Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin

Psilocybin, the psychoactive compound in magic mushrooms, rapidly alters the activity of genes linked to neuroplasticity, with stronger effects in the prefrontal cortex than in the hippocampus. In rats given a single dose of 0.5–20 mg/kg, psilocybin increased expression of ten genes in the prefrontal cortex (including c-Fos, Fosb, and Nr4a1) and decreased one. In the hippocampus, it increased four genes (e.g., Sgk1, Dusp1) and decreased four others (e.g., Arc, Egr2). Protein levels for three key genes only partly matched the gene activity changes, indicating that measuring gene expression alone may not fully capture the drug's effects. These findings support psilocybin's potential to rapidly promote brain plasticity.

Study at a glance

Abstract

Background: Psilocybin is a serotonergic psychedelic found in “magic mushrooms” with a putative therapeutic potential for treatment-resistant depression, anxiety, obsessive-compulsive disorder, and addiction. In rodents, psilocybin acutely induces plasticity-related immediate early genes in cortical tissue; however, studies into the effects on subcortical regions, of different doses, and the subsequent translation of corresponding proteins are lacking. Methods: We examined the acute effects of a single administration of psilocybin (0.5–20 mg/kg) on the expression of selected genes in the prefrontal cortex and hippocampus. In total, 46 target genes and eight reference genes were assessed using real-time quantitative polymerase chain reaction. Corresponding protein levels of the three most commonly regulated genes were assessed using Western blotting. Results: In the prefrontal cortex, psilocybin increased the expression of Cebpb, c-Fos, Dups1, Fosb, Junb, Iκβ-α, Nr4a1, P11, Psd95, and Sgk1, and decreased the expression of Clk1. In the hippocampus, psilocybin strongly increased the expression of Arrdc2, Dusp1, Iκβ-α, and Sgk1 in a dose-dependent manner, and decreased the expression of Arc, Clk1, Egr2, and Ptgs2. Protein levels of Sgk1, Dusp1, and Iκβ-α showed only partial agreement with transcriptional patterns, stressing the importance of assessing downstream translation when investigating rapid gene responses. Conclusion: The present study demonstrates that psilocybin rapidly induces gene expression related to neuroplasticity, biased towards the prefrontal cortex, compared to the hippocampus. Our findings provide further evidence for the rapid plasticity-promoting effects of psilocybin.