Menthol Enhances Nicotine Reward-Related Behavior by Potentiating Nicotine-Induced Changes in nAChR Function, nAChR Upregulation, and DA Neuron Excitability.
ABSTRACT: Understanding why the quit rate among smokers of menthol cigarettes is lower than non-menthol smokers requires identifying the neurons that are altered by nicotine, menthol, and acetylcholine. Dopaminergic (DA) neurons in the ventral tegmental area (VTA) mediate the positive reinforcing effects of nicotine. Using mouse models, we show that menthol enhances nicotine-induced changes in nicotinic acetylcholine receptors (nAChRs) expressed on midbrain DA neurons. Menthol plus nicotine upregulates nAChR number and function on midbrain DA neurons more than nicotine alone. Menthol also enhances nicotine-induced changes in DA neuron excitability. In a conditioned place preference (CPP) assay, we observed that menthol plus nicotine produces greater reward-related behavior than nicotine alone. Our results connect changes in midbrain DA neurons to menthol-induced enhancements of nicotine reward-related behavior and may help explain how smokers of menthol cigarettes exhibit reduced cessation rates.
Project description:OBJECTIVES:Menthol, a flavoring agent, is found in approximately 90% of cigarettes, but at much higher levels in menthol than non-menthol cigarettes. Menthol is reportedly included in cigarettes for its cooling and soothing effects, but also additional actions that affect smokers' receipt and processing of nicotine. In this study we investigated the response to short-term abstinence and acute nicotine delivery in menthol-preferring and non-menthol-preferring smokers. METHODS:Nicotine dependent participants (N = 134) participated in an intravenous nicotine delivery session following overnight smoking abstinence. Participants were intravenously administered a placebo and 2 escalating nicotine doses. We compare subjective and physiological responses to nicotine and smoking urges, withdrawal, and cognitive performance following overnight abstinence and post-nicotine between regular 'menthol' smokers and 'non-menthol' cigarette smokers. RESULTS:Relative to non-menthol-preferring smokers, menthol-preferring smokers re a smaller reduction in smoking urges from overnight abstinence baseline to post-nicotine end-of-session and rated less subjective differences between nicotine doses. CONCLUSIONS:Differences between menthol-preferring and non-menthol-preferring smokers' responses to abstinence or acute nicotine could reflect pre-existing individual differences that may have in initial development of menthol preferences, or could have arisen secondarily to pro use of menthol versus non-menthol cigarettes.
Project description:<h4>Introduction</h4>Because 30% of cigarettes sold in the United States are characterized as menthol cigarettes, it is important to understand how menthol preference may affect the impact of a nicotine reduction policy.<h4>Methods</h4>In a recent trial, non-treatment-seeking smokers were randomly assigned to receive very low nicotine cigarettes (VLNC; 0.4 mg nicotine/g tobacco) or normal nicotine cigarettes (NNC; 15.5 mg/g) for 20 weeks. On the basis of preference, participants received menthol or non-menthol cigarettes. We conducted multivariable regression analyses to examine whether menthol preference moderated the effects of nicotine content on cigarettes per day (CPD), breath carbon monoxide (CO), urinary total nicotine equivalents (TNE), urinary 2-cyanoethylmercapturic acid (CEMA), and abstinence.<h4>Results</h4>At baseline, menthol smokers (n = 346) reported smoking fewer CPD (14.9 vs. 19.2) and had lower TNE (52.8 vs. 71.6 nmol/mg) and CO (17.7 vs. 20.5 ppm) levels than non-menthol smokers (n = 406; ps < .05). At week 20, significant interactions indicated that menthol smokers had smaller treatment effects than non-menthol smokers for CPD (-6.4 vs. -9.3), TNE (ratio of geometric means, 0.22 vs. 0.10) and CEMA (ratio, 0.56 vs. 0.37; ps < .05), and trended toward a smaller treatment effect for CO (-4.5 vs. -7.3 ppm; p = .06). Odds ratios for abstinence at week 20 were 1.88 (95% confidence interval [CI] = 0.8 to 4.4) for menthol and 9.11 (95% CI = 3.3 to 25.2) for non-menthol VLNC smokers (p = .02) relative to the NNC condition.<h4>Conclusions</h4>Although menthol smokers experienced reductions in smoking, toxicant exposure, and increases in quitting when using VLNC cigarettes, the magnitude of change was smaller than that observed for non-menthol smokers.<h4>Implications</h4>Results of this analysis suggest that smokers of menthol cigarettes may respond to a nicotine reduction policy with smaller reductions in smoking rates and toxicant exposure than would smokers of non-menthol cigarettes.
