id_988. LONG-TERM ADMINISTRATION OF LOW DOSES OF PSILOCYBIN CAUSES EPIGENETIC CHANGES IN THE RAT MEDIAL PREFRONTAL CORTEX.
Agnieszka Wawrzczak-Bargieła, Małgorzata Jelonek-Kozioł, Weronika Kumorek, Korneliusz Banaś, Wiktor Bilecki, Marzena Maćkowiak
Department of Pharmacology and Brain Biostructure, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland
INTRODUCTION: Psychedelics have gained attention as potential treatments for depression, anxiety, PTSD, and substance use disorders. Compounds such as LSD, mescaline, ayahuasca, and psilocybin act mainly via 5-HT2A receptor activation, a key mediator of cortical signaling and neuroplasticity. A high-dose of psilocybin produces rapid antidepressant effects but may induce side effects. Low-dose of psilocybin “microdosing” may improve cognition and behavior while minimizing adverse effects, yet its molecular mechanisms remain unclear.
AIM(S): We examined whether psilocybin microdosing induces adaptive epigenetic changes in the rat medial prefrontal cortex (mPFC) of rats related to plasticity mechanisms.
METHOD(S): Male Wistar Han rats received psilocybin (0.05 mg/kg, s.c.) every 2 days for 21 days. Behavioral assessments included Acoustic Startle Response (ASR) and Novel Object Recognition (NOR) tests. Molecular analyses of the mPFC were performed 1 day or 8 days after the final dose, measuring total histone H3, acetylated H3K9/H3K27, BRD4/pBRD4, and HDAC2/HDAC4 using Western blot, PCR, and immunohistochemistry.
RESULTS: Psilocybin microdosing did not impair ASR or NOR and slightly increased novel object exploration,suggesting enhanced exploratory behavior.1 day post-treatment, H3K9ac and pBRD4 were elevated,with upregulation of Arc/Bdnf,indicating transient chromatin opening and increased transcription.Total BRD4 decreased,HDAC4 increased.By day 8, H3K9ac,pBRD4, and Arc/Bdnf normalized, whereas HDAC2 and total BRD4 remained reduced. 5-HT2A receptor levels were elevated, reflecting long-term transcriptional and serotonergic remodeling.
CONCLUSIONS: Repeated low-doses of psilocybin induces long lasting epigenetic adaptations without cognitive impairments. It triggers the two-phase molecular responses, with transient activation of plasticity genes (Arc/Bdnf) and enduring changes in HDAC2, BRD4, and 5-HT2A receptor, highlighting the role of epigenetic regulation in persistent cellular and serotonergic adaptations.
FINANCIAL SUPPORT: The research was funded by the National Science Center, Poland, grant 2024/08/B/NZ7/00930