCA) and partial least squares-discrimination analysis (PLS-DA) using the MetaboAnalyst software (version 6.0; https://www.metaboanalyst.ca/).

；https://www.metaboanalyst.ca/)。

The software automatically performed a model-fitting analysis of the three principal components. The data were scaled by auto scaling. A t-test with unequal variance, followed by multiple testing correction (Benjamini–Hochberg false discovery rate [FDR], adjusted p-value), was used to determine significant differences in ion features or metabolites.

该软件自动对三个主成分进行模型拟合分析。数据通过自动缩放进行缩放。使用方差不等的t检验，然后进行多重检验校正（Benjamini-Hochberg错误发现率[FDR]，调整后的p值），以确定离子特征或代谢物的显着差异。

For targeted and non-targeted analysis data, the following criteria were applied: fold change > 1.2 with p-values < 0.05 among the groups. For non-targeted analysis, the data reproducibility of the significantly altered ion features were examined in the quality control samples and those with relative standard deviation (RSD) less than 20% were finally selected.

对于有针对性和无针对性的分析数据，采用以下标准：组间p值<0.05的倍数变化>1.2。对于非靶向分析，在质量控制样品中检查了显着改变的离子特征的数据再现性，并最终选择了相对标准偏差（RSD）小于20%的样品。

Pathway analysis was also performed using the MetaboAnalyst 6.0 software..

还使用MetaboAnalyst 6.0软件进行了途径分析。。

ResultsMA self-administration, extinction, and reinstatementFigure 1B-D present the number of infusions and lever presses during the self-administration period of Groups S and M; the self-administration and extinction periods of Groups SS and MS; and the self-administration, extinction, and reinstatement periods of Groups MSS and MSM.

结果MA自我管理，灭绝和恢复图1B-D显示了S组和M组自我管理期间输注和杠杆按压的次数；SS和MS组的自我管理和灭绝期；MSS和MSM群体的自我管理，灭绝和恢复期。

During the first 16 days of the self-administration session, Groups M (F1,112 = 83.27, p < 0.0001) and MS (F1,144 = 180.5, p < 0.0001) had a significantly higher number of drug infusions than the control groups, Groups S and SS, respectively, and showed < 20% variation during the last 3 days (Days 14–16) of the experiment.

在自我管理会议的前16天，M组（F1112=83.27，p<0.0001）和MS组（F1144=180.5，p<0.0001）的药物输注量显着高于对照组，S组和SS组，并且在实验的最后3天（第14-16天）显示出20%的变化。

Moreover, Groups M (F1,112 = 41.45, p < 0.0001) and MS (F1,143 = 209.3, p < 0.0001) exhibited higher responses to the number of active levers than rats in Groups S and SS, respectively, with no significant differences observed in the number of inactive levers. Next, extinction training began the day after self-administration session.

此外，M组（F1112=41.45，p<0.0001）和MS组（F1143=209.3，p<0.0001）对活动杠杆数量的反应分别高于S组和SS组，无活动杠杆数量无显着差异。接下来，自我管理课程的第二天开始了灭绝训练。

When MA access was removed, Group MS, MSS, and MSM initially maintained active lever pressing compared to Group SS on day 17 (p < 0.05), however this behavior gradually extinguished over time. In contrast, Group SS maintained relatively low level of lever pressing behavior. Considering the extinction session, there was no significant difference in the number of drug infusions during Days 18–30 following self-administration between rats in Groups MS and MSM and those in groups SS and MSS (p > 0.05).

当MA通路被移除时，与第17天的SS组相比，MS，MSS和MSM组最初保持主动杠杆按压（p<0.05），但是这种行为随着时间的推移逐渐消失。相反，SS组保持相对较低水平的杠杆按压行为。考虑到灭绝期，MS组和MSM组大鼠与SS组和MSS组大鼠自我给药后第18-30天的药物输注次数无显着差异（p＞0.05）。

Additionally, there were no significant differences in the number of active and inactive levers between groups (p > 0.05). For drug-induced reinstatement, MA and SAL (control) were administered on the day after the last extinction session. Group MSM had a significantly higher number of drug infusi.

