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.
Exposure to a catastrophic event or intense stimulation can trigger fear memories, and the threatening memories persist even over a lifetime. Exposure therapy is based on extinction learning and is widely used to treat fear-related disorders, but its effect on remote fear memory is modest. Berberine, an isoquinoline alkaloid derived from Coptis chinensis or Berberis spp., has been recently reported to exert a diversity of pharmacological effects on the central nervous system, such as facilitating extinction of drug memory. Here, we explored the effect of berberine on extinction of fear memory using a classical contextual fear conditioning (CFC) paradigm, which is Pavlovian conditioning, can rapidly create fear memories related to contexts. Twenty-four hours or 30 days after CFC training, mice were subjected to context extinction (10 days) to extinguish their behaviors and treated with 12.5 or 25 mg/kg berberine intragastrically 1 or 6 h after each extinction session, followed by reinstatement and spontaneous recovery tests. The results showed that intragastric administration of 25 mg/kg berberine 1 h after extinction significantly promoted the extinction of recent and remote fear memories and prevented reinstatement and spontaneous recovery of extinguished fear in mice. These findings indicate that berberine combined with extinction training could serve as a promising novel avenue for the treatment of fear-related disorders.
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