Sayson Leandro Val, Kim Mikyung, Jeon Se Jin, Custodio Raly James Perez, Lee Hyun Jun, Ortiz Darlene Mae, Cheong Jae Hoon, Kim Hee Jin
Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, Seoul 01795, Republic of Korea.
Department of Chemistry & Life Science, Sahmyook University, Seoul 01795, Republic of Korea.
Biomol Ther (Seoul). 2022 May 1;30(3):238-245. doi: 10.4062/biomolther.2021.184.
Previous reports have demonstrated that genetic mechanisms greatly mediate responses to drugs of abuse, including methamphetamine (METH). The circadian gene Period 2 () has been previously associated with differential responses towards METH in mice. While the behavioral consequences of eliminating have been illustrated previously, overexpression has not yet been comprehensively described; although, -overexpressing ( OE) mice previously showed reduced sensitivity towards METH-induced addiction-like behaviors. To further elucidate this distinct behavior of OE mice to METH, we identified possible candidate biomarkers by determining striatal differentially expressed genes (DEGs) in both drug-naïve and METH-treated OE mice relative to wild-type (WT), through RNA sequencing. Of the several DEGs in drug naïve OE mice, we identified six genes that were altered after repeated METH treatment in WT mice, but not in OE mice. These results, validated by quantitative real-time polymerase chain reaction, could suggest that the identified DEGs might underlie the previously reported weaker METH-induced responses of OE mice compared to WT. Gene network analysis also revealed that , , and are possibly associated with through physical interactions and predicted correlations, and might potentially participate in addiction. Inhibiting the functional protein of prior to METH administration resulted in the partial reduction of METH-induced conditioned place preference in WT mice, supporting a possible involvement of in METH-induced reward. Although encouraging further investigations, our findings suggest that these DEGs, including , may play significant roles in the lower sensitivity of OE mice to METH.
先前的报告表明，遗传机制在很大程度上介导了对包括甲基苯丙胺（METH）在内的滥用药物的反应。昼夜节律基因Period 2（）先前已被证明与小鼠对METH的不同反应有关。虽然先前已经阐述了消除该基因的行为后果，但该基因过表达的情况尚未得到全面描述；尽管过表达（OE）的小鼠先前对METH诱导的成瘾样行为表现出较低的敏感性。为了进一步阐明OE小鼠对METH这种独特的行为，我们通过RNA测序确定了未接触过药物和经METH处理的OE小鼠相对于野生型（WT）小鼠纹状体中的差异表达基因（DEG），从而识别出可能的候选生物标志物。在未接触过药物的OE小鼠的多个DEG中，我们确定了六个基因，这些基因在WT小鼠反复接受METH治疗后发生了改变，但在OE小鼠中未改变。这些结果通过定量实时聚合酶链反应得到验证，这可能表明所识别的DEG可能是先前报道的与WT相比OE小鼠对METH诱导反应较弱的基础。基因网络分析还显示，、和可能通过物理相互作用和预测的相关性与相关联，并可能参与成瘾过程。在给予METH之前抑制的功能蛋白导致WT小鼠中METH诱导的条件性位置偏好部分降低，这支持了可能参与METH诱导的奖赏过程。尽管鼓励进一步研究，但我们的研究结果表明，这些DEG，包括，可能在OE小鼠对METH的较低敏感性中发挥重要作用。
