Depressive DisordersPsilocybin

Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

Psilocybin produces rapid antidepressant-like behavioural effects and enhances synaptic connectivity in mouse brain regions involved in reward and emotion. These therapeutic and synaptic actions occur despite blockade of prohallucinatory 5‑HT2A receptors, suggesting antidepressant mechanisms can be dissociated from its perceptual effects.

Authors

  • Hesselgrave, N.
  • Troppoli, T. A.
  • Wulff, A. B.

Published

PNAS
individual Study

Abstract

Significance Psychedelic compounds, such as psilocybin, have beneficial actions in several psychiatric diseases. They also produce strong alterations of consciousness, which may be a barrier to their widespread use. We found that psilocybin has fast-acting antidepressant-like properties in mice. Using multiple assays of hedonic behavior and an antagonist of prohallucinatory 5-HT2A receptors, we further suggest that altered perception may not be necessary for its therapeutic actions. We also showed that psilocybin strengthens connections between brain cells in regions important for processing rewards and emotions. These experiments suggest that it may be possible to retain the beneficial actions of psilocybin while minimizing the alterations in consciousness, thereby accelerating its use in the clinic.

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Research Summary of 'Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice'

Introduction

Depression is common and often treatment-resistant, and there is growing clinical evidence that the psychedelic compound psilocybin produces rapid and sustained antidepressant effects in humans. Psilocin, the active metabolite of psilocybin, is a potent agonist at multiple serotonin receptors, and the intense alterations of perception caused by psilocybin in humans have been linked to activation of the serotonin 2A receptor (5-HT2AR). A widespread assumption in the field is that these perceptual or ‘‘psychedelic’’ effects are necessary for therapeutic benefit, but that hypothesis has not been directly tested in humans or preclinical models. Hesselgrave and colleagues therefore tested whether a single dose of psilocybin produces antidepressant-like effects in a validated mouse model of stress-induced anhedonia and, crucially, whether those effects require 5-HT2R activation. They used behavioural assays of hedonic state together with electrophysiological measures of synaptic strength, and included pharmacological blockade of 5-HT2A/2C receptors with ketanserin as a functional test of the necessity of 5-HT2R-mediated psychedelic actions for any observed antidepressant-like outcomes.

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Study Details

  • Study Type
    individual
  • Journal
    PNAS
  • Compound
    Psilocybin
  • Topic
    Depressive Disorders
  • APA Citation

    Hesselgrave, N., Troppoli, T. A., Wulff, A. B., Cole, A. B., & Thompson, S. M. (2021). Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proceedings of the National Academy of Sciences, 118(17). https://doi.org/10.1073/pnas.2022489118

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