A Caltech Library Service

Menthol stereoisomers exhibit different effects on α4β2 nAChR upregulation and dopamine neuron spontaneous firing

Henderson, Brandon J. and Grant, Stephen and Chu, Betty W. and Shahoei, Rezvan and Huard, Stephanie M. and Saladi, Shyam S. M. and Tajkhorshid, Emad and Dougherty, Dennis A. and Lester, Henry A. (2018) Menthol stereoisomers exhibit different effects on α4β2 nAChR upregulation and dopamine neuron spontaneous firing. eNeuro, 5 (6). Art. No. e0465-18.2018. ISSN 2373-2822. PMCID PMC6325563. doi:10.1523/eneuro.0465-18.2018.

[img] PDF - Published Version
Creative Commons Attribution.


Use this Persistent URL to link to this item:


Menthol contributes to poor cessation rates among smokers, in part because menthol enhances nicotine reward and reinforcement. Mentholated tobacco products contain (−)-menthol and (+)-menthol, in varying proportions. We examined these two menthol stereoisomers for their ability to upregulate α4β2 nAChRs and to alter dopamine neuron firing frequency using long-term, low-dose (≤ 500 nM) exposure that is pharmacologically relevant to smoking. We found that (−)-menthol upregulates α4β2 nAChRs while (+)-menthol does not. We also found that (−)-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 α4β2 nAChR function at higher concentrations (>10 µM) using the Xenopus 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’ position on the TM2 helix. We found that menthol inhibition is dependent on the end-to-end distance of the side chain at the 9’ residue. Additionally, we have found that (−)-menthol is only modestly (∼25%) more potent than (+)-menthol at inhibiting wildtype α4β2 nAChRs and a series of L9’ mutant nAChRs. These data reveal that menthol exhibits a stereoselective effect on nAChRs and that the stereochemical effect is much greater for long-term, sub µM exposure in mice than for acute, higher level exposure. We hypothesize that of the two menthol stereoisomers, only (−)-menthol plays a role in enhancing nicotine reward through nAChRs on dopamine neurons.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Henderson, Brandon J.0000-0003-0381-028X
Grant, Stephen0000-0003-0923-8886
Huard, Stephanie M.0000-0002-2333-1852
Saladi, Shyam S. M.0000-0001-9701-3059
Tajkhorshid, Emad0000-0001-8434-1010
Dougherty, Dennis A.0000-0003-1464-2461
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2019 by the Society for Neuroscience. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. The authors declare no conflict of interest. Funding was provided by National Institutes of Health (NIH) DA036061, DA037161, and DA037743 (HAL); NIH DA033721 and DA040047 (BJH); and Marshall University Research Corporation (BJH); NIH GM104601, NIH GM087519, and NIH GM067887 (RS and ET). Computing resources were provided by Blue Waters at National Center for Supercomputing Applications and Extreme Science and Engineering Discovery Environment (XSEDE) (Grant TG-MCA06N060 to ET). B.J.H, S.G and B.W.C Designates co-first authorship.
Funding AgencyGrant Number
Subject Keywords:cigarettes; electronic nicotine delivery systems; nicotine; nicotine addiction; Xenopus oocyte
Issue or Number:6
PubMed Central ID:PMC6325563
Record Number:CaltechAUTHORS:20190111-101254546
Persistent URL:
Official Citation:Menthol stereoisomers exhibit different effects on α4β2 nAChR upregulation and dopamine neuron spontaneous firing. Brandon J. Henderson, Stephen Grant, Betty W. Chu, Rezvan Shahoei, Stephanie M. Huard, Shyam S. M. Saladi, Emad Tajkhorshid, Dennis A. Dougherty, Henry A. Lester. eNeuro 21 December 2018, ENEURO.0465-18.2018; DOI: 10.1523/ENEURO.0465-18.2018
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:92213
Deposited By: Tony Diaz
Deposited On:12 Jan 2019 05:52
Last Modified:16 Nov 2021 03:48

Repository Staff Only: item control page