Faculty Collaboration Database

Identification of 5-HT_2A receptor signaling pathways associated with psychedelic potential. Nat Commun 2023 Dec 15;14(1):8221

Date

12/16/2023

Pubmed ID

38102107

Pubmed Central ID

PMC10724237

DOI

10.1038/s41467-023-44016-1

Scopus ID

2-s2.0-85179903706 (requires institutional sign-in at Scopus site)   18 Citations

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.

Author List

Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, Hennessey JJ, Bock HA, Anderson EI, Sherwood AM, Morris H, de Klein R, Klein AK, Cuccurazzu B, Gamrat J, Fannana T, Zauhar R, Halberstadt AL, McCorvy JD

Author

John McCorvy PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Hallucinogens
Ligands
Male
Mice
Receptor, Serotonin, 5-HT2A
Serotonin
Signal Transduction
beta-Arrestins