COMPARISON OF GENE EXPRESSION AFTER SINGLE ADMINISTRATION OF KETAMINE AND PSILOCYBIN IN RATS

Psilocybin and ketamine have recently gained attention for their potential to treat depression, particularly in cases where traditional antidepressants have been ineffective. Ketamine primarily targets NMDA (N-methyl-D-aspartate) glutamate receptors in the brain, thereby affecting normal glutamate signaling producing anesthetic, analgesic, and dissociative effects. Psilocybin, a psychedelic substance, primarily targets the serotonin 5-HT2A receptor, which indirectly modulates excitatory and inhibitory neurotransmission in the brain. Since both substances have rapid antidepressant effects, we hypothesized that despite targeting different receptors, both substances may elicit a convergent long-term effect on neuronal plasticity and gene expression. In this study, we investigated changes in gene expression after administering psilocybin and ketamine. We performed bulk mRNA sequencing on samples from the prefrontal cortex of rats 24 hours after a single treatment with psilocybin, ketamine or a vehicle. Bioinformatic analysis revealed a significant reconfiguration of gene expression in the treated animals that was remarkably similar for both treatments. Specifically, we identified the regulation of genes associated with synaptic plasticity, which is consistent with the induction of the neuroplastic changes underlying the reconfiguration of brain functional networks. We further identified significant regulation of genes associated with myelination after both treatments. Finally, immunohistochemistry revealed changes in the extracellular matrix of the brain, a structure involved in regulating brain plasticity. Taken together, these data provide insight into the convergent molecular mechanisms by which the two treatments promote neural plasticity that is likely to underlie their therapeutic effects.