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Unraveling the Mechanisms of Propofol-Induced Psychological Dependence: A Multi-Omics Approach Linked to Gut Microbiota in Hippocampal Function

ABSTRACT:

Introduction: Drug abuse is becoming a global public health crisis. According to the United Nations, the number of drug users worldwide has increased dramatically over the past decade, with a surge in the number of drug abusers. The problem was exacerbated by the expanding market for illicit drugs and the increasing availability of synthetic drugs such as fentanyl. Clinical drug abuse is a problem that requires particular attention, and the potential addictive properties of some drugs and their mechanisms of action are currently unknown, which limits the development and implementation of drug addiction intervention strategies.

Methods: Eight-week-old C57BL/6J mice were used as study subjects. A mental dependence model was established using the conditional position preference experiment (CPP), and the hippocampal tissues of the model mice were subjected to RNA-seq transcriptome sequencing, LC-MS non-targeted metabolome sequencing and intestinal macro-genome sequencing in order to discover propofol mental dependence signature genes. Correlation analyses of transcriptomics and metabolomics were performed using the Spearman method, and gene-metabolite networks were mapped using Cytoscape software. Real-time fluorescence quantitative PCR and immunoprotein blotting (Western blotting) methods were used to validate the characterized genes.

Results: After the conditioned position preference experiment, the conditioned preference scores of the 75 mg/kg propofol and 2 g/kg alcohol groups were significantly higher than those of the control saline group. 152 differential genes and 214 differential metabolites were identified in the 75 mg/kg group. Cluster analysis revealed that changes in the neuroactive ligand receptor pathway were most pronounced. Gut microbiomics assays revealed significant changes in five differential enterobacterial phyla (Campylobacter phylum, Thick-walled phylum, Anaplasma phylum, Actinobacteria phylum, and Chlorella verticillata phylum) in the 75 mg/kg propofol group, which may be related to changes in the differential expression of dopamine.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12337 | MetaboLights | 2025-05-12

REPOSITORIES: MetaboLights

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Project description:In summary, we characterized genomic signatures of response to drugs of abuse and we found positive correlations between the drug-induced expression and various behavioral effects. These signatures are formed by two dynamically inducible transcriptional networks: (1) CREB/SRF-dependent gene pattern that appears to be related to drug-induced neuronal activity, (2) the pattern of genes controlled at least in part via release of glucocorticoids and androgens that are associated with rewarding and harmful drug effects. The discovery of co-expressed networks of genes allowed for the identification of master-switch controlling factors involved in molecular response to the drugs. Finally, using the pharmacological tools we were able to dissect and inhibit particular gene expression patterns from genomic profile. Type: Drug response, Time-course, Gene expression profiling with Illumina Microarrays Keywords: Addiction, Drugs of abuse, Time-course, Immediate Early Genes, Glucocorticoid receptor dependent genes, Cocaine, Heroin, Nicotine, Ethanol, Morphine, Methamphetamine The microarray experiment was performed to analyze time-course of drug-induced transcriptional response in C57BL/6J mouse striatum. Six the most addictive and harming drugs of abuse (morphine 20 mg/kg, heroin 10 mg/kg, ethanol 2 g/kg, nicotine 1 mg/kg, methamphetamine 2 mg/kg or cocaine 25 mg/kg, i.p.) were selected for the comparison. Drug doses were previously reported as rewarding in mice and further tested in our laboratory. To analyze dynamics of early, intermediate and relatively late changes of mRNA abundance the experiment was performed in four time points (1, 2, 4 and 8h after drug administration). To exclude influence of drug injection and circadian rhythm on gene expression profile, control groups of saline treated and naïve animals were prepared for each time point. Design of the experiment assumed pooling of two animals per each array and using of three independent arrays per group. To provide appropriate balance in the whole dataset groups were equally divided between the array hybridization batches. 'Complete' normalized data and non-normalized data (containing control rows not represented in Platform GPL6105) are linked below as supplementary files.

Project description:To identify the molecular mechanisms that may initiate therapeutic effects, whole-genome expression profiling (Illumina Mouse WG-6 microarrays) of drug-induced alterations in the mouse brain was undertaken, with a focus on the time-course (1, 2, 4 and 8h) of gene expression changes produced by eighteen major psychotropic drugs: antidepressants, antipsychotics, anxiolytics, psychostimulants and opioids. The resulting database is freely accessible at www.genes2mind.org. Bioinformatics approaches led to the identification of three main drug-responsive genomic networks and indicated neurobiological pathways that mediate the alterations in transcription. Each tested psychotropic drug was characterized by a unique gene network expression profile related to its neuropharmacological properties. Functional links that connect expression of the networks to the development of neuronal adaptations (MAPK signaling pathway), control of brain metabolism (adipocytokine pathway), and organization of cell projections (mTOR pathway) were found. The additional data-sets are available at GEOX1 and GEOX2. The microarray experiment was performed to analyze time-course of drug-induced transcriptional response in C57BL/6J mouse striatum. Three antidepressants (bupropion 20 mg/kg, tranylcypromine 20 mg/kg, mianserin 20 mg/kg, i.p.), three anxiolytics (diazepam 5 mg/kg, buspirone 10 mg/kg, hydroxyzine 10 mg/kg, i.p.), and three antipsychotics (clozapine 3 mg/kg, risperidone 0.5 mg/kg, haloperidol 1 mg/kg) were selected for the comparison. Drug doses were previously reported as effective in mice and further tested in our laboratory. To analyze dynamics of early, intermediate and relatively late changes of mRNA abundance the experiment was performed in four time points (1, 2, 4 and 8h after drug administration). To exclude influence of drug injection and circadian rhythm on gene expression profile, control groups of saline or tween (1% Tween 80) treated and naïve animals were prepared for each time point. Design of the experiment assumed pooling of two animals per each array and using of three independent arrays per group. To provide appropriate balance in the whole dataset groups were equally divided between the array hybridization batches.

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Unraveling the Mechanisms of Propofol-Induced Psychological Dependence: A Multi-Omics Approach Linked to Gut Microbiota in Hippocampal Function

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