This pre-print mice/cell study investigates the role of 5-HT2A receptor activation in mediating the effects of serotonergic psychedelics. It finds that 5-HT2A-Gq efficacy, not 5-HT2A-β-arrestin2, predicts psychedelic-like potential in male mice, using the head-twitch response (HTR) as a measure. The research also reveals that β-arrestin-biased 5-HT2A receptor agonists have an anti-psychotic-like behavioural profile and can induce receptor downregulation.
Abstract of Identification of 5-HT 2A Receptor Signaling Pathways Responsible for Psychedelic Potential
“Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and β-arrestin2 signaling, making their respective roles unclear. To elucidate this, we developed a series of 5-HT2A-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-β-arrestin2 efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT2A-Gq efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT2A agonists. We also demonstrate that β-arrestin-biased 5-HT2A receptor agonists induce receptor downregulation and tachyphylaxis, and have an anti-psychotic-like behavioral profile. Overall, 5-HT2A receptor signaling can be fine-tuned to generate ligands with properties distinct from classical psychedelics.”
Authors: Jason Wallach, Andrew B. Cao, Maggie M. Calkins, Andrew J. Heim, Janelle K. Lanham, Emma M. Bonniwell, Joseph J. Hennessey, Hailey A. Bock, Emilie I. Anderson, Alexander M. Sherwood, Hamilton Morris, Robbin de Klein, Adam K. Klein, Bruna Cuccurazzu, James Gamrat, Tilka Fannana, Randy Zauhar, Adam L. Halberstadt & John D. McCorvy
Summary of Identification of 5-HT 2A Receptor Signaling Pathways Responsible for Psychedelic Potential
Classical (serotonergic) psychedelics have grown in interest due to their potential to produce rapid and sustained therapeutic effects. However, their hallucinogenic effects may limit their use in some patients.
Serotonergic psychedelics are derived from multiple chemical scaffolds, and activate the 5-HT2A receptor (5-HT2AR), a G protein-coupled receptor (GPCR). Multiple receptors contribute to the behavioural effects of existing psychedelics, and ligand-dependent bias has important implications for drug development and clinical pharmacology.
The authors developed 5-HT2AR-selective ligands acting as biased agonists and utilized these compounds to develop a mechanistic and molecular explanation of biased 5-HT2AR signalling. They also probed the relationship between 5-HT2AR-Gq versus 5-HT2AR- -arrestin activity and psychedelic potential in vivo.
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Identification of 5-HT 2A Receptor Signaling Pathways Responsible for Psychedelic Potential
https://doi.org/10.1101/2023.07.29.551106
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Cite this paper (APA)
Wallach, J., Cao, A. B., Calkins, M. M., Heim, A. J., Lanham, J. K., Bonniwell, E. M., ... & McCorvy, J. D. (2023). Identification of 5-HT2A Receptor Signaling Pathways Responsible for Psychedelic Potential. bioRxiv, 2023-07.