National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Addict Biol. 2023 Oct;28(10):e13330. doi: 10.1111/adb.13330.
The susceptibility to drug cravings evoked by stimuli poses a formidable hurdle in the treatment of addiction and the prevention of relapse. Pharmacological interventions targeting drug-associated memories hold promise for curbing relapse by impeding the process of memory reconsolidation, predominantly governed by cAMP signalling. Exchange Protein Activated by cAMP (Epac) serves as a distinctive mediator of cAMP signalling, which has been implicated in reinforcing the effects of cocaine and facilitating the acquisition. Nonetheless, the role of Epac in heroin-related memory and the subsequent seeking behaviour remains enigmatic. In this study, we explored the impact of Epac activation on the reconsolidation process of drug-related memories associated with heroin self-administration. Over the course of 10 consecutive days, rats underwent training, wherein they acquired the behaviour of nose poking to obtain heroin accompanied by a tone + light cue. This nose-poking behaviour was subsequently extinguished when heroin infusion and cue presentation were discontinued. Subsequently, we administered 8-pCPT-cAMP (8-CPT), an Epac-specific activator, into the basolateral amygdala at various time points, either in the presence or absence of a conditioned stimulus. Our findings demonstrate that administering 8-CPT immediately after memory retrieval effectively reduces cue- and heroin-induced reinstatement, with the observed effects persisting significantly for a minimum of 28 days. However, infusion of 8-CPT for a duration of 6 h following the memory retrieval trial, or without it altogether, had no discernible impact. Thus, these findings strongly suggest that Epac activation can disrupt the reconsolidation of heroin-associated memory, thereby diminishing the reinstatement of heroin-seeking behaviour.
药物诱发的药物渴望易感性是治疗成瘾和预防复发的一个巨大障碍。针对与药物相关的记忆的药理学干预措施有望通过阻止记忆再巩固过程来抑制复发，而记忆再巩固过程主要由 cAMP 信号传导调控。环腺苷酸（cAMP）激活的交换蛋白（Epac）是 cAMP 信号转导的一个独特介质，它被认为可以增强可卡因的效果，并促进获得。然而，Epac 在海洛因相关记忆及其随后的寻求行为中的作用仍然是一个谜。在这项研究中，我们探讨了 Epac 激活对海洛因自我给药相关药物记忆再巩固过程的影响。在连续 10 天的时间里，大鼠接受了训练，在训练中，它们通过鼻子戳的行为来获得海洛因，并伴随着一个音调+灯光提示。当停止海洛因输注和提示呈现时，这种鼻子戳行为随后被消退。随后，我们在不同时间点将 Epac 特异性激活剂 8-pCPT-cAMP（8-CPT）注入外侧杏仁核，无论是在存在条件刺激还是不存在条件刺激的情况下。我们的研究结果表明，在记忆检索后立即给予 8-CPT 可有效减少线索和海洛因诱导的复燃，观察到的效果至少持续 28 天显著。然而，在记忆检索试验后持续输注 8-CPT 6 小时或完全不输注，没有明显影响。因此，这些发现强烈表明，Epac 激活可以破坏海洛因相关记忆的再巩固，从而减少海洛因寻求行为的复燃。
