Identification of 5-HT 2A Receptor Signaling Pathways Responsible for Psychedelic Potential
Anderson, E. I., Bock, H. A., Bonniwell, E. M., Calkins, M. M., Cao, A. B., Cuccurazzu, B., de Klein, R., Fannana, T., Gamrat, J., Halberstadt, A. L., Heim, A. J., Hennesssey, J. J., Klein, A. K., Lanham, J. K., McCorvy, J. D., Morris, H., Sherwood, A. M., Wallach, J. V., Zauhar, R.
This mice 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
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.