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In this study, we demonstrated significant downregulation of the tRNA\u2010derived small RNA (tsRNA) tRF\u2010M2 (tRF\u20101:32\u2010Gly\u2010GCC\u20102\u2010M2) in the nucleus accumbens (NAc) of rats exposed to methamphetamine self\u2010administration (METH SA). Through bioinformatic prediction and experimental validation via dual\u2010luciferase reporter assays, we identified that dopamine receptor D2 (\n                    <jats:italic>Drd2<\/jats:italic>\n                    ) mRNA is a direct molecular target of tRF\u2010M2. We found that NAc\u2010specific tRF\u2010M2 delivery attenuated reinstatement behaviors in METH SA rats, potentially mediated through downstream Akt\u2010Gsk3\u03b2 signaling cascade and the transcriptional regulator CREB. The antireinstatement effect mirrored the behavioral outcomes observed following\n                    <jats:italic>Drd2<\/jats:italic>\n                    knockdown in the NAc, which similarly showed concomitant changes in phosphorylated Akt (p\u2010Akt) and Gsk3\u03b2 (p\u2010Gsk3\u03b2). These findings show that tRF\u2010M2 regulates\n                    <jats:italic>Drd2<\/jats:italic>\n                    expression via Akt\u2010Gsk3\u03b2\u2010CREB signaling, thereby\u00a0inhibiting\u00a0drug\u2010seeking behavior in addiction models. These results provide valuable mechanistic insights into neuroepigenetic regulation of psychostimulant addiction and identify promising candidates for therapeutic intervention against methamphetamine relapse.\n                  <\/jats:p>","DOI":"10.1111\/nyas.70127","type":"journal-article","created":{"date-parts":[[2025,12,7]],"date-time":"2025-12-07T14:21:18Z","timestamp":1765117278000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["tRF\u2010M2\u2013Regulated Dopamine Receptor D2 Expression Attenuates Methamphetamine Reinstatement Behavior in Rats"],"prefix":"10.1111","volume":"1556","author":[{"given":"Yun","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Afflicted Kangning Hospital of Ningbo University Ningbo University  Ningbo China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingxiao","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Afflicted Kangning Hospital of Ningbo University Ningbo University  Ningbo China"},{"name":"Zhejiang Key Laboratory of Drug Addiction &amp; 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