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The ionotropic 5\u2010HT<jats:sub>3<\/jats:sub> receptor mediates immediate but transient spike discharge in human enteric neurons. We studied the role of the metabotropic 5\u2010HT<jats:sub>1P<\/jats:sub>, 5\u2010HT<jats:sub>4<\/jats:sub>, and 5\u2010HT<jats:sub>7<\/jats:sub> receptors to activate human submucous neurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Neuroimaging using the voltage sensitive dye Di\u20108\u2010ANEPPS was performed in submucous plexus preparations from human surgical specimens of the small and large intestine. We synthesized a new, stable 5\u2010HT<jats:sub>1P<\/jats:sub> agonist, 5\u2010benzyloxyhydrazonoindalpine (5\u2010BOHIP).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>5\u2010HT evoked a fast and late\u2010onset spike discharge in enteric neurons. The fast component was blocked by the 5\u2010HT<jats:sub>3<\/jats:sub> receptor antagonist cilansetron, while the remaining sustained response was significantly reduced by the 5\u2010HT<jats:sub>1P<\/jats:sub> receptor antagonist 5\u2010hydroxytryptophanyl\u20105\u2010hydroxytryptophan amide (5\u2010HTP\u2010DP). The newly synthesized 5\u2010HT<jats:sub>1P<\/jats:sub> agonist 5\u2010BOHIP induced a slowly developing, long\u2010lasting activation of submucous neurons, which was blocked by 5\u2010HTP\u2010DP. We could not demonstrate any 5\u2010HT<jats:sub>7<\/jats:sub> receptor\u2010induced spike discharge based on the lack of response to 5\u2010carboxamidotryptamine. Similarly, the 5\u2010HT<jats:sub>4<\/jats:sub> agonists 5\u2010methoxytryptamine and prucalopride evoked no immediate or late\u2010onset spike discharge.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions &amp; Inferences<\/jats:title><jats:p>Our work demonstrated for the first time the presence of functional 5\u2010HT<jats:sub>1P<\/jats:sub> receptors on human submucous neurons. Furthermore, we found no evidence for a role of 5\u2010HT<jats:sub>4<\/jats:sub> or 5\u2010HT<jats:sub>7<\/jats:sub> receptors in the postsynaptic activation of human submucous neurons by 5\u2010HT.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nmo.14380","type":"journal-article","created":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T09:39:22Z","timestamp":1650361162000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Metabotropic 5\u2010HT receptor\u2010mediated effects in the human submucous plexus"],"prefix":"10.1111","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8707-8331","authenticated-orcid":false,"given":"Anita","family":"Annah\u00e1zi","sequence":"first","affiliation":[{"name":"Chair of Human Biology Technical University of Munich  Freising Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas 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