Liang Jie, Li Jia-Li, Han Ying, Luo Yi-Xiao, Xue Yan-Xue, Zhang Yàn, Zhang Yán, Zhang Li-Bo, Chen Man-Li, Lu Lin, Shi Jie
National Institute on Drug Dependence and Beijing Key Laboratory on Drug Dependence Research, Peking University, Beijing 100191, China.
Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
J Neurosci. 2017 Sep 13;37(37):8938-8951. doi: 10.1523/JNEUROSCI.0703-17.2017. Epub 2017 Aug 14.
Exposure to drug-paired cues causes drug memories to be in a destabilized state and interfering with memory reconsolidation can inhibit relapse. Calpain, a calcium-dependent neutral cysteine protease, is involved in synaptic plasticity and the formation of long-term fear memory. However, the role of calpain in the reconsolidation of drug reward memory is still unknown. In the present study, using a conditioned place preference (CPP) model, we found that exposure to drug-paired contextual stimuli induced the activation of calpain and decreased the expression of glutamate receptor interacting protein 1 (GRIP1) in the nucleus accumbens (NAc) core, but not shell, of male rats. Infusions of calpain inhibitors in the NAc core immediately after retrieval disrupted the reconsolidation of cocaine/morphine cue memory and blocked retrieval-induced calpain activation and GRIP1 degradation. The suppressive effect of calpain inhibitors on the expression of drug-induced CPP lasted for at least 14 d. The inhibition of calpain without retrieval 6 h after retrieval or after exposure to an unpaired context had no effects on the expression of reward memory. Calpain inhibition after retrieval also decreased cocaine seeking in a self-administration model and this effect did not recover spontaneously after 28 d. Moreover, the knock-down of GRIP1 expression in the NAc core by lentivirus-mediated short-hairpin RNA blocked disruption of the reconsolidation of drug cue memories that was induced by calpain inhibitor treatment. These results suggest that calpain activity in the NAc core is crucial for the reconsolidation of drug reward memory via the regulation of GRIP1 expression. Calpain plays an important role in synaptic plasticity and long-term memory consolidation, however, its role in the reconsolidation of drug cue memory remains unknown. Using conditioned place preference and self-administration procedures, we found that exposure to drug-paired cues induced the activation of calpain and decreased glutamate receptor interacting protein 1 (GRIP1) expression in the nucleus accumbens (NAc) core. The inhibition of calpain activity in the NAc core immediately after retrieval disrupted the reconsolidation of cocaine/morphine cue memory that was blocked by prior GRIP1 knock-down. Our findings indicate that calpain-GRIP signaling is essential for the restabilization process that is associated with drug cue memory and the inhibition of calpain activity may be a novel strategy for the prevention of drug relapse.
暴露于与药物配对的线索会使药物记忆处于不稳定状态，而干扰记忆重新巩固可抑制复吸。钙蛋白酶是一种钙依赖性中性半胱氨酸蛋白酶，参与突触可塑性和长期恐惧记忆的形成。然而，钙蛋白酶在药物奖赏记忆重新巩固中的作用仍不清楚。在本研究中，我们使用条件性位置偏爱（CPP）模型发现，暴露于与药物配对的情境刺激会诱导雄性大鼠伏隔核（NAc）核心而非壳部的钙蛋白酶激活，并降低谷氨酸受体相互作用蛋白1（GRIP1）的表达。在记忆提取后立即向NAc核心注射钙蛋白酶抑制剂会破坏可卡因/吗啡线索记忆的重新巩固，并阻断提取诱导的钙蛋白酶激活和GRIP1降解。钙蛋白酶抑制剂对药物诱导的CPP表达的抑制作用持续至少14天。在记忆提取后6小时或暴露于非配对情境后不进行记忆提取而抑制钙蛋白酶对奖赏记忆的表达没有影响。记忆提取后抑制钙蛋白酶也会减少自我给药模型中的可卡因觅求行为，且这种作用在28天后不会自发恢复。此外，通过慢病毒介导的短发夹RNA敲低NAc核心中的GRIP1表达可阻断钙蛋白酶抑制剂处理诱导的药物线索记忆重新巩固的破坏。这些结果表明，NAc核心中的钙蛋白酶活性通过调节GRIP1表达对于药物奖赏记忆的重新巩固至关重要。钙蛋白酶在突触可塑性和长期记忆巩固中起重要作用，然而，其在药物线索记忆重新巩固中的作用仍不清楚。使用条件性位置偏爱和自我给药程序，我们发现暴露于与药物配对的线索会诱导钙蛋白酶激活并降低伏隔核（NAc）核心中谷氨酸受体相互作用蛋白1（GRIP1）的表达。记忆提取后立即抑制NAc核心中的钙蛋白酶活性会破坏可卡因/吗啡线索记忆的重新巩固，而先前的GRIP1敲低可阻断这种破坏。我们的研究结果表明，钙蛋白酶-GRIP信号对于与药物线索记忆相关的重新稳定过程至关重要，抑制钙蛋白酶活性可能是预防药物复吸的一种新策略。
