Identification of 5-HT2A Receptor Signaling Pathways Responsible for Psychedelic Potential

  • bioRxiv. 2023 Jul 31:2023.07.29.551106. doi: 10.1101/2023.07.29.551106.
Jason Wallach  1 ,  Andrew B Cao  2 ,  Maggie M Calkins  2 ,  Andrew J Heim  3 ,  Janelle K Lanham  2 ,  Emma M Bonniwell  2 ,  Joseph J Hennessey  2 ,  Hailey A Bock  2 ,  Emilie I Anderson  2 ,  Alexander M Sherwood  4 ,  Hamilton Morris  1 ,  Robbin de Klein  5 ,  Adam K Klein  6 ,  Bruna Cuccurazzu  6 ,  James Gamrat  1 ,  Tilka Fannana  1 ,  Randy Zauhar  3 ,  Adam L Halberstadt  6  5 ,  John D McCorvy  2
Affiliations
  • 1. Department of Pharmaceutical Sciences, Saint Joseph's University, Philadelphia, Pennsylvania 19104, United States.
  • 2. Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
  • 3. Department of Chemistry, Saint Joseph's University, Philadelphia, Pennsylvania 19104, United States.
  • 4. Usona Institute, Madison, Wisconsin, 53711, United States.
  • 5. Research Service, VA San Diego Healthcare System, San Diego, California 92161, United States.
  • 6. Department of Psychiatry, University of California San Diego, La Jolla, California 92093, United States.
PMID: 37577474 DOI: 10.1101/2023.07.29.551106
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 signaling, making their respective roles unclear. To elucidate this, we developed 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 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 induce receptor downregulation and tachyphylaxis, and have an anti-psychotic-like behavioral profile. Overall, 5-HT2A receptor signaling can be fine-tuned to generate ligands with properties distinct from classical psychedelics.

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