Project description:INTRODUCTION:Characterizing flavors are widely available in e-cigarettes and motivate initiation and continued use. Flavors may enhance appeal and facilitate development of addiction to tobacco products through modulation of tobacco products' reinforcing or aversive actions. Palatable flavors (eg, fruit) may increase appeal through primary reinforcing properties. Menthol's cooling and anesthetic effects may increase appeal by counteracting nicotine's aversive effects. Genetics provide a method for modeling individual differences in sensitivity to nicotine's effects. A common polymorphism, rs16969968, encoded in the ?5 nicotinic acetylcholine receptor subunit gene (CHRNA5), is a well-recognized marker for smoking risk and reduces sensitivity to nicotine aversiveness. METHODS:This pilot study tested how flavors impacted e-cigarette appeal and self-administration. In a single testing day, cigarette smokers (N = 32; 94% menthol-smokers) self-administered e-cigarettes containing e-liquids differing in nicotine level (0 mg/mL, 24 mg/mL) and flavor (unflavored, menthol, fruit-flavored) within directed and ad libitum e-cigarette paradigms. Subjective drug effects, number of puffs, rs16969968 genotype, plasma nicotine, and menthol glucuronide levels were collected. RESULTS:Menthol partially ameliorated nicotine aversiveness; fruit did not. In nicotine's absence, fruit flavor increased self-reported preference and ad libitum use relative to menthol-containing or unflavored e-liquids. Individuals with high-smoking-risk rs16969968 genotype (N = 7) reported greater craving alleviation following directed administration of nicotine-containing e-liquids, showed a trend rating nicotine-containing e-liquids as less harsh, and self-administered more nicotine during ad libitum compared to individuals with low-smoking-risk genotype (N = 23). CONCLUSIONS:While menthol countered aversiveness of nicotine-containing e-liquids, fruit flavor increased appeal of nicotine-free e-liquids. These preliminary findings suggest menthol and fruit flavor increase e-cigarettes' appeal through distinct mechanisms. IMPLICATIONS:This study provides a detailed characterization of the effects of flavors (unflavored, menthol, fruit), nicotine (0 mg/mL, 24 mg/mL) and their interactions on the subjective drug effects and ad libitum self-administration of e-cigarettes. Genetics were used to assess these effects in higher-smoking-risk (diminished sensitivity to nicotine aversiveness) and lower-risk groups. Findings could inform impact of regulation of flavors or nicotine in e-cigarettes, and their impacts on vulnerable sub-populations.
Project description:Objectives:In this study, we investigated potential effects of being a menthol smoker on response to reduced nicotine content (RNC) cigarettes in smokers especially vulnerable to smoking. Method:Participants were 169 smokers (61 menthol and 108 non-menthol smokers) with comorbid mental illness, substance use disorder, or socioeconomic disadvantage. Participants completed a double-blind study assessing addiction potential, withdrawal/craving, and compensatory smoking across 4 research cigarettes varying in nicotine content from very low levels to commercial levels (0.4, 2.4, 5.2, 15.8mg/g of tobacco). Repeated measures analysis of variance was used to examine potential moderating effects of menthol status. Results:Statistically significant effects of nicotine dose were noted across measures, with higher doses producing greater economic demand and relief from withdrawal/craving. The relationships between nicotine dose and response to RNC cigarettes do not differ by menthol status. Conclusions:Results of this study suggest menthol does not have a differential impact on response to RNC cigarettes across measures of economic demand, withdrawal/craving, or smoking topography. These results suggest that any potential beneficial effects of RNC cigarettes should extend to menthol smokers including those especially vulnerable to smoking.
