Identification of 5-HT 2A receptor signaling pathways associated with psychedelic potential

• Published in: Nature communications 2023-12, Vol.14 (1), p.8221
• Main Authors: Wallach, Jason, Cao, Andrew B, Calkins, Maggie M, Heim, Andrew J, Lanham, Janelle K, Bonniwell, Emma M, Hennessey, Joseph J, Bock, Hailey A, Anderson, Emilie I, Sherwood, Alexander M, Morris, Hamilton, de Klein, Robbin, Klein, Adam K, Cuccurazzu, Bruna, Gamrat, James, Fannana, Tilka, Zauhar, Randy, Halberstadt, Adam L, McCorvy, John D
• Format: Article
• Language: English
• Subjects: Animals; beta-Arrestins; Hallucinogens - pharmacology; Ligands; Male; Mice; Receptor, Serotonin, 5-HT2A; Serotonin; Signal Transduction
• ISSN: 2041-1723
• DOI: 10.1038/s41467-023-44016-1

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT -Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT -selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT -Gq but not 5-HT -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 partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT agonists. We also demonstrate that β-arrestin-biased 5-HT receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.