Metabolomics profiling of methamphetamine addicted human serum and three rat brain areas

Abstract

Methamphetamine (METH) has already been a serious problem all over the world. The identification of related biomarkers and pathways is helpful to evaluate the degree of METH addiction, develop appropriate treatment during abstinence, and explore the mechanism. Here, it is the first time to perform metabolomics profiling of METH addicted human serum and three regions of METH-induced conditioned place preference (CPP) rat brain by using UHPLC-MS/MS and matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI), respectively. Untargeted metabolomics analysis demonstrated clear differences between METH abusers and the healthy control by finding 35 distinct expressed metabolites in serum, including 5 TCA intermediates, 17 amino acids and 13 other biomolecules, 15 of which were newly identified following METH exposure. By using MALDI-MSI, the relative quantification and distribution of 14 metabolites were investigated in the nucleus accumbens (NAc), dorsal hippocampus (dHPC) and ventral hippocampus (vHPC) of CPP rat brain. Taken together, METH addiction could influence energy metabolism, amino acids metabolism, and phospholipids metabolism. A multi-parameter model consisting of these related metabolites can be established as a METH addiction biomarker in the future. The mapping of phospholipids provided new insights into the mechanism of METH addiction. Notably, the trend of metabolite changes in NAc and dHPC was almost the same, while it was opposite between dHPC and vHPC. It seems that NAc and dHPC were the two regions more susceptible to METH administration in the brain. And dHPC and vHPC play different roles in METH addiction proved by metabolites mapping.

Metabolic phenotyping of opioid and psychostimulant addiction: A novel approach for biomarker discovery and biochemical understanding of the disorder

“…Together with a general increase in nucleotides like ADP, GMP and AMP in nucleus accumbens and dorsal hippocampus (but a decrease in the ventral hippocampus), these findings point towards an alteration in energy homeostasis in a brain region-dependent manner. A reduction in the antioxidant GSH was reported in both studies (Bu et al, 2013;Lin et al, 2019). Moreover, a reduction in N-acetylaspartate and an increase of phosphocholine were observed in brain regions of chronically treated rats, indicating that oxidative damage was present alongside neuronal and mitochondrial dysfunction (Bu et al, 2013).…”

“…Succinic acid semialdehyde levels increased, consistent with its role as an intermediate of GABA catabolism. A decrease in Glu and Gln was also observed in the nucleus accumbens and dorsal hippocampus by Lin et al (2019), although these metabolites, along with the amino acid and excitatory neurotransmitter aspartate, were down-regulated in the ventral hippocampus. Together, these findings suggest that the disturbance to Gln-Glu-GABA axis in the brain may be involved in the behavioural sensitisation to methamphetamine.…”

“…Psychostimulants also stimulate the release of other monoamines such as 5-HT and noradrenaline (Kim et al, 2019). Rodent metabolomic studies using brain tissue have explored the abnormalities in central metabolic processes driven by acute (Kaplan et al, 2013;Li et al, 2012;Olesti et al, 2019) and repeated psychostimulant administration (Adkins et al, 2013;Bu et al, 2013;Kong et al, 2018;Li et al, 2014Li et al, , 2012Lin et al, 2019;McClay et al, 2013).…”

“…Psychostimulants also stimulate the release of other monoamines such as 5‐HT and noradrenaline (Kim et al, 2019). Rodent metabolomic studies using brain tissue have explored the abnormalities in central metabolic processes driven by acute (Kaplan et al, 2013; Li et al, 2012; Olesti et al, 2019) and repeated psychostimulant administration (Adkins et al, 2013; Bu et al, 2013; Kong et al, 2018; Li et al, 2014, 2012; Lin et al, 2019; McClay et al, 2013). Biofluids including urine, blood and hair samples have also been studied to understand the metabolic consequences of exposure (Choi et al, 2017; Goodwin et al, 2014; Olesti et al, 2019; Sánchez‐López et al, 2017; Yao et al, 2013), abstinence (Kim et al, 2019; Shima et al, 2011; Zhang, Chiu, et al, 2016; Zheng et al, 2014) and the establishment of drug reinforcement (Zaitsu et al, 2014).…”

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

“…Based on the theory proposed from the development of methadone maintenance programs, addiction could be considered a metabolic disease as it initiates from a disruption in metabolism and causes persistent neurochemical disturbances leading to addiction [ 8 , 9 ]. Several metabolomic studies in animals were recently conducted to investigate MA use and revealed that MA exposure caused an imbalance in metabolites related to energy metabolism, amino acid metabolism, phospholipids metabolism, oxidative stress, and neurotransmitters [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ] However, the altered metabolites or metabolic pathways were inconsistent, depending on the doses and durations of MA administration and targeted animal model samples [ 17 ]. Moreover, knowledge gained from the metabolic analysis is often fragmentary owing to the bottleneck in identifying metabolites in case of untargeted metabolomics and the lack of further in-depth study based on the biological importance of metabolic alterations caused by MA.…”