Kou Xiaolin, Xian Jiayun, Huang Zhenquan, Tao Yan, Lin Yuhui, Qin Cheng, Wu Haiyin, Chang Lei, Luo Chunxia, Zhu Dongya
Cereb Cortex. 2022 Jan 22;32(3):569-582. doi: 10.1093/cercor/bhab234.
Drug abuse is a dramatic challenge for the whole society because of high relapse rate. Environmental cues are crucial for the preference memory of drug abuse. Extinction therapy has been developed to inhibit the motivational effect of drug cues to prevent the reinstatement of morphine abuse. However, extinction therapy alone only forms a new kind of unstable inhibitory memory. We found that morphine conditioned place preference (CPP) extinction training increased the association of nitric oxide synthase (nNOS) with its carboxy-terminal PDZ ligand (CAPON) in the dorsal hippocampus (dHPC) significantly and blocking the morphine-induced nNOS-CAPON association using Tat-CAPON-12C during and after extinction training reversed morphine-induced hippocampal neuroplasticity defect and prevented the reinstatement and spontaneous recovery of morphine CPP. Moreover, in the hippocampal selective ERK2 knock-out or nNOS knockout mice, the effect of Tat-CAPON-12C on the reinstatement of morphine CPP and hippocampal neuroplasticity disappeared, suggesting ERK2 is necessary for the effects of Tat-CAPON-12C. Together, our findings suggest that nNOS-CAPON interaction in the dHPC may affect the consolidation of morphine CPP extinction and dissociating nNOS-CAPON prevents the reinstatement and spontaneous recovery of morphine CPP, possibly through ERK2-mediated neuroplasticity and extinction memory consolidation, offering a new target to prevent the reinstatement of drug abuse.
由于高复发率，药物滥用对整个社会来说是一个严峻的挑战。环境线索对药物滥用的偏好记忆至关重要。消退疗法已被开发出来，以抑制药物线索的动机效应，防止吗啡滥用的复吸。然而，单独的消退疗法只形成了一种新的不稳定的抑制性记忆。我们发现，吗啡条件性位置偏爱（CPP）消退训练显著增加了背侧海马体（dHPC）中一氧化氮合酶（nNOS）与其羧基末端PDZ配体（CAPON）的关联，并且在消退训练期间和之后使用Tat-CAPON-12C阻断吗啡诱导的nNOS-CAPON关联可逆转吗啡诱导的海马神经可塑性缺陷，并防止吗啡CPP的复吸和自发恢复。此外，在海马体选择性ERK2基因敲除或nNOS基因敲除小鼠中，Tat-CAPON-12C对吗啡CPP复吸和海马神经可塑性的作用消失，这表明ERK2对于Tat-CAPON-12C的作用是必需的。总之，我们的研究结果表明，dHPC中的nNOS-CAPON相互作用可能会影响吗啡CPP消退的巩固，而解离nNOS-CAPON可防止吗啡CPP的复吸和自发恢复，可能是通过ERK2介导的神经可塑性和消退记忆巩固，为预防药物滥用的复吸提供了一个新靶点。
