Identification of 5-HT2A receptor signaling pathways associated with 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
Nat Commun December 15, 2023 DOI: 10.1038/s41467-023-44016-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male mice |
| Intervention | including β-arrestin-biased ligands |
| Topics | Serotonin |
| Keywords | Psychedelics Hallucinogens Psychoactive compounds Mind-altering substances Brain chemistry Neurobiology Brain research Molecular signaling Psychopharmacology Drug research Drug discovery Receptor interaction Therapeutics Drug development Medical treatments Non-hallucinogenic therapies Novel therapies |
| Citations | 153 |
| Key findings | 5-HT2A-Gq signaling efficacy, not β-arrestin2 recruitment, predicts psychedelic potential in male mice, and β-arrestin-biased agonists can block psychedelic effects. |
Abstract
Abstract 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 transducers, making their respective roles unclear. To elucidate this, we develop 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 recruitment 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 block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT 2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.