{"doi":"10.1101/2023.07.29.551106","title":"Identification of 5-HT <sub>2A</sub> Receptor Signaling Pathways Responsible for Psychedelic Potential","abstract":"Summary Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT 2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT 2A -Gq/11 and β-arrestin2 signaling, making their respective roles unclear. To elucidate this, we developed a series of 5-HT 2A -selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT 2A -Gq but not 5-HT 2A -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-HT 2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT 2A -Gq efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT 2A agonists. We also demonstrate that β-arrestin-biased 5-HT 2A receptor agonists induce receptor downregulation and tachyphylaxis, and have an anti-psychotic-like behavioral profile. Overall, 5-HT 2A receptor signaling can be fine-tuned to generate ligands with properties distinct from classical psychedelics.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":390416,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9495,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":958170,"name":"Andrew B. Cao","orcid":null,"position":1,"is_corresponding":false},{"id":863460,"name":"Maggie M. Calkins","orcid":"0000-0001-5639-0739","position":2,"is_corresponding":false},{"id":800050,"name":"Andrew Heim","orcid":"0009-0003-0845-6635","position":3,"is_corresponding":false},{"id":1016736,"name":"Janelle K. Lanham","orcid":"0000-0002-0603-4581","position":4,"is_corresponding":false},{"id":1016737,"name":"Emma M. Bonniwell","orcid":"0000-0001-5743-852X","position":5,"is_corresponding":false},{"id":1014006,"name":"Joseph J. Hennessey","orcid":"0000-0003-0981-4695","position":6,"is_corresponding":false},{"id":1017532,"name":"Hailey A. Bock","orcid":null,"position":7,"is_corresponding":false},{"id":229727,"name":"Emilie I. Anderson","orcid":null,"position":8,"is_corresponding":false},{"id":782357,"name":"Alexander M. Sherwood","orcid":"0000-0003-0895-0791","position":9,"is_corresponding":false},{"id":1017533,"name":"Hamilton Morris","orcid":null,"position":10,"is_corresponding":false},{"id":1017534,"name":"Robbin de Klein","orcid":null,"position":11,"is_corresponding":false},{"id":1016738,"name":"Adam K. Klein","orcid":"0000-0002-1640-9324","position":12,"is_corresponding":false},{"id":1016739,"name":"Bruna Cuccurazzu","orcid":"0009-0003-2517-2546","position":13,"is_corresponding":false},{"id":1016740,"name":"James M. Gamrat","orcid":"0000-0003-3863-3340","position":14,"is_corresponding":false},{"id":1017535,"name":"Tilka Fannana","orcid":null,"position":15,"is_corresponding":false},{"id":678975,"name":"Randy J. Zauhar","orcid":"0009-0001-6807-3834","position":16,"is_corresponding":false},{"id":503406,"name":"Adam L. Halberstadt","orcid":"0000-0001-5096-5829","position":17,"is_corresponding":false},{"id":225472,"name":"John D. McCorvy","orcid":"0000-0001-7555-9413","position":18,"is_corresponding":false},{"id":1016734,"name":"Jason Wallach","orcid":"0000-0002-2467-5761","position":0,"is_corresponding":true}],"reference_count":91,"raw_metadata":null,"created_at":"2026-07-19T01:18:37.743462Z","pmid":"37577474","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}