此外，组间活动和非活动杠杆的数量没有显着差异（p>0.05）。对于药物诱导的恢复，在最后一次灭绝后的第二天给予MA和SAL（对照）。MSM组的药物输注数量明显较高。

Data availability

数据可用性

All data generated and/or analyzed during the current study available from the corresponding author upon reasonable request.

。

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Download referencesAcknowledgementsThis research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) and was funded by the Ministry of Education (NRF-2016R1A6A1A03011325 and RS-2023-00242428).Author informationAuthor notesSang-Hoon Song and Suji Kim contributed equally to this work.Authors and AffiliationsCollege of Pharmacy, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu, 42601, Republic of KoreaSang-Hoon Song, Suji Kim, Won-Jun Jang, Chul-Ho Jeong & Sooyeun LeeBiorchestra Co., Ltd, Techno4-ro 17, Daejeon, 34013, Republic of KoreaIn Soo RyuAuthorsSang-Hoon SongView author publicationsYou can also search for this author in.

下载参考文献致谢本研究由韩国国家研究基金会（NRF）的基础科学研究计划支持，并由教育部资助（NRF-2016R1A6A1A03011325和RS-2023-00242428）。作者信息作者notesSang Hoon Song和Suji Kim对这项工作做出了同样的贡献。作者和附属机构庆明大学药学院，1095 Dalgubeoldaero，Dalseo gu，Daegu，42601，大韩民国Sang Hoon Song，Suji Kim，Won Jun Jang，Chul Ho Jeong&Sooyun LeeBiorchestra Co.，Ltd，Techno4 ro 17，Daejeon，34013，大韩民国Soo Ryuauthorsang Hoon SongView作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsSang-Hoon Song: Methodology, Formal analysis, Writing - original draft, Visualization. Suji Kim: Methodology, Formal analysis, Writing original draft. Won-Jun Jang: Formal analysis, Visualization. In Soo Ryu: Investigation, Formal analysis. Chul-Ho Jeong: Conceptualization, Supervision, Writing - review & editing.

PubMed谷歌学术贡献Sang Hoon Song：方法论，形式分析，写作-原稿，可视化。金素姬：方法论，形式分析，撰写原稿。张元军：形式分析，可视化。。Chul Ho Jeong：概念化，监督，写作-评论和编辑。

Sooyeun Lee: Conceptualization, Supervision, Writing - review & editing.Corresponding authorsCorrespondence to.

李秀云：概念化，监督，写作-评论和编辑。通讯作者通讯。

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All animal procedures performed during this study were reviewed and approved by the Institutional Animal Care and Use Committee of the Korea Institute of Toxicology.

本研究期间进行的所有动物程序均由韩国毒理学研究所机构动物护理和使用委员会审查和批准。

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Reprints and permissionsAbout this articleCite this articleSong, SH., Kim, S., Jang, WJ. et al. Exploring the progression of drug dependence in a methamphetamine self-administration rat model through targeted and non-targeted metabolomics analyses.

转载和许可本文引用本文Song，SH.，Kim，S.，Jang，WJ。等人。通过靶向和非靶向代谢组学分析探索甲基苯丙胺自我给药大鼠模型中药物依赖的进展。

Sci Rep 14, 22543 (2024). https://doi.org/10.1038/s41598-024-73247-5Download citationReceived: 14 June 2024Accepted: 16 September 2024Published: 29 September 2024DOI: https://doi.org/10.1038/s41598-024-73247-5Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

科学报告1422543（2024）。https://doi.org/10.1038/s41598-024-73247-5Download引文接收日期：2024年6月14日接受日期：2024年9月16日发布日期：2024年9月29日OI：https://doi.org/10.1038/s41598-024-73247-5Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。。

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KeywordsDrug dependenceMethamphetamineSelf-administrationReinstatementMetabolomicsMass spectrometry

药物依赖性甲基苯丙胺自我给药恢复代谢组学质谱

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