Integrated Non-targeted and Targeted Metabolomics Uncovers Dynamic Metabolic Effects during Short-Term Abstinence in Methamphetamine Self-Administering Rats

Abstract

Persistent neurochemical disturbances by repeating drug reward and withdrawal lead to addiction. Particularly, drug withdrawal, usually starting within hours of the last dose, is considered as a critical step in the transition to addiction and a treatment clue. The aim of this study was to uncover metabolic effects associated with methamphetamine (MA) short-term abstinence using both non-targeted and targeted metabolomics. Metabolic alterations were investigated in rat plasma collected immediately after 16 days of MA self-administration and after 12 and 24 h of abstinence. Principal component analysis revealed that the highest level of separation occurred between the 24 h and saline (control) groups based on the significantly changed ion features, 257/320/333 and 331/409/388, in the SA/12 h/24 h groups in positive and negative modes of UPLC-QTOF-ESI-MS, respectively. Targeted metabolomics revealed dynamic changes in the biosynthesis/metabolism of amino acids, including the phenylalanine, tyrosine, and tryptophan biosynthesis and the valine, leucine, and isoleucine biosynthesis. Integrating non-targeted and targeted metabolomics data uncovered rapid and distinct changes in the metabolic pathways involved in energy metabolism, the nervous system, and membrane lipid metabolism. These findings provide essential knowledge of the dynamic metabolic effects associated with short-term MA abstinence and may help identify early warning signs of MA dependence.

Revealing Metabolic Perturbation Following Heavy Methamphetamine Abuse by Human Hair Metabolomics and Network Analysis

“…Only a few studies on amino acid profiling related to MA exposure have been conducted. In a previous study, dynamic changes were observed in the biosynthesis/metabolism of amino acids, including the phenylalanine, tyrosine, and tryptophan biosynthesis and the valine, leucine, and isoleucine biosynthesis, during 24 h of short-term abstinence in plasma from MA self-administering rats [ 48 ]. In another previous study, administration of a single dose (10 mg/kg) or escalating doses (10–30 mg/kg) of MA for five consecutive days in rats was followed by withdrawal for two days, after which 20 amino acids were profiled in the rat serum.…”

“…Additionally, all three among the seven SM were upregulated, and sphinganine, a precursor of ceramide, which is converted into a variety of sphingolipids, was down-regulated as shown in the results from the untargeted metabolomics. The dysregulation of membrane lipids, such as glycerophospholipids and sphingolipids, due to psychostimulants, such as MA and cocaine, have been previously demonstrated in human and animal studies [ 48 , 49 , 50 , 51 , 52 ]. However, the changes in these studies varied depending on the chemical nature of these lipids, sampling sites such as subparts of the brain [ 49 , 50 ], and sampling time [ 48 ].…”

“…The dysregulation of membrane lipids, such as glycerophospholipids and sphingolipids, due to psychostimulants, such as MA and cocaine, have been previously demonstrated in human and animal studies [ 48 , 49 , 50 , 51 , 52 ]. However, the changes in these studies varied depending on the chemical nature of these lipids, sampling sites such as subparts of the brain [ 49 , 50 ], and sampling time [ 48 ]. In particular, the levels of some of lysoPC, PC and SM fluctuated during 24 h of abstinence following MA self-administration in rat plasma [ 48 ].…”

“…However, the changes in these studies varied depending on the chemical nature of these lipids, sampling sites such as subparts of the brain [ 49 , 50 ], and sampling time [ 48 ]. In particular, the levels of some of lysoPC, PC and SM fluctuated during 24 h of abstinence following MA self-administration in rat plasma [ 48 ]. In a previous study, a significant increase in ceramide contents was noted, whereas no difference was observed in the levels of PCs and SMs in the brains of rats following MA self-administration (0.1 mg/kg, FR1, 15-hour sessions for eight days).…”

Metabolic Alterations Associated with γ-Hydroxybutyric Acid and the Potential of Metabolites as Biomarkers of Its Exposure

“…To investigate the maximum number of metabolites possible, non-selective approaches have been adopted for sample preparation and instrumental analysis [2,4]. In particular, metabolomics is currently being used to identify endogenous metabolites generated after exposure to addictive drugs [8][9][10][11]. This metabolomics approach can provide a new foundation for identifying effective diagnostic markers or therapeutic targets, if the knowledge of the mechanisms of a drug's pharmacodynamic or pharmacokinetic properties is limited [12].…”