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

Author

Listed:
  • 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
    Chemical Computing Group ULC)

  • 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
    Gilgamesh Pharmaceuticals)

  • 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
    Artemis Discovery, LLC)

  • Adam L. Halberstadt

    (Research Service, VA San Diego Healthcare System
    University of California San Diego
    University of California San Diego)

  • John D. McCorvy

    (Medical College of Wisconsin
    Neuroscience Research Center, Medical College of Wisconsin
    Cancer Center, Medical College of Wisconsin)

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.

Suggested Citation

  • 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 & Hamilto, 2023. "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44016-1
    DOI: 10.1038/s41467-023-44016-1
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    References listed on IDEAS

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    1. Jérémy Besnard & Gian Filippo Ruda & Vincent Setola & Keren Abecassis & Ramona M. Rodriguiz & Xi-Ping Huang & Suzanne Norval & Maria F. Sassano & Antony I. Shin & Lauren A. Webster & Frederick R. C. S, 2012. "Automated design of ligands to polypharmacological profiles," Nature, Nature, vol. 492(7428), pages 215-220, December.
    2. Carmen Klein Herenbrink & David A. Sykes & Prashant Donthamsetti & Meritxell Canals & Thomas Coudrat & Jeremy Shonberg & Peter J. Scammells & Ben Capuano & Patrick M. Sexton & Steven J. Charlton & Jon, 2016. "The role of kinetic context in apparent biased agonism at GPCRs," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    3. Lindsay P. Cameron & Robert J. Tombari & Ju Lu & Alexander J. Pell & Zefan Q. Hurley & Yann Ehinger & Maxemiliano V. Vargas & Matthew N. McCarroll & Jack C. Taylor & Douglas Myers-Turnbull & Taohui Li, 2021. "A non-hallucinogenic psychedelic analogue with therapeutic potential," Nature, Nature, vol. 589(7842), pages 474-479, January.
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