Peking University Sixth Hospital/Peking University Institute of Mental Health, Peking University, Beijing, China.
Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
Addict Biol. 2020 Jul;25(4):e12793. doi: 10.1111/adb.12793. Epub 2019 Jul 24.
Postretrieval extinction procedures are effective nonpharmacological interventions for disrupting drug-associated memories. Nonetheless, the conditioned stimulus (CS) memory retrieval-extinction procedure is ineffective in inhibiting drug craving and relapse after prolonged withdrawal, which significantly undermines its therapeutic potential. In the present study, we showed that, unlike the CS memory retrieval-extinction procedure, noncontingent heroin injections (unconditioned stimulus [UCS]) 1 hour before the extinction sessions decreased the heroin-priming-induced reinstatement, renewal, and spontaneous recovery of heroin seeking after 28 days of withdrawal (ie, remote heroin-associated memories) in rats. The UCS retrieval manipulation induced reactivation of the basolateral amygdala (BLA) after prolonged withdrawal, and this reactivation was absent with the CS retrieval manipulation. Chemogenetic inactivation of the BLA abolished the inhibitory effect of the UCS memory retrieval-extinction procedure on heroin-priming-induced reinstatement after prolonged withdrawal. Furthermore, the combination of chemogenetic reactivation of BLA and CS retrieval-extinction procedure resembled the inhibitory effect of UCS retrieval-extinction procedure on heroin seeking after prolonged withdrawal. We also observed that the inhibitory effect of the UCS retrieval-extinction procedure is mediated by regulation of AMPA receptor endocytosis in the BLA. Our results demonstrate critical engagement of the BLA in reconsolidation updating of heroin-associated memory after prolonged withdrawal, extending our knowledge of the boundary conditions of the reconsolidation of drug-associated memories.
检索后消退程序是一种有效的非药物干预措施，可破坏与药物相关的记忆。尽管如此，条件刺激（CS）记忆检索-消退程序在抑制长期戒断后药物渴求和复发方面效果不佳，这极大地削弱了其治疗潜力。在本研究中，我们发现，与 CS 记忆检索-消退程序不同，非条件刺激（unconditioned stimulus，UCS）-海洛因注射 1 小时前进行消退，可降低海洛因引发的觅药行为复燃、更新和自发恢复（即远程海洛因相关记忆），而在 28 天戒断后，这些觅药行为复燃、更新和自发恢复仍存在。UCS 检索操作诱导了长期戒断后外侧杏仁核（basolateral amygdala，BLA）的重新激活，而 CS 检索操作则不存在这种重新激活。BLA 的化学遗传失活消除了 UCS 记忆检索-消退程序对长期戒断后海洛因引发的复燃的抑制作用。此外，BLA 的化学遗传再激活与 CS 检索-消退程序的组合，类似于 UCS 检索-消退程序对长期戒断后海洛因觅药行为的抑制作用。我们还观察到，UCS 检索-消退程序的抑制作用是通过调节 BLA 中的 AMPA 受体内吞作用来介导的。我们的研究结果表明，长期戒断后，外侧杏仁核在海洛因相关记忆的再巩固更新中起着关键作用，这扩展了我们对药物相关记忆再巩固的边界条件的认识。
