Impact of Altered Gut Microbiota on Ketamine-Induced Conditioned Place Preference in Mice.

Repeated ketamine administration (20 mg/kg) induces conditioned place preference (CPP) in mice, a model of addiction, and significantly alters gut microbiota diversity and composition. Compared to controls, ketamine exposure increased the relative abundance of four microbial families (Lachnospiraceae, Ruminococcaceae, Desulfovibrionaceae, Family-XIII) and decreased one (Prevotellaceae). At the genus level, five genera increased and one decreased. Ketamine dependence reduced levels of tight junction proteins, GABA, and GABRA1, while increasing BDNF and 5-HT. However, an oral antibiotic cocktail that created pseudo-germ-free mice did not enhance ketamine-induced addictive behavior, suggesting the gut microbiota mediates ketamine-induced CPP.

Study at a glance

Abstract

Ketamine is a drug of abuse worldwide and current treatments for ketamine abuse are inadequate. It is an urgent need to develop novel anti-addictive strategy. Since gut microbiota plays a crucial role in drug abuse, the present study investigates the impact and mechanisms of the gut microbiota in addictive behaviors induced by ketamine addiction. Conditioned place preference (CPP) was employed to assess addiction, followed by 16S rRNA gene sequencing to elucidate alterations in the gut microbiota. Furthermore, qRT-PCR, ELISA, and immunohistochemistry were conducted to evaluate the expression levels of crucial genes and proteins associated with the gut-brain axis. Additionally, we investigated whether ketamine addiction is regulated through the gut microbiota by orally administering antibiotics to establish pseudo-germ-free mice. We found that repeated ketamine administration (20 mg/kg) induced CPP and significantly altered gut microbiota diversity and composition, as revealed by 16S rRNA gene sequencing. Compared to the control group, ketamine exposure exhibited differences in the relative abundance of 5 microbial families, with 4 (Lachnospiraceae, Ruminococcaceae, Desulfovibrionaceae and Family-XIII) showing increases, while one (Prevotellaceae) displayed a decrease. At the genus level, five genera were upregulated, while one was downregulated. Furthermore, COG analysis revealed significant differences in protein functionality between the two groups. Additionally, axis series studies showed that ketamine dependence reduced levels of tight junction proteins, GABA and GABRA1, while increasing BDNF and 5-HT. Moreover, an oral antibiotic cocktail simulating pseudo germ-free conditions in mice did not enhance the addictive behavior induced by ketamine. Our study supports the hypothesis that ketamine-induced CPP is mediated through the gut microbiota. The present study provides new insights into improvement of efficient strategy for addiction treatment.