Project description:<h4>Background</h4>Menthol cigarettes appeal to adolescents because they mask the harsh taste and sensation of tobacco smoke thereby making it easier to inhale the smoke. As a result, menthol cigarette users expose themselves to higher levels of nicotine relative to non-menthol cigarettes and increase their risk for developing nicotine dependence. We examined whether adolescent menthol smokers (vs. non-menthol smokers) reported higher nicotine dependence.<h4>Methods</h4>Data were from adolescent past 30-day cigarette smokers participating in Wave 2 of the Population Assessment of Tobacco and Health survey (n?=?434). Nicotine dependence was assessed using eight items from the Wisconsin Inventory of Smoking Dependence Motives corresponding to individual subscale constructs. Linear regression models evaluated the association of past 30-day menthol (vs. non-menthol) cigarette use with each dependence outcome in separate models, adjusting for age, gender, race, and other tobacco product use.<h4>Results</h4>49.5% of past 30-day youth cigarette smokers reported smoking menthol cigarettes. In adjusted models, menthol smokers (vs. non-menthol smokers) reported significantly higher nicotine dependence for three constructs: craving (p?=?0.005), affiliative attachment (p?=?0.005), and tolerance (p?=?0.003). No differences for menthol vs. non-menthol smokers were observed for loss of control, negative reinforcement, cognitive enhancement, automaticity, or social environment after correction for multiple comparisons.<h4>Conclusions</h4>Findings suggest that menthol cigarette smokers are not just more physically dependent on nicotine but also experience increased emotional attachments to cigarettes compared to their non-menthol smoking peers. Because adolescents are vulnerable to developing nicotine dependence, tobacco control policies that restrict youth access to menthol cigarettes are urgently needed.
Project description:Midbrain dopaminergic (DA) neurons are governed by an endogenous cholinergic system, originated in the mesopontine nuclei. Nicotine hijacks nicotinic acetylcholine receptors (nAChRs) and interferes with physiological function of the cholinergic system. In this review, we describe the anatomical organization of the cholinergic system and the key nAChR subtypes mediating cholinergic regulation of DA transmission and nicotine reward and dependence, in an effort to identify potential targets for smoking intervention. Cholinergic modulation of midbrain DA systems relies on topographic organization of mesopontine cholinergic projections, and activation of nAChRs in midbrain DA neurons. Previous studies have revealed that α4, α6, and β2 subunit-containing nAChRs expressed in midbrain DA neurons and their terminals in the striatum regulate firings of midbrain DA neurons and activity-dependent dopamine release in the striatum. These nAChRs undergo modification upon chronic nicotine exposure. Clinical investigation has demonstrated that partial agonists of these receptors elevate the success rate of smoking cessation relative to placebo. However, further investigations are required to refine the drug targets to mitigate unpleasant side-effects.
Project description:BACKGROUND:E-cigarette regulations targeting products that disproportionately appeal to never-smokers may optimize population health. This laboratory study of young adults tested whether differences in appeal between e-cigarettes with non-tobacco-flavored (vs. tobacco-flavored) and nicotine-containing (vs. nicotine-free) solutions varied by smoking history. METHODS:Current (N?=?53), former (N?=?25), and never (N?=?22) cigarette smokers who vape (Mean[SD] age?=?25.4[4.4] years) administered standardized e-cigarette doses varied by a Flavor (fruit, menthol, tobacco) × Nicotine (nicotine-containing [6?mg/mL], nicotine-free) within-subject double-blind design. Participants rated each dose's appeal (0-100 scale). Covariate-adjusted interactions tested whether smoking history moderated flavor and nicotine effects. RESULTS:Appeal was higher for fruit and menthol than tobacco flavors in each group. The fruit vs. tobacco appeal difference was greater in never smokers (fruit-tobacco estimate?=?19.6) than current smokers (estimate?=?12.1) but not former smokers (estimate?=?12.6). The menthol vs. tobacco difference was greater in never smokers (menthol-tobacco estimate?=?17.3) than former (estimate?=?6.0) and current (estimate?=?7.2) smokers. Appeal was lower for nicotine-containing than nicotine-free solutions in each group; this difference was greater in never smokers (nicotine-nicotine-free estimate?=?-17.3) than former (estimate?=?-7.0) and current (estimate?=?-10.6) smokers. Compared to tobacco flavors, nicotine's appeal-reducing effects were suppressed by fruit and menthol flavors in never smokers. CONCLUSIONS:Higher appeal of non-tobacco-flavored (vs. tobacco-flavored) and lower appeal of nicotine-containing (vs. nicotine-free) e-cigarettes may be widespread in young adults but disproportionately amplified in never smokers. Non-tobacco flavors may suppress nicotine's appeal-lowering qualities in never smokers. The impact of regulating non-tobacco flavors in e-cigarettes may vary by smoking history.
