The anxiety caused by long-term low-dose ketamine, and related metabolomics characteristics change in rat

Abstract

Abstract Ketamine is a kind of dissociation anesthesia, clinical studies have demonstrated the ability of ketamine to induce rapid and sustained antidepressant actions. However, considering the side effects such as dissociative properties, psychotomimetic effect, neurotoxicity, and abuse potential, the safety profile of prolonged use of ketamine still needs to be investigated. To investigate the effects of repeated administration of low-dose ketamine on locomotor activity, and mood changes in rats. To explore the metabolome and metabolic pathway change in plasma, and prefrontal cortex of rats after chronic administration and withdrawal of low-dose ketamine.To provide evidence for toxicity studies of ketamine as an antidepressant. Rat’s behavior changes induced by ketamine administration and withdrawal 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.