Qian Shuyi, Shi Cuijie, Huang Shihao, Yang Chang, Luo Yixiao
Department of Nephrology and Laboratory of Kidney Disease, Hunan Provincial People's Hospital, Hunan Normal University, Changsha, China.
Hunan Province People's Hospital, The First-Affiliated Hospital of Hunan Normal University, Changsha, China.
Front Mol Neurosci. 2022 Sep 13;15:1002139. doi: 10.3389/fnmol.2022.1002139. eCollection 2022.
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 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.
药物记忆的持续存在会导致复吸。反复接触毒品与毒品相关线索之间的关联会引发由与毒品配对的线索所触发的渴望。消除药物记忆被认为是抑制渴望和预防复吸的一种有前景的方法。再次接触毒品相关线索会使巩固良好的药物记忆变得不稳定，在此期间会发生一个依赖蛋白质合成的过程，称为“重新巩固”，以重新稳定重新激活的药物记忆。破坏药物记忆的重新巩固会导致动物模型和成瘾者的觅药行为减弱。此外，由DNA甲基转移酶（DNMT）调节的表观遗传机制参与恐惧和可卡因奖赏记忆的重新巩固。在本研究中，我们调查了DNMT在海洛因奖赏记忆重新巩固中的作用。在大鼠海洛因自我给药模型中，我们测试了在重新巩固过程中抑制DNMT对线索诱导的复吸、海洛因激发诱导的复吸以及海洛因觅药行为的自发恢复的影响。我们发现，在海洛因奖赏记忆恢复后立即向基底外侧杏仁核（BLA）双侧注射抑制DNMT的5-氮杂胞苷（5-AZA），而不是在恢复后延迟6小时注射或不进行恢复处理，会减少随后线索诱导的和海洛因激发诱导的海洛因觅药行为的复吸。这些发现表明，在海洛因奖赏记忆重新巩固过程中抑制BLA中DNMT的活性会减弱海洛因觅药行为，这可能为海洛因成瘾的治疗提供一种潜在策略。
