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It displays a unique pattern of receptor interaction, with only weak (partial agonist) activity at dopamine D\n                    <jats:sub>2<\/jats:sub>\n                    receptors, yet more potent agonist activity at the trace amine associated receptor (TAAR1) and 5-hydroxytryptamine 1\u2009A receptor (5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    ). Nonetheless, these observations await independent confirmation and more detailed characterization of the in vitro and in vivo actions of SEP-856 at TAAR1 and 5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    receptors would be instructive. Herein, we employed luminescence complementation technology in heterologous live cell systems, confocal microscopy, voltage clamp electrophysiology, behavioral readouts and TAAR1 knockout (KO) mice to study SEP-856 in further detail. We provide evidence for the ability of SEP-856 to activate TAAR1 at the surface plasma membrane, and show that this interaction results in G\u03b1\n                    <jats:sub>s<\/jats:sub>\n                    recruitment (pEC\n                    <jats:sub>50<\/jats:sub>\n                    : 6.08\u2009\u00b1\u20090.22 E\n                    <jats:sub>MAX<\/jats:sub>\n                    : 96.41%\u2009\u00b1\u200915.26) and by extension, to G-protein inwardly rectifying potassium (GIRK) channel activation. Using TAAR1-KO mice, we find TAAR1 to be indispensable for SEP-856 control of body temperature, baseline locomotion reduction and for \u201cantipsychotic-like\u201d efficacy as characterized by a reversal of dizocilipine (MK-801) mediated disruption of pre-pulse inhibition. Conversely, the inhibition by SEP-856 of MK-801 induced locomotion was unaffected in TAAR1 KO mice. SEP-856 behaved as a low-potency, partial agonist at the 5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    receptor, while it partially inhibited recruitment of D\n                    <jats:sub>2<\/jats:sub>\n                    receptor-coupled G\u03b1 and GIRK by DA and acted as a weak partial agonist with low potency at the same receptor when applied alone. Our findings corroborate and extend previous observations on the molecular substrates engaged by this unique, dual TAAR1\/5-HT\n                    <jats:sub>1A<\/jats:sub>\n                    receptor agonist and potential antipsychotic that could prove to have major advantages in the treatment of schizophrenia and other psychotic disorders.\n                  <\/jats:p>","DOI":"10.1038\/s41386-022-01421-2","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T02:05:31Z","timestamp":1663034731000},"page":"2319-2329","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1\/5-HT1A receptor agonist SEP-363856"],"prefix":"10.1038","volume":"47","author":[{"given":"Marcus","family":"Saarinen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Mantas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Flais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"\u00c5gren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristoffer","family":"Sahlholm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Millan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Svenningsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"1421_CR1","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1093\/schbul\/sby058","volume":"44","author":"FJ Charlson","year":"2018","unstructured":"Charlson FJ, Ferrari AJ, Santomauro DF, Diminic S, Stockings E, Scott JG, et al. 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At that time, he was not involved with the Company. He has no other interests to declare. All other authors do not have anything to disclose. This study was supported by grants from Karolinska Institutet (to MS, PS), Vetenskapsr\u00e5det (to PS, MS, IM, IF, number 2019-01422), Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, John and Lucille van Geest Foundation (to PS) \u00c5hl\u00e9nstiftelsen (to KS, number mB3 h18), Stiftelsen Lars Hiertas Minne (to KS and R\u00c5 grant numbers FO2013-0609 and FO2020-0289), and Magnus Bergvalls stiftelse (to KS and R\u00c5, grant numbers 2018-02980 and 2020-04055). KS is currently a fellow at the Wallenberg Center for Molecular Medicine at Ume\u00e5 University. PS and R\u00c5 are funded by Region Stockholm.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}