Identification of 5-HT 2A Receptor Signaling Pathways Responsible for Psychedelic Potential
Jason Wallach, Andrew B. Cao, Maggie M. Calkins, Andrew 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 M. Gamrat, Tilka Fannana, Randy J. Zauhar, Adam L. Halberstadt, John D. Mccorvy
bioRxiv (Cold Spring Harbor Laboratory) July 31, 2023 preprint DOI: 10.1101/2023.07.29.551106 via OpenAlex
Summary
AI-generated from the abstractSerotonergic psychedelics show therapeutic promise, but the specific signaling pathways responsible for their effects have been unclear. Researchers developed a series of 5-HT2A receptor ligands with varying Gq efficacies, including β-arrestin-biased ligands. They found that 5-HT2A-Gq efficacy, not β-arrestin2 efficacy, predicts psychedelic potential, measured by head-twitch response in male mice. Disrupting Gq-PLC signaling reduced this response, and a threshold of Gq activation is needed for psychedelic-like effects, explaining why some partial agonists like lisuride are non-psychedelic. β-arrestin-biased agonists caused receptor downregulation and tachyphylaxis, and showed an anti-psychotic-like profile. This fine-tuning of 5-HT2A signaling can generate ligands distinct from classical psychedelics.
Study at a glance
| Characteristics | Experimental study |
|---|---|
| Population | Male mice |
| Intervention | including β-arrestin-biased ligands |
| Topics | Serotonin |
| Keywords | Arrestin 5-HT Receptor Neuroscience Signal transduction |
| Citations | 11 |
| Key finding | 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.