多巴胺D3受体通过调节小鼠脑核中miR-29c的表达介导天然和甲基苯丙胺奖励

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Rui Wang , Li Zhu , Yunting Fan , Huiqing Du , Wei Han , Fanglin Guan , Yingjie Zhu , Tong Ni , Teng Chen
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引用次数: 0

摘要

多巴胺 D3 受体(D3R)主要局限于脑核(NAc),参与调节自然和药物奖赏;然而,相关过程的分子机制仍不清楚。早先的研究报道了在NAc中表达的D3R和miR-29c同时影响甲基苯丙胺(METH)诱导的奖赏行为和小胶质细胞活化,暗示了在奖赏处理过程中的调节作用。在此,我们对雄性D3R基因敲除小鼠和野生型小鼠的整个NAc进行了病毒操作介导的D3R/miR-29c过表达和抑制,以研究这种潜在的关系。我们使用蔗糖偏好评分、METH 诱导的运动敏化和 METH 诱导的条件性位置偏好测试评估了对奖赏刺激的行为反应。总体而言,我们观察到 D3R 缺陷小鼠对蔗糖和 METH 的行为反应明显降低,同时 NAc 中 miR-29c 的表达下调。D3R缺陷小鼠对这些奖赏刺激的反应减弱主要源于GSK3β活性的降低以及随后NAc中miR-29c的下调。NAc中的小胶质细胞活化介导了D3R-miR-29c缺陷对蔗糖和METH奖赏效应的影响。药物抑制小胶质细胞的活性可以挽救在NAc中缺乏D3R-miR-29c的小鼠的反应减弱。总之,本研究揭示了小鼠NAc中D3R通过miR-29c调节自然奖赏和药物奖赏的机制,突出了NAc D3R-miR-29c通路作为奖赏关键调节因子的作用,并为NAc D3R-miR-29c在编码奖赏体验中的作用提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Dopamine D3 receptor mediates natural and methamphetamine rewards via regulating the expression of miR-29c in the nucleus accumbens of mice

Dopamine D3 receptor mediates natural and methamphetamine rewards via regulating the expression of miR-29c in the nucleus accumbens of mice
The dopamine D3 receptor (D3R), principally confined to the nucleus accumbens (NAc), is involved in regulating natural and drug rewards; however, the molecular mechanisms underlying the associated process remain unclear. Earlier research has reported the concurrent influence of D3R and miR-29c expressed in the NAc on methamphetamine (METH)-induced reward behaviors and microglial activation, hinting at regulatory roles in reward processing. Herein, we performed viral manipulation-mediating D3R/miR-29c overexpression and inhibition in the whole NAc in male D3R knockout and wild-type mice to investigate this potential relationship. Behavioral responses to the rewarding stimuli were assessed using sucrose preference score, METH-induced locomotor sensitization, and METH-induced conditioned place preference tests. Overall, we observed a notable decrease in the behavioral response to sucrose and METH in D3R-deficient mice, accompanied by the downregulation of miR-29c expression in the NAc. Diminished responses to those rewarding stimuli in D3R-deficient mice primarily stemmed from the reduction of GSK3β activity and subsequent down-regulation of miR-29c in the NAc. Microglial activation in the NAc mediates the effect of D3R-miR-29c deficiency on the reward effects of sucrose and METH. Pharmacological suppression of microglial activity rescued the reduced response in mice lacking D3R-miR-29c in the NAc. Overall, this study revealed the mechanism by which D3R regulates both natural and drug rewards via miR-29c in the murine NAc, highlighting the role of the NAc D3R-miR-29c pathway as a critical regulator of rewards, and providing new insights into the role of NAc D3R-miR-29c in encoding rewarding experiences.
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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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