Identification of 5-HT 2A Receptor Signaling Pathways Responsible for Psychedelic Potential
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
bioRxiv (Cold Spring Harbor Laboratory) July 31, 2023 preprint DOI: 10.1101/2023.07.29.551106 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Male mice |
| Intervention | including β-arrestin-biased ligands |
| Topics | Serotonin |
| Keywords | Arrestin 5-HT Receptor Signal transduction Tachyphylaxis Pharmacology G protein-coupled receptor Cell biology Biochemistry |
| Citations | 11 |
| Key findings | 5-HT2A-Gq efficacy, but not β-arrestin2 efficacy, predicts psychedelic potential, and β-arrestin-biased agonists produce receptor downregulation and an anti-psychotic-like profile. |
Abstract
Summary Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT 2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT 2A -Gq/11 and β-arrestin2 signaling, making their respective roles unclear. To elucidate this, we developed a series of 5-HT 2A -selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT 2A -Gq but not 5-HT 2A -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-HT 2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT 2A -Gq efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT 2A agonists. We also demonstrate that β-arrestin-biased 5-HT 2A receptor agonists induce receptor downregulation and tachyphylaxis, and have an anti-psychotic-like behavioral profile. Overall, 5-HT 2A receptor signaling can be fine-tuned to generate ligands with properties distinct from classical psychedelics.