Impact of Altered Gut Microbiota on Ketamine-Induced Conditioned Place Preference in Mice.
Chan Li, Chen Zhu, Genghong Tu, Zhijie Chen, Zhixian Mo, Chaohua Luo
Neuropsychiatric Disease and Treatment 2024 DOI: 10.2147/NDT.S476420 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Ketamine |
| Dose | 20 mg/kg |
| Topics | Esketamine Ketamine |
| Keywords | Bdnf Gabra1 Gut-brain axis Ketamine abuse Addiction substance abuse Drug dependence Microbiome gut microbiota Gut bacteria Intestinal flora Neuroscience brain chemistry |
| Citations | 4 |
| Key findings | Ketamine-induced conditioned place preference in mice is mediated through alterations in the gut microbiota, as indicated by changes in microbial composition and gut-brain axis markers, but pseudo-germ-free conditions did not enhance addictive behavior. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 2
- Non-targeted and Targeted Metabolomics Techniques Reveal Striatal Metabolome Characteristics in the Ketamine-Induced Conditioned Place Preference Mice Model. Journal of Molecular Neuroscience July 12, 2025
- Pleiotropic modulation of the gut-brain-lung axis by ketamine and its enantiomers. Molecular Psychiatry April 13, 2026
Cites 3
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- The destruction of the lower urinary tract by ketamine abuse: a new syndrome? British Journal of Urology August 1, 2008
- Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology August 1, 1995