| First Author | Henderson BJ | Year | 2018 |
| Journal | eNeuro | Volume | 5 |
| Issue | 6 | PubMed ID | 30627659 |
| Mgi Jnum | J:288769 | Mgi Id | MGI:6430066 |
| Doi | 10.1523/ENEURO.0465-18.2018 | Citation | Henderson BJ, et al. (2018) Menthol Stereoisomers Exhibit Different Effects on alpha4beta2 nAChR Upregulation and Dopamine Neuron Spontaneous Firing. eNeuro 5(6):ENEURO.0465-18.2018 |
| abstractText | 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 alpha4beta2 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 alpha4beta2 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 alpha4beta2 nAChR function at higher concentrations (>10 microm) 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 (transmembrane M2) 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 ( approximately 25%) more potent than (+)-menthol at inhibiting wild-type alpha4beta2 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, submicromolar 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. |
