Psilocybin induces acute anxiety and changes in amygdalar phosphopeptides independently from the 5-HT2A receptor

Ram Harari, Ipsita Chatterjee, Dmitriy Getselter, Evan Elliott

Research output: Contribution to journalArticlepeer-review

Abstract

Psilocybin, and its metabolite psilocin, induces psychedelic effects through activation of the 5-HT2A receptor. Psilocybin has been proposed as a treatment for depression and anxiety but sometimes induces anxiety in humans. An understanding of mechanisms underlying the anxiety response will help to better develop therapeutic prospects of psychedelics. In the current study, psilocybin induced an acute increase in anxiety in behavioral paradigms in mice. Importantly, pharmacological blocking of the 5-HT2A receptor attenuates psilocybin-induced head twitch response, a behavioral proxy for the psychedelic response, but does not rescue psilocybin's effect on anxiety-related behavior. Phosphopeptide analysis in the amygdala uncovered signal transduction pathways that are dependent or independent of the 5-HT2A receptor. Furthermore, presynaptic proteins are specifically involved in psilocybin-induced acute anxiety. These insights into how psilocybin may induce short-term anxiety are important for understanding how psilocybin may best be used in the clinical framework.

Original languageEnglish
Article number109686
JournaliScience
Volume27
Issue number5
DOIs
StatePublished - 17 May 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s)

Keywords

  • Behavioral neuroscience
  • Biological sciences
  • Natural sciences
  • Neuroscience
  • Pharmacology

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