2. Academic Validation
  3. Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential

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

Affiliations

  • 1 Department of Pharmaceutical Sciences, Saint Joseph's University, Philadelphia, PA, 19104, USA. jwallach@sju.edu.
  • 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. ahalberstadt@health.ucsd.edu.
  • 12 Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA. ahalberstadt@health.ucsd.edu.
  • 13 Center for Psychedelic Research, University of California San Diego, La Jolla, CA, 92093, USA. ahalberstadt@health.ucsd.edu.
  • 14 Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. jmccorvy@mcw.edu.
  • 15 Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. jmccorvy@mcw.edu.
  • 16 Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. jmccorvy@mcw.edu.
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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