The side effect of long-term low-dose ketamine: anxiety and relatedmetabolomics characteristics change in rat

Clinical studies have demonstrated the ability of ketamine to induce rapid antidepressant actions. However, considering the side effects such as neurotoxicity and abuse potential, the safety profile of prolonged use of ketamine still needs to be investigated. To provide evidence for toxicity studies of ketamine as an antidepressant.Rat’s locomotor activity and mood changes changes were observed by elevated plus-maze experiments. Untargeted metabolomics analysis of rat plasma and prefrontal cortex tissues was performed by UHPLC-QE/MS to screen differential expression metabolites and explore differential metabolic pathways. The number of entries into (0.80 ± 1.17 times, p  < 0.05) and duration in (12.48 ± 13.65s, p  < 0.01) open-arms were significantly lower than that of the control group (3.40 ± 1.62 times, 59.74 ± 23.32s), showing stronger anxiety degree.After withdrawal, the anxiety of rats was relieved. 74 differential metabolites were screened in the plasma of ketamine group, involving cysteine and methionine metabolism, valine and isoleucine biosynthesis, glutamine and glutamate metabolism. After one week of withdrawal, the cysteine and methionine metabolic pathways were still significantly different with the saline group; 87 metabolites in the prefrontal cortex significantly changed, which involved purine metabolism, ascorbic acid, and aldose metabolism pathways.