Menthol Enhances Nicotine Reward-Related Behavior by Potentiating Nicotine-Induced Changes in nAChR Function, nAChR Upregulation, and DA Neuron Excitability

Henderson, Brandon J.; Wall, Teagan R.; Henley, Beverley M.; Kim, Charlene H.; McKinney, Sheri; Lester, Henry A.

doi:10.1038/npp.2017.72

Cited by 92 publications

(122 citation statements)

References 21 publications

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“…The results of our study in youth suggest that high concentrations of menthol increase the rewarding effects of higher concentrations of nicotine, which we hypothesize could promote the development of nicotine dependence. Consistent with our findings, pre-clinical research has demonstrated that menthol enhances nicotine-induced reward in a conditioned place-preference test in mice (Henderson et al, 2017), perhaps via nicotine-induced upregulation of nicotinic receptors on midbrain dopamine neurons, and can also become a conditioned cue that reinforces nicotine use (Wang et al, 2014). …”

Section: Discussionsupporting

confidence: 90%

Studying the interactive effects of menthol and nicotine among youth: An examination using e-cigarettes

Krishnan‐Sarin

Green

Kong

et al. 2017

Drug and Alcohol Dependence

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Background Tobacco products containing menthol are widely used by youth. We used ecigarettes to conduct an experimental evaluation of the independent and interactive effects of menthol and nicotine among youth. Procedures Pilot chemosensory experiments with fourteen e-cigarette users identified low (barely perceptible, 0.5%) and high (similar to commercial e-liquid, 3.5%) menthol concentrations. Sixty e-cigarette users were randomized to a nicotine concentration (0 mg/ml, 6 mg/ml, 12 mg/ml) and participated in 3 laboratory sessions. During each session, they received their assigned nicotine concentration, along with one of three menthol concentrations in random counterbalanced order across sessions (0, 0.5%, 3.5%), and participated in three fixed-dose, and an ad-lib, puffing period. Urinary menthol glucuronide and salivary nicotine levels validated menthol and nicotine exposure. We examined changes in e-cigarette liking/wanting and taste, coolness, stimulant effects, nicotine withdrawal and ad-lib use. Results Overall, the high concentration of menthol (3.5%) significantly increased e-cigarette liking/wanting relative to no menthol (p<0.001); there was marginal evidence of nicotine* menthol interactions (p=0.06), with an increase in liking/wanting when 3.5% menthol was combined with 12 mg/ml nicotine, but not 6 mg/ml nicotine. Importantly, both 0.5% and 3.5% menthol concentrations significantly improved taste and increased coolness. We did not observe nicotine or menthol-related changes in stimulant effects, nicotine withdrawal symptoms or ad-lib use. Conclusions Menthol, even at very low doses, alters the appeal of e-cigarettes among youth. Further, menthol enhances positive rewarding effects of high nicotine-containing e-cigarettes among youth.

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Section: Discussionsupporting

confidence: 90%

Studying the interactive effects of menthol and nicotine among youth: An examination using e-cigarettes

Krishnan‐Sarin

Green

Kong

et al. 2017

Drug and Alcohol Dependence

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“…Recently, data have emerged to implicate menthol more directly in the underlying neurobiology of nicotine dependence. Menthol binds to and modulates the function of nicotinic acetylcholine receptors (nAChRs) [13] and administration of menthol alone is sufficient to up-regulate midbrain nAChRs in mice, which has somewhat conflicting behavioral effects, either facilitating behaviors related to nicotine addiction [14] or preventing nicotine reward [15]. In human subjects, menthol slows nicotine metabolism [16, 17] and adolescent smokers with slow nicotine metabolism, in contrast to adults, are more likely to progress to addiction [18].…”

Section: Introductionmentioning

confidence: 99%

Menthol disrupts nicotine’s psychostimulant properties in an age and sex-dependent manner in C57BL/6J mice

