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Most methadone maintenance treatment patients are smokers, and methadone administration has been shown to increase cigarette smoking. Previous<jats:italic>in vitro<\/jats:italic>studies have shown that methadone is a non\u2010competitive antagonist at rat \u03b13\u03b24 nicotinic acetylcholine receptors (<jats:styled-content style=\"fixed-case\">nAChR<\/jats:styled-content>) and an agonist at human \u03b17<jats:styled-content style=\"fixed-case\">nAChR<\/jats:styled-content>s. In this study, we used cell lines expressing human \u03b14\u03b22, \u03b17 and \u03b13*<jats:styled-content style=\"fixed-case\">nAChR<\/jats:styled-content>s to compare the interactions of methadone at the various human<jats:styled-content style=\"fixed-case\">nAChR<\/jats:styled-content>s under the same experimental conditions. A [<jats:sup>3<\/jats:sup>H]epibatidine displacement assay was used to determine whether methadone binds to the nicotinic receptors, and<jats:sup>86<\/jats:sup>Rb<jats:sup>+<\/jats:sup>efflux and changes in intracellular calcium [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>were used to assess changes in the functional activity of the receptors. Methadone displaced [<jats:sup>3<\/jats:sup>H]epibatidine from nicotinic agonist\u2010binding sites in SH\u2010EP1\u2010h\u03b17 and SH\u2010SY5Y cells, but not in SH\u2010EP1\u2010h\u03b14\u03b22 cells. The<jats:italic>K<\/jats:italic><jats:sub><jats:italic>i<\/jats:italic><\/jats:sub>values for methadone were 6.3\u00a0\u03bcM in SH\u2010EP1\u2010h\u03b17 cells and 19.4\u00a0\u03bcM and 1008\u00a0\u03bcM in SH\u2010SY5Y cells. Methadone increased [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>in all cell lines in a concentration\u2010dependent manner, and in SH\u2010EP1\u2010h\u03b17 cells, the effect was more pronounced than the effect of nicotine treatment. In SH\u2010EP1\u2010h\u03b14\u03b22 cells, the effect of methadone was negligible compared to that of nicotine. Methadone pre\u2010treatment abolished the nicotine\u2010induced response in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>in all cell lines expressing<jats:styled-content style=\"fixed-case\">nAChR<\/jats:styled-content>s. In SH\u2010EP1\u2010h\u03b14\u03b22 and SH\u2010SY5Y cells, methadone had no effect on the<jats:sup>86<\/jats:sup>Rb<jats:sup>+<\/jats:sup>efflux, but it antagonized the nicotine\u2010induced<jats:sup>86<\/jats:sup>Rb<jats:sup>+<\/jats:sup>ion efflux in a non\u2010competitive manner. These results suggest that methadone is an agonist at human \u03b17<jats:styled-content style=\"fixed-case\">nAChR<\/jats:styled-content>s and a non\u2010competitive antagonist at human \u03b14\u03b22 and \u03b13*<jats:styled-content style=\"fixed-case\">nAChR<\/jats:styled-content>s. This study adds further support to the previous findings that opioids interact with<jats:styled-content style=\"fixed-case\">nAChR<\/jats:styled-content>s, which may underlie their frequent co\u2010administration in human beings and might be of interest to the field of drug discovery.<\/jats:p>","DOI":"10.1111\/bcpt.12317","type":"journal-article","created":{"date-parts":[[2014,9,5]],"date-time":"2014-09-05T00:31:39Z","timestamp":1409877099000},"page":"321-328","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Methadone is a Non\u2010Competitive Antagonist at the \u03b14\u03b22 and \u03b13* Nicotinic Acetylcholine Receptors and an Agonist at the \u03b17 Nicotinic Acetylcholine Receptor"],"prefix":"10.1111","volume":"116","author":[{"given":"Reeta","family":"Talka","sequence":"first","affiliation":[{"name":"Division of Pharmacology and Pharmacotherapy Faculty of Pharmacy University of Helsinki Helsinki 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