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Mentholated tobacco products contain (\u2212)-menthol and (+)-menthol, in varying proportions. We examined these two menthol stereoisomers for their ability to upregulate \u03b14\u03b22 nAChRs and to alter dopamine neuron firing frequency using long-term, low-dose (\u2264500 n<jats:sc>m<\/jats:sc>) exposure that is pharmacologically relevant to smoking. We found that (\u2212)-menthol upregulates \u03b14\u03b22 nAChRs while (+)-menthol does not. We also found that (\u2212)-menthol decreases dopamine neuron baseline firing and dopamine neuron excitability, while (+)-menthol exhibits no effect. We then examined both stereoisomers for their ability to inhibit \u03b14\u03b22 nAChR function at higher concentrations (&gt;10 \u00b5<jats:sc>m<\/jats:sc>) using the<jats:italic>Xenopus<\/jats:italic>oocyte expression system. To probe for the potential binding site of menthol, we conducted flooding simulations and site-directed mutagenesis. We found that menthol likely binds to the 9\u00b4 position on the TM2 (transmembrane M2) helix. We found that menthol inhibition is dependent on the end-to-end distance of the side chain at the 9\u00b4 residue. Additionally, we have found that (\u2212)-menthol is only modestly (\u223c25%) more potent than (+)-menthol at inhibiting wild-type \u03b14\u03b22 nAChRs and a series of L9\u00b4 mutant nAChRs. These data reveal that menthol exhibits a stereoselective effect on nAChRs and that the stereochemical effect is much greater for long-term, submicromolar exposure in mice than for acute, higher-level exposure. We hypothesize that of the two menthol stereoisomers, only (\u2212)-menthol plays a role in enhancing nicotine reward through nAChRs on dopamine neurons.<\/jats:p>","DOI":"10.1523\/eneuro.0465-18.2018","type":"journal-article","created":{"date-parts":[[2018,12,21]],"date-time":"2018-12-21T23:15:10Z","timestamp":1545434110000},"page":"ENEURO.0465-18.2018","source":"Crossref","is-referenced-by-count":20,"title":["Menthol Stereoisomers Exhibit Different Effects on \u03b14\u03b22 nAChR Upregulation and Dopamine Neuron Spontaneous Firing"],"prefix":"10.1523","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0381-028X","authenticated-orcid":false,"given":"Brandon J.","family":"Henderson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0923-8886","authenticated-orcid":false,"given":"Stephen","family":"Grant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty K.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rezvan","family":"Shahoei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2333-1852","authenticated-orcid":false,"given":"Stephanie M.","family":"Huard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyam S. 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