Identification of 5-HT2A Receptor Signaling Pathways Responsible for Psychedelic Potential

Wallach, J.; Cao, A. B.; Calkins, M. M.; Heim, A. J.; Lanham, J. K.; Bonniwell, E. M.; Hennessey, J. J.; Bock, H. A.; Anderson, E. I.; Sherwood, A. M.; Morris, H.; de Klein, R.; Klein, A. K.; Cuccurazzu, B.; Gamrat, J.; Fannana, T.; Zauhar, R.; Halberstadt, A. L.; McCorvy, J. D.

doi:10.1101/2023.07.29.551106

bioRxiv · 10.1101/2023.07.29.551106

Identification of 5-HT2A Receptor Signaling Pathways Responsible for Psychedelic Potential

Wallach, J.·Cao, A. B.·Calkins, M. M.·Heim, A. J.·Lanham, J. K.·Bonniwell, E. M.·Hennessey, J. J.·Bock, H. A.·Anderson, E. I.·Sherwood, A. M.·Morris, H.·de Klein, R.·Klein, A. K.·Cuccurazzu, B.·Gamrat, J.·Fannana, T.·Zauhar, R.·Halberstadt, A. L.·McCorvy, J. D.

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Abstract

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and {beta}-arrestin2 signaling, making their respective roles unclear. To elucidate this, we developed a series of 5-HT2A-selective ligands with varying Gq efficacies, including {beta}-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-{beta}-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 {beta}-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.

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Wallach, J., Cao, A. B., Calkins, M. M., Heim, A. J., Lanham, J. K., Bonniwell, E. M., Hennessey, J. J., Bock, H. A., Anderson, E. I., Sherwood, A. M., Morris, H., de Klein, R., Klein, A. K., Cuccurazzu, B., Gamrat, J., Fannana, T., Zauhar, R., Halberstadt, A. L., McCorvy, J. D.. 2023-07-31. Identification of 5-HT2A Receptor Signaling Pathways Responsible for Psychedelic Potential. https://doi.org/10.1101/2023.07.29.551106

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