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 Klein, Adam K. Klein, Bruna Cuccurazzu, James Gamrat, Tilka Fannana, Randy Zauhar, Adam L. Halberstadt () and John D. McCorvy ()
Additional contact information
Jason Wallach: Saint Joseph’s University
Andrew B. Cao: Medical College of Wisconsin
Maggie M. Calkins: Medical College of Wisconsin
Andrew J. Heim: Saint Joseph’s University
Janelle K. Lanham: Medical College of Wisconsin
Emma M. Bonniwell: Medical College of Wisconsin
Joseph J. Hennessey: Medical College of Wisconsin
Hailey A. Bock: Medical College of Wisconsin
Emilie I. Anderson: Medical College of Wisconsin
Alexander M. Sherwood: Usona Institute
Hamilton Morris: Saint Joseph’s University
Robbin Klein: Research Service, VA San Diego Healthcare System
Adam K. Klein: University of California San Diego
Bruna Cuccurazzu: University of California San Diego
James Gamrat: Saint Joseph’s University
Tilka Fannana: Saint Joseph’s University
Randy Zauhar: Saint Joseph’s University
Adam L. Halberstadt: Research Service, VA San Diego Healthcare System
John D. McCorvy: Medical College of Wisconsin

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT2A-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-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-HT2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT2A Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT2A agonists. We also demonstrate that β-arrestin-biased 5-HT2A receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-44016-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44016-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-44016-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().