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Differentially Expressed Genes in Period 2-Overexpressing Mice Striatum May Underlie Their Lower Sensitivity to Methamphetamine Addiction-Like Behavior

  • Sayson, Leandro Val (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University) ;
  • Kim, Mikyung (Department of Chemistry & Life Science, Sahmyook University) ;
  • Jeon, Se Jin (School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Custodio, Raly James Perez (School of Pharmacy, Jeonbuk National University) ;
  • Lee, Hyun Jun (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University) ;
  • Ortiz, Darlene Mae (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University) ;
  • Cheong, Jae Hoon (School of Pharmacy, Jeonbuk National University) ;
  • Kim, Hee Jin (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University)
  • Received : 2021.12.08
  • Accepted : 2022.01.26
  • Published : 2022.05.01

Abstract

Previous reports have demonstrated that genetic mechanisms greatly mediate responses to drugs of abuse, including methamphetamine (METH). The circadian gene Period 2 (Per2) has been previously associated with differential responses towards METH in mice. While the behavioral consequences of eliminating Per2 have been illustrated previously, Per2 overexpression has not yet been comprehensively described; although, Per2-overexpressing (Per2 OE) mice previously showed reduced sensitivity towards METH-induced addiction-like behaviors. To further elucidate this distinct behavior of Per2 OE mice to METH, we identified possible candidate biomarkers by determining striatal differentially expressed genes (DEGs) in both drug-naïve and METH-treated Per2 OE mice relative to wild-type (WT), through RNA sequencing. Of the several DEGs in drug naïve Per2 OE mice, we identified six genes that were altered after repeated METH treatment in WT mice, but not in Per2 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 Per2 OE mice compared to WT. Gene network analysis also revealed that Asic3, Hba-a1, and Rnf17 are possibly associated with Per2 through physical interactions and predicted correlations, and might potentially participate in addiction. Inhibiting the functional protein of Asic3 prior to METH administration resulted in the partial reduction of METH-induced conditioned place preference in WT mice, supporting a possible involvement of Asic3 in METH-induced reward. Although encouraging further investigations, our findings suggest that these DEGs, including Asic3, may play significant roles in the lower sensitivity of Per2 OE mice to METH.

Keywords

Acknowledgement

This work was supported by the Ministry of Food and Drug Safety (19182MFDS410) and the National Research Foundation of Korea (2020R1F1A1075633 and 20211R1G1A1093620).

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