Accumulation of NMDA receptors in accumbal neuronal ensembles mediates increased conditioned place preference for cocaine after prolonged withdrawal

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology Pub Date : 2024-03-01 DOI:10.1016/j.pneurobio.2024.102573

Ziqing Huai , Bing Huang , Guanhong He , Haibo Li , Yonghui Liu , Qiumin Le , Feifei Wang , Lan Ma , Xing Liu

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Abstract

Cue-induced cocaine craving gradually intensifies following abstinence, a phenomenon known as the incubation of drug craving. Neuronal ensembles activated by initial cocaine use, are critically involved in this process. However, the mechanisms by which neuronal changes occurring in the ensembles after withdrawal contribute to incubation remain largely unknown. Here we labeled neuronal ensembles in the shell of nucleus accumbens (NAcSh) activated by cocaine conditioned place preference (CPP) training. NAcSh ensembles showed an increasing activity induced by CPP test after 21-day withdrawal. Inhibiting synaptic transmission of NAcSh ensembles suppressed the preference for cocaine paired-side after 21-day withdrawal, demonstrating a critical role of NAcSh ensembles in increased preference for cocaine. The density of dendritic spines in dopamine D1 receptor expressing ensembles was increased after 21-day withdrawal. Moreover, the expression of Grin1, a subunit of the N-methyl-D-aspartate (NMDA) receptor, specifically increased in the NAcSh ensembles after cocaine withdrawal in both CPP and self-administration (SA) mouse models. Targeted knockdown or dysfunction of Grin1 in NAcSh ensembles significantly suppressed craving for cocaine. Our results suggest that the accumulation of NMDA receptors in NAcSh ensembles mediates increased craving for cocaine after prolonged withdrawal, thereby providing potential molecular targets for treatment of drug addiction.

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在长期戒断后，accumbal神经元集合中NMDA受体的积累介导了对可卡因的条件性位置偏好的增加。

线索诱发的可卡因渴求会在戒断后逐渐增强，这种现象被称为药物渴求的潜伏期。最初使用可卡因时激活的神经元集合在这一过程中起着至关重要的作用。然而，戒断后神经元集合中发生的神经元变化是如何导致潜伏现象的，其机制在很大程度上仍不为人所知。在这里，我们标记了由可卡因条件性位置偏好（CPP）训练激活的NAc外壳（NAcSh）中的神经元集合。经过21天的戒断后，可卡因条件性位置偏好（CPP）测试诱导的NAcSh神经元集合的激活程度不断增加。抑制NAcSh集合的突触传递可抑制21天戒断后的可卡因配对偏好，这表明NAcSh集合在可卡因偏好增加中起着关键作用。多巴胺 D1 受体表达集合的树突棘密度在戒断 21 天后有所增加。此外，在CPP和自我给药（SA）小鼠模型中，N-甲基-D-天冬氨酸（NMDA）受体亚基Grin1的表达在可卡因戒断后在NAcSh集合中特异性增加。在 NAcSh 集合中靶向敲除 Grin1 或使其功能失调可显著抑制对可卡因的渴求。我们的研究结果表明，NAcSh集合体中NMDA受体的积累介导了长期戒断后可卡因渴求的增加，从而为治疗药物成瘾提供了潜在的分子靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Progress in Neurobiology 医学-神经科学

CiteScore

12.80

自引率

1.50%

发文量

107

审稿时长

33 days

期刊介绍： Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.