Metabolomics changes after exercise intervention reveal potential peripheral biomarkers in repeated methamphetamine exposure.

Methamphetamine (MA) use disorder has become a global public health problem, and the peripheral mechanisms underlying exercise as a potential treatment for MA addiction are still not fully understood. This study aims to identify a plasma metabolic biomarker in MA-administered mice under exercise interventions. The peripheral plasma metabolic profiles of C57BL/6 J mice were quantified by ultra-high-performance liquid chromatography and tandem mass spectrometry metabolomics methods. The mice were randomized into saline control (C), MA model control (NE-MA) and MA model exercise intervention (E-MA) groups, and a conditioned place preference paradigm was used to assess drug reward. Anxiety-like behavior and cognitive behavior was evaluated using the open field and Y-maze tests. A total of 35 differential metabolites effectively distinguished between NE-MA and C groups. These metabolites are mainly involved in membrane lipid, energy, and amino acid metabolism. Compared with the NE-MA group, the expression of five reward-related metabolites in the E-MA group was reversed: l-tryptophan, niacinamide, uridine, 2'-deoxyuridine, and uric acid, which are involved in amino acid, energy, purine, and pyrimidine metabolism. Upregulation in uric acid and l-tryptophan levels was associated with improved anxiety-like behavior and cognitive function after exercise intervention. These metabolites may serve as markers of exercise intervention in MA addiction and deserve further study.