The psychedelic Psilocybin induces short term anxiety through a different molecular pathway from the psychedelic response

Psilocybin has emerged as a major research interest due to its potential as a treatment for several neuropsychological disorders, in particular anxiety and depression. Psilocybin is known to induce psychedelic and hallucinogenic effects which is mediated by its metabolite psilocin, a non-selective serotonin 5-HT2A receptor agonist, which through modulation of the serotonergic (5-HT) systems leads to regulation of excitatory neurotransmission and gene transcription in the brain. However, there is little knowledge regarding the brain regions, cell types, genes and mechanisms through which psilocybin may affect depression and anxiety related behaviors. The purpose of our study is to investigate how psilocybin affects anxiety and depressive-related behaviors, and how neuronal activity and molecular pathways change in association with behavioral changes. We found that Psilocybin induced an acute increase in anxiety-related behavior in multiple behavioral paradigms in mice. Immunohistochemistry analysis revealed that psilocybin induces a specific activation of neurons in the amygdala. In addition, we found that pharmacological blocking of 5-HT2A receptor attenuates psilocybin-induced head twitch response, a mouse correlate of psychedelic response, but did not rescue psilocybin effect on anxiety-related behavior. We have further performed phosphoprotein analysis in the amygdala to discover signal transduction pathways that are activated by psilocybin either in the presence or absence of the 5-HT2A receptor antagonist. Our data suggests that Psilocybin induces changes in anxiety-related behaviors through a molecular pathway which is distinct from the 5-HT2A psychedelic inducing pathway. These results give important insights into how psilocybin may induce short-term anxiety-causing effects.