{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:16:11Z","timestamp":1789474571982,"version":"build-2803163510"},"posted":{"date-parts":[[2023,6,5]]},"group-title":"Pharmacology and Toxicology","reference-count":99,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,6,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>There is now evidence from multiple Phase II clinical trials that psychedelic drugs can exert long-lasting anxiolytic, anti-depressant, and anti-drug abuse (nicotine and ethanol) effects in patients. Despite these benefits, the hallucinogenic actions of these drugs at the serotonin 2A receptor (5-HT2AR) limit their clinical use in diverse settings. Activation of the 5-HT2AR can stimulate both G protein and \u03b2-arrestin (\u03b2Arr) -mediated signaling. Lisuride is a G protein biased agonist at the 5-HT2AR and, unlike the structurally-related LSD, the drug does not typically produce hallucinations in normal subjects at routine doses. Here, we examined behavioral responses to lisuride, in wild-type (WT), \u03b2Arr1-KO, and \u03b2Arr2-KO mice. In the open field, lisuride reduced locomotor and rearing activities, but produced a U-shaped function for stereotypies in both \u03b2Arr lines of mice. Locomotion was decreased overall in \u03b2Arr1-KOs and \u03b2Arr2-KOs, relative to WT controls. Incidences of head twitches and retrograde walking to lisuride were low in all genotypes. Grooming was depressed in \u03b2Arr1 mice, but was increased then decreased in \u03b2Arr2 animals with lisuride. Prepulse inhibition (PPI) was unaffected in \u03b2Arr2 mice, whereas 0.5 mg\/kg lisuride disrupted PPI in \u03b2Arr1 animals. The 5-HT2AR antagonist MDL100907 failed to restore PPI in \u03b2Arr1 mice, whereas the dopamine D2\/D3 antagonist raclopride normalized PPI in WTs but not in \u03b2Arr1-KOs. Using vesicular monoamine transporter 2 mice, lisuride reduced immobility times in tail suspension and promoted a preference for sucrose that lasted up to 2 days. Together, it appears \u03b2Arr1 and \u03b2Arr2 play minor roles in lisuride\u2019s actions on many behaviors, while this drug exerts anti-depressant drug-like responses without hallucinogenic-like activities.<\/jats:p>","DOI":"10.1101\/2023.06.01.543310","type":"posted-content","created":{"date-parts":[[2023,6,5]],"date-time":"2023-06-05T12:55:15Z","timestamp":1685969715000},"source":"Crossref","is-referenced-by-count":2,"title":["The G protein biased serotonin 5-HT 2A receptor agonist lisuride exerts anti-depressant drug-like activities in mice"],"prefix":"10.64898","author":[{"given":"Vladimir M.","family":"Pogorelov","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramona M.","family":"Rodriguiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8632-7503","authenticated-orcid":false,"given":"Bryan L.","family":"Roth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3592-7397","authenticated-orcid":false,"given":"William C.","family":"Wetsel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023060812100435000_2023.06.01.543310v1.1","doi-asserted-by":"publisher","DOI":"10.1037\/0735-7044.99.5.881"},{"key":"2023060812100435000_2023.06.01.543310v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2015.03.002"},{"key":"2023060812100435000_2023.06.01.543310v1.3","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5449.2495"},{"key":"2023060812100435000_2023.06.01.543310v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/0166-4328(96)00102-7"},{"key":"2023060812100435000_2023.06.01.543310v1.5","doi-asserted-by":"publisher","DOI":"10.1007\/s002130100810"},{"key":"2023060812100435000_2023.06.01.543310v1.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl8615"},{"key":"2023060812100435000_2023.06.01.543310v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(16)30065-7"},{"key":"2023060812100435000_2023.06.01.543310v1.8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1518377113"},{"key":"2023060812100435000_2023.06.01.543310v1.9","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-017-4771-x"},{"key":"2023060812100435000_2023.06.01.543310v1.10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2032994"},{"key":"2023060812100435000_2023.06.01.543310v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(80)90036-9"},{"key":"2023060812100435000_2023.06.01.543310v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(85)90074-7"},{"key":"2023060812100435000_2023.06.01.543310v1.13","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1021729"},{"key":"2023060812100435000_2023.06.01.543310v1.14","doi-asserted-by":"publisher","DOI":"10.1007\/BF00401509"},{"key":"2023060812100435000_2023.06.01.543310v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2008.07.040"},{"key":"2023060812100435000_2023.06.01.543310v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/s0091-3057(97)00548-0"},{"key":"2023060812100435000_2023.06.01.543310v1.17","doi-asserted-by":"publisher","DOI":"10.1007\/s007020070043"},{"key":"2023060812100435000_2023.06.01.543310v1.18","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2020.3285"},{"key":"2023060812100435000_2023.06.01.543310v1.19","doi-asserted-by":"publisher","DOI":"10.1007\/s002130050585"},{"key":"2023060812100435000_2023.06.01.543310v1.20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