Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action

Lindsay P. Cameron, Joseph Benetatos, Vern Lewis, Emma M. Bonniwell, Alaina M. Jaster, Rafael Moliner, Eero Castrén, John D. McCorvy, Mikael Palner, Argel Aguilar-Valles*

*Kontaktforfatter

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Abstract

Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2A receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2A receptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1A and 5-HT2C receptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action.

OriginalsprogEngelsk
TidsskriftJournal of Neuroscience
Vol/bind43
Udgave nummer45
Sider (fra-til)7472-7482
ISSN0270-6474
DOI
StatusUdgivet - 8. nov. 2023

Bibliografisk note

Funding Information:
Received July 20, 2023; revised Aug. 13, 2023; accepted Aug. 18, 2023. This work was supported by National Institutes of Health/National Institute of General Medical Sciences R35GM133421 to J.D.M. MITACS accelerate grants IT27497 and IT24847 to A.A.-V. The authors declare no competing financial interests. Correspondence should be addressed to Argel Aguilar-Valles at [email protected]. https://doi.org/10.1523/JNEUROSCI.1384-23.2023 Copyright © 2023 the authors

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