School of Life Sciences, Arizona State University, Tempe, AZ, USA.
Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Drug Alcohol Depend. 2021 Apr 1;221:108585. doi: 10.1016/j.drugalcdep.2021.108585. Epub 2021 Feb 16.
MicroRNAs (miRNAs) are "master post-transcriptional regulators" of gene expression. Here we investigate miRNAs involved in the incentive motivation for cocaine elicited by exposure to cocaine-associated cues.
We conducted NanoString nCounter analyses of microRNA expression in the nucleus accumbens shell of male rats that had been tested for cue reactivity in a previous study. These rats had been trained to self-administer cocaine while living in isolate housing, then during a subsequent 21-day forced abstinence period they either stayed under isolate housing or switched to environmental enrichment (EE), as this EE intervention is known to decrease cocaine seeking. This allowed us to create groups of "high" and "low" cocaine seekers using a median split of cocaine-seeking behavior.
Differential expression analysis across high- and low-seekers identified 33 microRNAs that were differentially expressed in the nucleus accumbens shell. Predicted mRNA targets of these microRNAs are implicated in synaptic plasticity, neuronal signaling, and neuroinflammation signaling, and many are known addiction-related genes. Of the 33 differentially-expressed microRNAs, 8 were specifically downregulated in the low-seeking group and another set of 8 had expression levels that were significantly correlated with cocaine-seeking behavior.
These findings not only confirm the involvement of previously identified microRNAs (e.g., miR-212, miR-495) but also reveal novel microRNAs (e.g., miR-3557, miR-377) that alter, or are altered by, processes associated with cocaine-seeking behavior. Further research examining the mechanisms involved in these microRNA changes and their effects on signaling may reveal novel therapeutic targets for attenuating drug craving.
microRNAs（miRNAs）是基因表达的“主转录后调控因子”。在这里，我们研究了与可卡因相关线索暴露引起可卡因激发的激励动机相关的 miRNAs。
我们对曾在先前研究中接受线索反应性测试的雄性大鼠伏隔核壳中的 microRNA 表达进行了 NanoString nCounter 分析。这些大鼠被训练在隔离笼中自我给予可卡因，然后在随后的 21 天强制禁欲期间，它们要么继续在隔离笼中，要么切换到环境丰富（EE），因为这种 EE 干预已知会减少可卡因的寻求。这使我们能够使用可卡因寻求行为的中位数分割创建“高”和“低”可卡因寻求者群体。
高和低寻求者之间的差异表达分析确定了 33 种在伏隔核壳中差异表达的 microRNAs。这些 microRNA 的预测 mRNA 靶标涉及突触可塑性、神经元信号和神经炎症信号，并且许多是已知的与成瘾相关的基因。在 33 个差异表达的 microRNAs 中，8 个在低寻求者组中特异性下调，另一组 8 个的表达水平与可卡因寻求行为显著相关。
这些发现不仅证实了先前鉴定的 microRNAs（例如，miR-212、miR-495）的参与，而且还揭示了改变或受与可卡因寻求行为相关的过程改变的新型 microRNAs（例如，miR-3557、miR-377）。进一步研究检查这些 microRNA 变化及其对信号的影响的机制可能会揭示减轻药物渴望的新治疗靶点。
