Abstract
Amphetamine is widely consumed as drug of abuse due to its stimulating and cognitive enhancing effects. Since amphetamine has been on the market for quite a long time and it is one of the most commonly used stimulants worldwide, to date there is still limited information on its effects on the metabolome. In recent years, untargeted toxicometabolomics have been increasingly used to study toxicity-related pathways of such drugs of abuse to find and identify important endogenous and exogenous biomarkers. In this study, the acute effects of amphetamine intake on plasma and urinary metabolome in rats were investigated. For this purpose, samples of male Wistar rats after a single dose of amphetamine (5 mg/kg) were compared to a control group using an untargeted metabolomics approach. Analysis was performed using normal and reversed phase liquid chromatography coupled to high-resolution mass spectrometry using positive and negative ionization mode. Statistical evaluation was performed using Welch’s two-sample t test, hierarchical clustering, as well as principal component analysis. The results of this study demonstrate a downregulation of amino acids in plasma samples after amphetamine exposure. Furthermore, four new potential biomarkers N-acetylamphetamine, N-acetyl-4-hydroxyamphetamine, N-acetyl-4-hydroxyamphetamine glucuronide, and amphetamine succinate were identified in urine. The present study complements previous data and shows that several studies are necessary to elucidate altered metabolic pathways associated with acute amphetamine exposure.
Highlights
Once introduced as a treatment against narcolepsy, mild depression, post-encephalitic parkinsonism, and several other disorders (Heal et al 2013), amphetamine nowadays has a limited therapeutic use but is widely consumed as a drug of abuse (DOA) due to its stimulating properties (Carvalho et al 2012)
Amphetamine exposed animals in this study showed no effect on their stereotyped behavior or exploratory activity after administration
Due to the complexity of the metabolome in plasma and urine with its multitude of different metabolites, it is not possible to establish an untargeted metabolomics approach that allows a holistic view on the metabolome
Summary
Once introduced as a treatment against narcolepsy, mild depression, post-encephalitic parkinsonism, and several other disorders (Heal et al 2013), amphetamine nowadays has a limited therapeutic use but is widely consumed as a drug of abuse (DOA) due to its stimulating properties (Carvalho et al 2012). Toxicometabolomics, a sub-discipline of metabolomics, is dedicated to elucidate the pattern of small molecules (usually below 1500 Da) within an in vitro or in vivo system related to a certain stimulus such as DOA intake. Under highly controlled study conditions, changes of the metabolome can be observed that may indicate or be the result of a certain drug intake (Wang et al 2016). Toxicometabolomics can, be used to study toxicity-related pathways such as the mode of action of xenobiotics or in screening of drug induced cellular or organ toxicity, or to discover new biomarkers (Bouhifd et al 2013; Ramirez et al 2013). Steuer et al (2020) investigated changes of the plasma metabolome after amphetamine intake in a controlled human study of 13 participants and identified an increased energy and steroid metabolism. To the best of our knowledge, there are no studies on the urinary metabolome after amphetamine exposure available
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