Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential
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 se...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44016-1 |
| _version_ | 1797388189651959808 |
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| author | 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 de Klein Adam K. Klein Bruna Cuccurazzu James Gamrat Tilka Fannana Randy Zauhar Adam L. Halberstadt John D. McCorvy |
| author_facet | 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 de Klein Adam K. Klein Bruna Cuccurazzu James Gamrat Tilka Fannana Randy Zauhar Adam L. Halberstadt John D. McCorvy |
| author_sort | Jason Wallach |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T22:37:10Z |
| format | Article |
| id | doaj.art-30bf5d9d5f33452682a561177a856eb2 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T22:37:10Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-30bf5d9d5f33452682a561177a856eb22023-12-17T12:22:24ZengNature PortfolioNature Communications2041-17232023-12-0114111910.1038/s41467-023-44016-1Identification of 5-HT2A receptor signaling pathways associated with psychedelic potentialJason Wallach0Andrew B. Cao1Maggie M. Calkins2Andrew J. Heim3Janelle K. Lanham4Emma M. Bonniwell5Joseph J. Hennessey6Hailey A. Bock7Emilie I. Anderson8Alexander M. Sherwood9Hamilton Morris10Robbin de Klein11Adam K. Klein12Bruna Cuccurazzu13James Gamrat14Tilka Fannana15Randy Zauhar16Adam L. Halberstadt17John D. McCorvy18Department of Pharmaceutical Sciences, Saint Joseph’s UniversityDepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of WisconsinDepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of WisconsinDepartment of Chemistry, Saint Joseph’s UniversityDepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of WisconsinDepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of WisconsinDepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of WisconsinDepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of WisconsinDepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of WisconsinUsona InstituteDepartment of Pharmaceutical Sciences, Saint Joseph’s UniversityResearch Service, VA San Diego Healthcare SystemDepartment of Psychiatry, University of California San DiegoDepartment of Psychiatry, University of California San DiegoDepartment of Pharmaceutical Sciences, Saint Joseph’s UniversityDepartment of Pharmaceutical Sciences, Saint Joseph’s UniversityDepartment of Chemistry, Saint Joseph’s UniversityResearch Service, VA San Diego Healthcare SystemDepartment of Cell Biology, Neurobiology, and Anatomy, Medical College of WisconsinAbstract 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.https://doi.org/10.1038/s41467-023-44016-1 |
| spellingShingle | 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 de Klein Adam K. Klein Bruna Cuccurazzu James Gamrat Tilka Fannana Randy Zauhar Adam L. Halberstadt John D. McCorvy Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential Nature Communications |
| title | Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential |
| title_full | Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential |
| title_fullStr | Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential |
| title_full_unstemmed | Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential |
| title_short | Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential |
| title_sort | identification of 5 ht2a receptor signaling pathways associated with psychedelic potential |
| url | https://doi.org/10.1038/s41467-023-44016-1 |
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