.6.2187"},{"key":"2023060812100435000_2023.06.01.543310v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/0091-3057(92)90212-x"},{"key":"2023060812100435000_2023.06.01.543310v1.22","doi-asserted-by":"publisher","DOI":"10.1007\/BF00429666"},{"key":"2023060812100435000_2023.06.01.543310v1.23","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM195412162512504"},{"key":"2023060812100435000_2023.06.01.543310v1.24","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4388-06.2007"},{"key":"2023060812100435000_2023.06.01.543310v1.25","doi-asserted-by":"publisher","DOI":"10.1177\/0269881114555249"},{"key":"2023060812100435000_2023.06.01.543310v1.26","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1999.0722206.x"},{"key":"2023060812100435000_2023.06.01.543310v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(85)90245-9"},{"key":"2023060812100435000_2023.06.01.543310v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2008.06.006"},{"key":"2023060812100435000_2023.06.01.543310v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(83)90464-8"},{"key":"2023060812100435000_2023.06.01.543310v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(84)90436-3"},{"key":"2023060812100435000_2023.06.01.543310v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.01.008"},{"key":"2023060812100435000_2023.06.01.543310v1.32","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2206443"},{"key":"2023060812100435000_2023.06.01.543310v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2023.01.108"},{"key":"2023060812100435000_2023.06.01.543310v1.34","doi-asserted-by":"publisher","DOI":"10.1001\/archneurpsyc.1958.02340020088016"},{"key":"2023060812100435000_2023.06.01.543310v1.35","doi-asserted-by":"publisher","DOI":"10.1177\/0269881116675513"},{"key":"2023060812100435000_2023.06.01.543310v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111211"},{"key":"2023060812100435000_2023.06.01.543310v1.37","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-009-1718-x"},{"key":"2023060812100435000_2023.06.01.543310v1.38","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-013-3006-z"},{"key":"2023060812100435000_2023.06.01.543310v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2019.107933"},{"key":"2023060812100435000_2023.06.01.543310v1.40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1254\/fpj.80.1","article-title":"[Effects of an ergot derivative, lisuride, on the central dopaminergic system \u2013 studies of behavioral pharmacology]","volume":"80","year":"1982","journal-title":"Nihon Yakurigaku Zasshi"},{"key":"2023060812100435000_2023.06.01.543310v1.41","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4610.1977.hed1702054.x"},{"key":"2023060812100435000_2023.06.01.543310v1.42","doi-asserted-by":"publisher","DOI":"10.1007\/BF00427818"},{"key":"2023060812100435000_2023.06.01.543310v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2022.08.025"},{"key":"2023060812100435000_2023.06.01.543310v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(76)90091-1"},{"key":"2023060812100435000_2023.06.01.543310v1.45","doi-asserted-by":"crossref","first-page":"52","DOI":"10.3143\/geriatrics.31.52","article-title":"[Therapeutic effect of lisuride maleate on post-stroke depression","volume":"31","year":"1994","journal-title":"Nihon Ronen Igakkai Zasshi"},{"key":"2023060812100435000_2023.06.01.543310v1.46","first-page":"157","article-title":"International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin)","volume":"46","year":"1994","journal-title":"Pharmacol Rev"},{"key":"2023060812100435000_2023.06.01.543310v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/0091-3057(95)00160-X"},{"key":"2023060812100435000_2023.06.01.543310v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05258-z"},{"key":"2023060812100435000_2023.06.01.543310v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/nature08506"},{"key":"2023060812100435000_2023.06.01.543310v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(00)89032-X"},{"key":"2023060812100435000_2023.06.01.543310v1.51","doi-asserted-by":"publisher","DOI":"10.1186\/s13395-018-0184-8"},{"key":"2023060812100435000_2023.06.01.543310v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.024"},{"key":"2023060812100435000_2023.06.01.543310v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3014"},{"key":"2023060812100435000_2023.06.01.543310v1.54","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.042184"},{"key":"2023060812100435000_2023.06.01.543310v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2015.08.018"},{"key":"2023060812100435000_2023.06.01.543310v1.56","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.44.4.347"},{"key":"2023060812100435000_2023.06.01.543310v1.57","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.32.1.69"},{"key":"2023060812100435000_2023.06.01.543310v1.58","doi-asserted-by":"publisher","DOI":"10.1159\/000284842"},{"key":"2023060812100435000_2023.06.01.543310v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/0091-3057(77)90032-6"},{"key":"2023060812100435000_2023.06.01.543310v1.60","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-002-1141-z"},{"key":"2023060812100435000_2023.06.01.543310v1.61","first-page":"706","article-title":"Mouse locomotor