Overexpression of miR-9 in the Nucleus Accumbens Increases Oxycodone Self-Administration
Overexpression of miR-9 in the Nucleus Accumbens Increases Oxycodone Self-Administration
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DOI：
10.1093/ijnp/pyz015
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发表时间：
2019-06-01
影响因子：
4.8
通讯作者：
Chartoff, Elena H.
中科院分区：
文献类型：
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作者：
Mavrikaki, Maria;Anastasiadou, Eleni;Chartoff, Elena H.
背景资料：迫切需要确定增加阿片类药物成瘾脆弱性的因素，以帮助遏制阿片类药物流行并开发更有效的药物治疗。MicroRNA是在转录后水平调节基因表达的小的非编码RNA，并且已经涉及人类和啮齿动物模型中的慢性药物服用。最近的证据表明，慢性阿片类药物治疗调节microRNA miR-9。本研究旨在检验延髓核中的miR-9增强羟考酮成瘾样行为的假设。我们利用腺相关病毒（AAV）在雄性大鼠的丘脑核中过表达miR-9，并在1小时的短期接触和6小时的长期接触中测试了对高度滥用的处方阿片类药物羟考酮静脉自我给药的影响，后者导致药物摄入量的增加。在单独的大鼠中，我们评估了核内miR-9过表达对mRNA靶点的影响，包括RE 1沉默转录因子（REST）和多巴胺D2受体（DRD 2），这些靶点已被证明受药物滥用的调节。结果：与表达对照、乱序microRNA的大鼠相比，核内miR-9过表达显著增加了羟考酮自我给药。对羟考酮摄入模式的分析显示，miR-9过表达增加了摄入的“爆发”发作，并缩短了输注间隔。此外，miR-9过表达减少REST的表达，并增加DRD 2在神经核的时间点，符合behavioral effects.Conclusions：这些结果表明，神经核miR-9调节羟考酮成瘾样行为以及参与药物成瘾的基因的表达。
Background: There is an urgent need to identify factors that increase vulnerability to opioid addiction to help stem the opioid epidemic and develop more efficient pharmacotherapeutics. MicroRNAs are small non-coding RNAs that regulate gene expression at a posttranscriptional level and have been implicated in chronic drug-taking in humans and in rodent models. Recent evidence has shown that chronic opioid treatment regulates the microRNA miR-9. The present study was designed to test the hypothesis that miR-9 in the nucleus accumbens potentiates oxycodone addictive-like behavior.Methods: We utilized adeno-associated virus (AAV) to overexpress miR-9 in the nucleus accumbens of male rats and tested the effects on intravenous self-administration of the highly abused prescription opioid, oxycodone, in 1-hour short-access followed by 6-h long-access sessions, the latter of which leads to escalation of drug intake. In separate rats, we assessed the effects of nucleus accumbens miR-9 overexpression on mRNA targets including RE1-silencing transcription factor (REST) and dopamine D2 receptor (DRD2), which have been shown to be regulated by drugs of abuse.Results: Overexpression of miR-9 in the nucleus accumbens significantly increased oxycodone self-administration compared with rats expressing a control, scrambled microRNA. Analysis of the pattern of oxycodone intake revealed that miR-9 overexpression increased "burst" episodes of intake and decreased the inter-infusion interval. Furthermore, miR-9 overexpression decreased the expression of REST and increased DRD2 in the nucleus accumbens at time points that coincided with behavioral effects.Conclusions: These results suggest that nucleus accumbens miR-9 regulates oxycodone addictive-like behavior as well as the expression of genes that are involved in drug addiction.