biostudies-literatureGlatfelter GCIntramural NIH HHSNational Institute on Drug Abuse641-653https://www.ebi.ac.uk/biostudies/studies/S-EPMC10928901biostudies-literatureUnknown7(3)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 <i>in vitro</i> 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 <i>in vitro</i> 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 <i>E</i>_max) and antagonized the effects of LSD. The mouse experiments demonstrated that LSD induces head twitch responses (HTRs)(ED₅₀ = 0.039 mg/kg), while lisuride suppresses HTRs (ED₅₀ = 0.006 mg/kg). Lisuride also produced potent hypothermia and hypolocomotion (ED₅₀ = 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.ACS pharmacology & translational scienceComparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited.PMC10928901DA000522-13Z01 DA000522Baumann MHPottie EGlatfelter GCPartilla JSStove CPfalseComparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited.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 <i>in vitro</i> 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 <i>in vitro</i> 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 <i>E</i>_max) and antagonized the effects of LSD. The mouse experiments demonstrated that LSD induces head twitch responses (HTRs)(ED₅₀ = 0.039 mg/kg), while lisuride suppresses HTRs (ED₅₀ = 0.006 mg/kg). Lisuride also produced potent hypothermia and hypolocomotion (ED₅₀ = 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.2024-01-01T00:00:00Z2024 Mar2025-04-05T11:34:22.304Z2025-04-05T11:34:22.304ZS-EPMC109289013848168410.1021/acsptsci.3c00192