{"doi":"10.1021/acsptsci.3c00192","title":"Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited","abstract":"Lisuride is a non-psychedelic serotonin (5-HT) 2A receptor (5-HT 2A ) agonist and analogue of the psychedelic lysergic acid diethylamide (LSD). Lisuride also acts as an agonist at the serotonin 1A receptor (5-HT 1A ), a property known to counter psychedelic effects. Here, we tested whether lisuride lacks psychedelic activity due to a dual mechanism: (1) partial agonism at 5-HT 2A and (2) potent agonism at 5-HT 1A . The in vitro effects of lisuride, LSD, and related analogues on 5-HT 2A signaling were characterized by using miniGα q and β-arrestin 2 recruitment assays. The 5-HT 1A - and 5-HT 2A -mediated effects of lisuride and LSD were also compared in male C57BL/6J mice. The in vitro results confirmed that LSD is an agonist at 5-HT 2A, with high efficacy and potency for recruiting miniGα q and β-arrestin 2. By contrast, lisuride displayed partial efficacy for both functional end points (6–52% of 5-HT or LSD E max ) and antagonized the effects of LSD. The mouse experiments demonstrated that LSD induces head twitch responses (HTRs)(ED 50 = 0.039 mg/kg), while lisuride suppresses HTRs (ED 50 = 0.006 mg/kg). Lisuride also produced potent hypothermia and hypolocomotion (ED 50 = 0.008–0.023 mg/kg) that was blocked by the 5-HT 1A antagonist WAY100635 (3 mg/kg). Blockade of 5-HT 1A prior to lisuride restored basal HTRs, but it failed to increase HTRs above baseline levels. HTRs induced by LSD were blocked by lisuride (0.03 mg/kg) or the 5-HT 1A agonist 8-OH-DPAT (1 mg/kg). Overall, our findings show that lisuride is an ultrapotent 5-HT 1A agonist in C57BL/6J mice, limiting its use as a 5-HT 2A ligand in mouse studies examining acute drug effects. Results also indicate that the 5-HT 2A partial agonist-antagonist activity of lisuride explains its lack of psychedelic effects.","journal":"ACS Pharmacology & Translational Science","year":2024,"id":421785,"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":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":460863,"name":"Eline Pottie","orcid":"0000-0002-9077-4055","position":1,"is_corresponding":false},{"id":405573,"name":"John S. Partilla","orcid":null,"position":2,"is_corresponding":false},{"id":460864,"name":"Christophe P. Stove","orcid":"0000-0001-7126-348X","position":3,"is_corresponding":false},{"id":289506,"name":"Michael H. Baumann","orcid":"0000-0001-7758-1470","position":4,"is_corresponding":false},{"id":376730,"name":"Grant C. Glatfelter","orcid":"0000-0003-1011-9083","position":0,"is_corresponding":true}],"reference_count":89,"raw_metadata":null,"created_at":"2026-07-19T01:57:41.370244Z","pmid":"38481684","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":[]}