Project description:Menthol is the only available flavor in combusted tobacco cigarettes; however, e-cigarettes are available in thousands of flavors. Research on flavors and rewarding properties of nicotine is limited. The present study sought to examine the acute rewarding effects of flavors inhaled from an e-cigarette, in combination with intravenous (IV) nicotine among cigarette smokers. In the present study, 24 menthol-preferring young adult (aged 18 to 30) cigarette smokers were tested under 3 different e-cigarette flavor conditions (menthol, green apple, or menthol + green apple) in a within-subject cross-over design. During each test session, each participant received 3 IV infusions (saline, 0.25 mg/70 kg nicotine, 0.5 mg/70 kg nicotine) administered 1 hr apart. The main outcome measures assessed cardiovascular, subjective, and cognitive domains. Compared with green apple or green apple + menthol, menthol produced higher ratings of "cooling" (<i>p</i>s < 0.01). Craving was rated higher following administration of green apple and the combined menthol + apple flavor compared to menthol alone (<i>p</i>s < 0.05). As expected, IV-nicotine dose-dependently increased the ratings of subjective liking/disliking and peak heart rate, improved cognitive performance, and reduced smoking urges (all <i>p</i>s < 0.05). These subjective, cognitive, and physiological effects of nicotine were not affected by any flavor condition. The present findings did not support an interaction between IV-nicotine dose and inhaled flavor for acute effects of nicotine. Green apple flavor, alone or in combination with menthol, could result in higher craving or insufficiently alleviate craving, relative to menthol flavor alone. Additional research is warranted to examine extended exposure to inhaled flavors on the rewarding and addictive effects of nicotine. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Project description:Systematic review of research examining consumer preference for the main electronic cigarette (e-cigarette) attributes namely flavor, nicotine strength, and type.A systematic search of peer-reviewed articles resulted in a pool of 12,933 articles. We included only articles that meet all the selection criteria: (1) peer-reviewed, (2) written in English, and (3) addressed consumer preference for one or more of the e-cigarette attributes including flavor, strength, and type.66 articles met the inclusion criteria for this review. Consumers preferred flavored e-cigarettes, and such preference varied with age groups and smoking status. We also found that several flavors were associated with decreased harm perception while tobacco flavor was associated with increased harm perception. In addition, some flavor chemicals and sweeteners used in e-cigarettes could be of toxicological concern. Finally, consumer preference for nicotine strength and types depended on smoking status, e-cigarette use history, and gender.Adolescents could consider flavor the most important factor trying e-cigarettes and were more likely to initiate vaping through flavored e-cigarettes. Young adults overall preferred sweet, menthol, and cherry flavors, while non-smokers in particular preferred coffee and menthol flavors. Adults in general also preferred sweet flavors (though smokers like tobacco flavor the most) and disliked flavors that elicit bitterness or harshness. In terms of whether flavored e-cigarettes assisted quitting smoking, we found inconclusive evidence. E-cigarette users likely initiated use with a cigarette like product and transitioned to an advanced system with more features. Non-smokers and inexperienced e-cigarettes users tended to prefer no nicotine or low nicotine e-cigarettes while smokers and experienced e-cigarettes users preferred medium and high nicotine e-cigarettes. Weak evidence exists regarding a positive interaction between menthol flavor and nicotine strength.