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Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward

Henderson, Brandon J. and Wall, Teagan R. and Henley, Beverley M. and Kim, Charlene H. and Nichols, Weston A. and Moaddel, Ruin and Xiao, Cheng and Lester, Henry A. (2016) Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward. Journal of Neuroscience, 36 (10). pp. 2957-2974. ISSN 0270-6474. PMCID PMC4783498. doi:10.1523/JNEUROSCI.4194-15.2016.

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Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nM menthol alone also increased nAChR number and favored the formation of (α4)_3(β2)_2 nAChRs; this contrasts with the action of nicotine itself, which favors (α4)_2(β2)_3 nAChRs. Menthol alone also increases the number of α6β2 receptors that exclude the β3 subunit. Thus, menthol stabilizes lower-sensitivity α4* and α6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Henderson, Brandon J.0000-0003-0381-028X
Xiao, Cheng0000-0001-9649-7450
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2016 the authors. For the first six months after publication SfN’s license will be exclusive. Beginning six months after publication the Work will be made freely available to the public on SfN’s website to copy, distribute, or display under a Creative Commons Attribution 4.0 International (CC BY 4.0) license ( Received Nov. 21, 2015; revised Jan. 19, 2016; accepted Jan. 29, 2016. This work was supported by the National Institutes of Health (NIH; DA017279, DA019375, DA033721, DA036061, DA037161, and DA037743), the National Institute on Aging (NIH) Intramural Research Program, and the California Tobacco-Related Disease Research Program (17RT0127). We thank Michael Marks, Sharon Grady, and Ying Xie for menthol assays. We thank Heather Gold for help with bioinformatics. Author contributions: B.J.H., C.X., and H.A.L. designed research; B.J.H., T.R.W., B.M.H., C.H.K., and W.A.N. performed research; B.J.H., C.H.K., and R.M. contributed unpublished reagents/analytic tools; B.J.H., T.R.W., B.M.H., and W.A.N. analyzed data; B.J.H., B.M.H., C.X., and H.A.L. wrote the paper. The authors declare no competing financial interests.
Funding AgencyGrant Number
National Institute on AgingUNSPECIFIED
California Tobacco-Related Disease Research Program17RT0127
Subject Keywords:dopamine neuron; electrophysiology; menthol; nicotine; nicotinic receptor; reward
Issue or Number:10
PubMed Central ID:PMC4783498
Record Number:CaltechAUTHORS:20160315-105822806
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Official Citation:Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward Brandon J. Henderson, Teagan R. Wall, Beverley M. Henley, Charlene H. Kim, Weston A. Nichols, Ruin Moaddel, Cheng Xiao, and Henry A. Lester The Journal of Neuroscience, 9 March 2016, 36(10):2957-2974; doi:10.1523/JNEUROSCI.4194-15.2016
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:65359
Deposited By: Tony Diaz
Deposited On:15 Mar 2016 18:44
Last Modified:10 Nov 2021 23:44

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