Integrated metabolomics and gut microbiota analysis to explore the potential mechanism of levo-tetrahydropalmatine against ketamine addiction

Study at a glance

Abstract

Introduction Metabolic and gut microbiota (GM) disturbance play a significant role in the complex pathogenesis of substance dependence. Although levo-tetrahydropalmatine (l-THP) demonstrates therapeutic potential in drug addiction, the underlying mechanism remains elusive. Methods The efficacy of l-THP was assessed using a conditioned place preference (CPP) paradigm. In this research, we combined metabolomics with gut microbiota analysis to investigate the potential mechanisms underlying l-THP’s intervention in ketamine (KET) addiction. Results L-THP effectively relieved hippocampus (Hip) pathological changes and attenuated KET-induced rewarding effects. Metabolomic profiling of serum and urine samples revealed a total of 194 distinct metabolites, including 3-methoxytyramine, 3-hydroxyphenylacetic acid, and phosphorylcholine, involving glycerophospholipid metabolism, tyrosine metabolism, phenylalanine metabolism, dopaminergic synapse, teichoic acid biosynthesis, staurosporine biosynthesis, and lysine biosynthesis metabolism pathways. L-THP also enriched Firmicutes, Lactobacillus , Dubosiella , unclassified_ Clostridia _UCG_014, and Ligilactobacillus while decreasing the levels of Bacteroidota , Campylobacterota , Patescibacteria , unclassified_ Bacilli , UCG_005, Prevotella , and Romboutsia. Moreover, Spearman’s correlation analysis showed that discriminative metabolites were closely correlated with special bacteria. Conclusion The findings demonstrated that l-THP might serve as a promising intervention strategy for KET addiction by regulating serum and urine metabolism and gut microbiota.