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Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal \u03b15 subunit\u2010containing GABA<jats:sub>A<\/jats:sub> receptors. The purpose of this study is to investigate the effects of tricyclic compounds on \u03b15 subunit\u2010containing receptor subtypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABA<jats:sub>A<\/jats:sub> receptor subtypes by two\u2010electrode voltage\u2010clamp electrophysiology using <jats:styled-content style=\"fixed-case\"><jats:italic>Xenopus laevis<\/jats:italic><\/jats:styled-content> oocytes. Computational structural analysis was employed to design mutated constructs of the \u03b15 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The antipsychotic drugs clozapine and chlorpromazine exerted functional inhibition on multiple GABA<jats:sub>A<\/jats:sub> receptor subtypes, including those containing \u03b15\u2010subunits. Based on a chlorpromazine binding site observed in a GABA\u2010gated bacterial homologue, we identified a novel site in \u03b15 GABA<jats:sub>A<\/jats:sub> receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The chlorpromazine site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABA<jats:sub>A<\/jats:sub> receptor subtypes.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15807","type":"journal-article","created":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T02:53:35Z","timestamp":1643338415000},"page":"3675-3692","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Tricyclic antipsychotics and antidepressants can inhibit \u03b15\u2010containing GABA<sub>A<\/sub> receptors by two distinct mechanisms"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5063-4675","authenticated-orcid":false,"given":"Konstantina","family":"Bampali","sequence":"first","affiliation":[{"name":"Department of Pathobiology of the Nervous System, Center for Brain Research Medical University Vienna  Vienna 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