activity: an in vivo test for dopamine autoreceptor activation","volume":"229","year":"1984","journal-title":"J Pharmacol Exp Ther"},{"key":"2023060812100435000_2023.06.01.543310v1.62","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-022-00421-7"},{"key":"2023060812100435000_2023.06.01.543310v1.63","doi-asserted-by":"publisher","DOI":"10.1159\/000115567"},{"key":"2023060812100435000_2023.06.01.543310v1.64","doi-asserted-by":"publisher","DOI":"10.1172\/JCI70678"},{"key":"2023060812100435000_2023.06.01.543310v1.65","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.039867"},{"key":"2023060812100435000_2023.06.01.543310v1.66","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(92)90212-m"},{"key":"2023060812100435000_2023.06.01.543310v1.67","doi-asserted-by":"publisher","DOI":"10.1016\/S0893-133X(01)00282-2"},{"key":"2023060812100435000_2023.06.01.543310v1.68","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2010.02.008"},{"key":"2023060812100435000_2023.06.01.543310v1.69","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410090109"},{"key":"2023060812100435000_2023.06.01.543310v1.70","doi-asserted-by":"publisher","DOI":"10.1007\/BF02244547"},{"key":"2023060812100435000_2023.06.01.543310v1.71","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(96)00454-2"},{"key":"2023060812100435000_2023.06.01.543310v1.72","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4610.1983.hed2303117.x"},{"key":"2023060812100435000_2023.06.01.543310v1.73","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2019.19010035"},{"key":"2023060812100435000_2023.06.01.543310v1.74","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-96736-3"},{"key":"2023060812100435000_2023.06.01.543310v1.75","doi-asserted-by":"publisher","DOI":"10.1177\/0269881116675512"},{"key":"2023060812100435000_2023.06.01.543310v1.76","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(87)90621-7"},{"key":"2023060812100435000_2023.06.01.543310v1.77","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1346"},{"key":"2023060812100435000_2023.06.01.543310v1.78","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(79)92523-6"},{"key":"2023060812100435000_2023.06.01.543310v1.79","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.122.5.509"},{"key":"2023060812100435000_2023.06.01.543310v1.80","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2014.11.015"},{"key":"2023060812100435000_2023.06.01.543310v1.81","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(94)90643-2"},{"key":"2023060812100435000_2023.06.01.543310v1.82","first-page":"101","article-title":"(1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine (5-HT) 2A receptors: modulation by novel 5-HT2A\/2C antagonists, D1 antagonists and 5-HT1A agonists","volume":"273","year":"1995","journal-title":"J Pharmacol Exp Ther"},{"key":"2023060812100435000_2023.06.01.543310v1.83","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000219761.05466.43"},{"key":"2023060812100435000_2023.06.01.543310v1.84","doi-asserted-by":"publisher","DOI":"10.1007\/BF00492209"},{"key":"2023060812100435000_2023.06.01.543310v1.85","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(94)90074-4"},{"key":"2023060812100435000_2023.06.01.543310v1.86","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4610.1978.hed1802075.x"},{"key":"2023060812100435000_2023.06.01.543310v1.87","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.289.6452.1101"},{"key":"2023060812100435000_2023.06.01.543310v1.88","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/114.1.601"},{"key":"2023060812100435000_2023.06.01.543310v1.89","doi-asserted-by":"publisher","DOI":"10.1007\/BF03349379"},{"key":"2023060812100435000_2023.06.01.543310v1.90","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2022.101809"},{"key":"2023060812100435000_2023.06.01.543310v1.91","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301324"},{"key":"2023060812100435000_2023.06.01.543310v1.92","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.104463"},{"key":"2023060812100435000_2023.06.01.543310v1.93","doi-asserted-by":"publisher","DOI":"10.1111\/j.2042-7158.1983.tb04318.x"},{"key":"2023060812100435000_2023.06.01.543310v1.94","doi-asserted-by":"publisher","DOI":"10.1126\/science.1232808"},{"key":"2023060812100435000_2023.06.01.543310v1.95","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.12.033"},{"key":"2023060812100435000_2023.06.01.543310v1.96","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80419-5"},{"key":"2023060812100435000_2023.06.01.543310v1.97","doi-asserted-by":"publisher","DOI":"10.1126\/science.1232807"},{"key":"2023060812100435000_2023.06.01.543310v1.98","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-022-00796-6"},{"key":"2023060812100435000_2023.06.01.543310v1.99","doi-asserted-by":"publisher","DOI":"10.1135\/cccc19601922"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.06.01.543310","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:44:07Z","timestamp":1768452247000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.06.01.543310"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,5]]},"references-count":99,"URL":"https:\/\/doi.org\/10.1101\/2023.06.01.543310","relation":{},"subject":[],"published":{"date-parts":[[2023,6,5]]},"subtype":"preprint"}}