Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential

  • Nat Commun. 2023 Dec 15;14(1):8221. doi: 10.1038/s41467-023-44016-1.
Jason Wallach  1 ,  Andrew B Cao  2 ,  Maggie M Calkins  2 ,  Andrew J Heim  3  4 ,  Janelle K Lanham  2 ,  Emma M Bonniwell  2 ,  Joseph J Hennessey  2 ,  Hailey A Bock  2 ,  Emilie I Anderson  2 ,  Alexander M Sherwood  5 ,  Hamilton Morris  6 ,  Robbin de Klein  7 ,  Adam K Klein  8  9 ,  Bruna Cuccurazzu  8 ,  James Gamrat  6 ,  Tilka Fannana  6 ,  Randy Zauhar  3  10 ,  Adam L Halberstadt  11  12  13 ,  John D McCorvy  14  15  16
Affiliations
  • 1. Department of Pharmaceutical Sciences, Saint Joseph's University, Philadelphia, PA, 19104, USA. [email protected].
  • 2. Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
  • 3. Department of Chemistry, Saint Joseph's University, Philadelphia, PA, 19104, USA.
  • 4. Chemical Computing Group ULC, 910-1010 Sherbrooke W, Montréal, QC, H3A 2R7, Canada.
  • 5. Usona Institute, Madison, WI, 53711, USA.
  • 6. Department of Pharmaceutical Sciences, Saint Joseph's University, Philadelphia, PA, 19104, USA.
  • 7. Research Service, VA San Diego Healthcare System, San Diego, CA, 92161, USA.
  • 8. Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA.
  • 9. Gilgamesh Pharmaceuticals, New York, NY, 10003, USA.
  • 10. Artemis Discovery, LLC, Suite 300, 709 N 2nd Street, Philadelphia, PA, 19123, USA.
  • 11. Research Service, VA San Diego Healthcare System, San Diego, CA, 92161, USA. [email protected].
  • 12. Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA. [email protected].
  • 13. Center for Psychedelic Research, University of California San Diego, La Jolla, CA, 92093, USA. [email protected].
  • 14. Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. [email protected].
  • 15. Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. [email protected].
  • 16. Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. [email protected].
PMID: 38102107 DOI: 10.1038/s41467-023-44016-1
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.

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