Fait

Thompson

Mose

et al. 2017

Behavioural Brain Research

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Menthol is a commonly used flavorant in tobacco and e-cigarettes, and could contribute to nicotine sensitivity. To understand how menthol could contribute to nicotine intake and addiction, it is important to determine whether specific mechanisms related to sex and age could underlie behavioral changes induced by menthol-laced nicotinic products. Using a validated paradigm of nicotine-dependent locomotor stimulation, adolescent and adult C57BL/6J mice of both sexes were exposed to nicotine, or nicotine laced with menthol, as their sole source of fluid, and psychostimulant effects were evaluated by recording home cage locomotor activity for ten days. Nicotine and cotinine blood levels were measured following exposure. Results show an interaction between treatment, age, and sex on liquid consumption, indicating that mice responded differently to menthol and nicotine based on their age and sex. Adult male mice greatly increased their nicotine intake when given menthol. In female mice of both age groups, menthol did not have this effect. Despite an increase in nicotine intake promoted by menthol, adult male mice showed a significant decrease in locomotion, suggesting that menthol blunted nicotine-induced psychostimulation. This behavioral response to menthol was not detected in adolescent mice of either sex. These data confirm that menthol is more than a flavorant, and can influence both nicotine intake and its psychostimulant effects. These results suggest that age- and sex-dependent mechanisms could underlie menthol’s influence on nicotine intake and that studies including adolescent and adult menthol smokers of both sexes are warranted.

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“…However, as one of the nAChR-agonists, nicotine could initiate receptor-related pathways, and nicotine aerosol inhalation also induce inflammation [8]. Other chemicals may induce activation of nAChRs, and they may also trigger feedback-loops, similar to flavoring chemicals [17][18][19]. Although the biological structure and function of nAChRs has been well studied, limited information exists on how nAChRs are affected during e-cig induced lung dysregulation processes.…”

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confidence: 99%

E-cigarette-Induced Pulmonary Inflammation and Dysregulated Repair are Mediated by nAChR α7 Receptor

Wang¹,

Sundar²,

Li³

et al. 2020

Preprint

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Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has conducted to understand the mechanism of toxicological and pulmonary effects of e-cigs. We hypothesized that sub-chronic exposure of e-cigs induced inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChR α7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial-cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lungs were collected for determination of inflammatory responses and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased the lung influx of macrophages and T-lymphocytes, and the levels of pro-inflammatory cytokines, while nAChR α7 knockdown blocked the inflammatory responses. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8, and MMP9, in both sex mice were altered at both protein and gene levels when WT mice were exposed to PG alone in a sex-dependent manner. Moreover, MMP12 increased significantly in male mice exposed to PG with or without nicotine in a nAChR α7 dependent manner.Additionally, the abundance of ECM proteins, such as collagen and fibronectin, was significantly altered after sub-chronic e-cig exposure with or without nicotine in a sex-dependent manner, but nAChR α7 independent manner. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChR α7 in a sexdependent manner. electronic cigarette aerosol and inhaled nicotine effects on periodontal and pulmonary tissues. Oral Dis 2017, 23:1052-1057. 3. Kaur G, Muthumalage T, Rahman I: Mechanisms of toxicity and biomarkers of flavoring and flavor enhancing chemicals in emerging tobacco and nontobacco products. Toxicol Lett 2018, 288:143-155.4.

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Menthol Enhances Nicotine Reward-Related Behavior by Potentiating Nicotine-Induced Changes in nAChR Function, nAChR Upregulation, and DA Neuron Excitability

Cited by 92 publications

References 21 publications

Studying the interactive effects of menthol and nicotine among youth: An examination using e-cigarettes

Studying the interactive effects of menthol and nicotine among youth: An examination using e-cigarettes

Menthol disrupts nicotine’s psychostimulant properties in an age and sex-dependent manner in C57BL/6J mice

E-cigarette-Induced Pulmonary Inflammation and Dysregulated Repair are Mediated by nAChR α7 Receptor

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