The persistence of drug memory contributes to relapse to drug seeking. The association between repeated drug exposure and drug-related cues leads to cravings triggered by drug-paired cues. The erasure of drug memories has been considered a promising way to inhibit cravings and prevent relapse. The re-exposure to drug-related cues destabilizes well-consolidated drug memories, during which a de novo protein synthesis-dependent process termed “reconsolidation” occurs to restabilize the reactivated drug memory. Disrupting reconsolidation of drug memories leads to the attenuation of drug-seeking behavior in both animal models and people with addictions. Additionally, epigenetic mechanisms regulated by DNA methyltransferase (DNMT) are involved in the reconsolidation of fear and cocaine reward memory. In the present study, we investigated the role of DNMT in the reconsolidation of heroin reward memory. In the heroin self-administration model in rats, we tested the effects of DNMT inhibition during the reconsolidation process on cue-induced reinstatement, heroin-priming-induced reinstatement, and spontaneous recovery of heroin-seeking behavior. We found that the bilateral infusion of 5-azacytidine (5-AZA) inhibiting DNMT into the basolateral amygdala (BLA) immediately after heroin reward memory retrieval, but not delayed 6 h after retrieval or without retrieval, decreased subsequent cue-induced and heroin-priming-induced reinstatement of heroin-seeking behavior. These findings demonstrate that inhibiting the activity of DNMT in BLA during the reconsolidation of heroin reward memory attenuates heroin-seeking behavior, which may provide a potential strategy for the therapeutic of heroin addiction.

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Objectives To analyze the tissue heterogeneity of hormone-sensitive and drug-resistant nephrotic syndrome genes using a bioinformatics approach and to analyze gene-related functional pathways. Methods The limma package of R software was used to screen differential genes from the nephropathy datasets GSE145969 and GSE189734. The differential genes were analyzed for functional and pathway enrichment in terms of biological processes, cellular components, and molecular functions. The Metascape tool was used to construct protein networks for the differential genes, and the results were imported into Cytoscape software for visualization. The genes were identified as key modules and genes using the MCODE plug-in. Gene set enrichment analysis was performed for the HALLMARK analysis of the two microarray key genes to obtain the relevant pathways. Results GSE145969 screened 351 differential genes, 168 upregulated genes, and 183 downregulated genes. The differential genes were enriched in biological processes, cellular components, and molecular functions, such as myocardial contraction, intracellular nonmembrane organelles, and structural molecular activities. The protein-protein interaction (PPI) network contained 140 nodes, with the highest-scoring module containing seven genes, and the MCODE plug-in calculated the downseed. The key gene was KIAA0101, whose HALLMARK pathway was significantly enriched in the mTORC1 signaling pathway. A total of 263 differential genes were screened by GSE189734, and they were enriched in biological processes, molecular functions, and cellular components, such as immune system processes, signaling receptor binding, and the cytoplasmic matrix. The PPI network contained 253 nodes, with the highest-scoring module containing 37 genes. The seed gene obtained through the MCODE plug-in calculation was IL2RA, whose HALLMARK pathway was significantly enriched in the KRAS signaling pathway. Conclusion By analyzing the gene sets of different tissues in nephropathy, two key genes, namely KIAA0101 and IL2RA, were obtained. Their gene function enrichment is related to cell growth, development, and reproduction. Therefore, IL2RA and KIAA0101 can be used as diagnostic markers for hormone-resistant nephropathy.