Non-targeted and Targeted Metabolomics Techniques Reveal Striatal Metabolome Characteristics in the Ketamine-Induced Conditioned Place Preference Mice Model.

Ketamine, originally developed as an anesthetic, is now being studied for depression treatment, but its addictive potential is a growing concern. This research used a mouse model of ketamine-induced conditioned place preference (CPP) to investigate changes in the striatum, a brain region involved in reward. Advanced metabolomics techniques revealed that ketamine abuse alters striatal metabolites, affecting pathways related to arginine synthesis, purine metabolism, and morphine addiction. Specifically, ketamine increased the neurotransmitter kynurenine (Kyn) and decreased dopamine (DA) in the striatum. These disturbances in Kyn and DA metabolism may underlie the addictive behaviors seen in the CPP model, offering new insights into ketamine addiction mechanisms.

Study at a glance

Abstract

Ketamine is a synthesized anesthetic drug that was used extensively as a surgical anesthetic in the 1960s. Currently, ketamine is being investigated extensively for its potential as a treatment for depression. However, the addictive nature of ketamine has become an issue that cannot be ignored at this stage. As of now, there is no clear understanding of the changes in striatal metabolites and their relative metabolic pathways under the addictive effect of ketamine. In this study, a stable model of ketamine-induced conditioned place preference (CPP) was established. Non-targeted metabolomics and targeted metabolomics techniques, based on the ultra-performance liquid chromatography-Q Exactive hybrid quadrupole-Orbitrap mass spectrometry (UHPLC-QE/MS) and the UHPLC-MS platform, were employed to uncover the metabolic characteristics and neurotransmitter profiles of the striatum after ketamine abuse in mice. Potential biomarkers and related differential metabolic pathways of this model have been revealed. In non-targeted metabolomics analysis, striatal differential metabolites mainly involve pathways related to arginine synthesis, purine metabolism, and morphine addiction. In targeted metabolism, the striatum of mice receiving ketamine showed an increase in the content of the neurotransmitter kynurenine (Kyn) and a decrease in the content of the neurotransmitter dopamine (DA). Our study suggested that Kyn and DA metabolism disturbances might be associated with ketamine-induced CPP phenotypes and provided a new perspective for investigating the addiction mechanisms of ketamine.