Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers.
ABSTRACT: One-third of smokers primarily use menthol cigarettes and usage of these cigarettes leads to elevated serum nicotine levels and more difficulty quitting in standard treatment programmes. Previous brain imaging studies demonstrate that smoking (without regard to cigarette type) leads to up-regulation of ?(2)*-containing nicotinic acetylcholine receptors (nAChRs). We sought to determine if menthol cigarette usage results in greater nAChR up-regulation than non-menthol cigarette usage. Altogether, 114 participants (22 menthol cigarette smokers, 41 non-menthol cigarette smokers and 51 non-smokers) underwent positron emission tomography scanning using the ?(4)?(2)* nAChR radioligand 2-[(18)F]fluoro-A-85380 (2-FA). In comparing menthol to non-menthol cigarette smokers, an overall test of 2-FA total volume of distribution values revealed a significant between-group difference, resulting from menthol smokers having 9-28% higher ?(4)?(2)* nAChR densities than non-menthol smokers across regions. In comparing the entire group of smokers to non-smokers, an overall test revealed a significant between-group difference, resulting from smokers having higher ?(4)?(2)* nAChR levels in all regions studied (36-42%) other than thalamus (3%). Study results demonstrate that menthol smokers have greater up-regulation of nAChRs than non-menthol smokers. This difference is presumably related to higher nicotine exposure in menthol smokers, although other mechanisms for menthol influencing receptor density are possible. These results provide additional information about the severity of menthol cigarette use and may help explain why these smokers have more trouble quitting in standard treatment programmes.
Project description: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: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.
Project description:Heteromeric ?3?4 nicotinic acetylcholine (ACh) receptors (nAChRs) are pentameric ligand-gated cation channels that include at least two ?3 and two ?4 subunits. They have functions in peripheral tissue and peripheral and central nervous systems. We examined the effects of chronic treatment with menthol, a major flavor additive in tobacco cigarettes and electronic nicotine delivery systems, on mouse ?3?4 nAChRs transiently transfected into neuroblastoma-2a cells. Chronic menthol treatment at 500 nM, near the estimated menthol concentration in the brain following cigarette smoking, altered neither the [ACh]-response relationship nor Zn2+ sensitivity of ACh-evoked currents, suggesting that menthol does not change ?3?4 nAChR subunit stoichiometry. Chronic menthol treatment failed to change the current density (peak current amplitude/cell capacitance) of 100 ?M ACh-evoked currents. Chronic menthol treatment accelerated desensitization of 100 and 200 ?M ACh-evoked currents. Chronic nicotine treatment (250 ?M) decreased ACh-induced currents, and we found no additional effect of including chronic menthol. These data contrast with previously reported, marked effects of chronic menthol on ?2* nAChRs studied in the same expression system. Mechanistically, the data support the emerging interpretation that both chronic menthol and chronic nicotine act on nAChRs in the early exocytotic pathway, and that this pathway does not present a rate-limiting step to the export of ?3?4 nAChRs; these nAChRs include endoplasmic reticulum (ER) export motifs but not ER retention motifs. Previous reports show that smoking mentholated cigarettes enhances tobacco addiction; but our results show that this effect is unlikely to arise via menthol actions on ?3?4 nAChRs.
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: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:Cigarette smoking leads to upregulation of nicotinic acetylcholine receptors (nAChRs) in the human brain, including the common ?4?2* nAChR subtype. While subjective aspects of tobacco dependence have been extensively examined as predictors of quitting smoking with treatment, no studies to our knowledge have yet reported the relationship between the extent of pretreatment upregulation of nAChRs and smoking cessation.To determine whether the degree of nAChR upregulation in smokers predicts quitting with a standard course of treatment.Eighty-one tobacco-dependent cigarette smokers (volunteer sample) underwent positron emission tomographic (PET) scanning of the brain with the radiotracer 2-FA followed by 10 weeks of double-blind, placebo-controlled treatment with nicotine patch (random assignment). Pretreatment specific binding volume of distribution (VS/fP) on PET images (a value that is proportional to ?4?2* nAChR availability) was determined for 8 brain regions of interest, and participant-reported ratings of nicotine dependence, craving, and self-efficacy were collected. Relationships between these pretreatment measures, treatment type, and outcome were then determined. The study took place at academic PET and clinical research centers.Posttreatment quit status after treatment, defined as a participant report of 7 or more days of continuous abstinence and an exhaled carbon monoxide level of 3 ppm or less.Smokers with lower pretreatment VS/fP values (a potential marker of less severe nAChR upregulation) across all brain regions studied were more likely to quit smoking (multivariate analysis of covariance, F8,69?=?4.5; P?<?.001), regardless of treatment group assignment. Furthermore, pretreatment average VS/fP values provided additional predictive power for likelihood of quitting beyond the self-report measures (stepwise binary logistic regression, likelihood ratio ?21?=?19.8; P?<?.001).Smokers with less upregulation of available ?4?2* nAChRs have a greater likelihood of quitting with treatment than smokers with more upregulation. In addition, the biological marker studied here provided additional predictive power beyond subjectively rated measures known to be associated with smoking cessation outcome. While the costly, time-consuming PET procedure used here is not likely to be used clinically, simpler methods for examining ?4?2* nAChR upregulation could be tested and applied in the future to help determine which smokers need more intensive and/or lengthier treatment.clinicaltrials.gov Identifier: NCT01526005.
Project description:Nicotine promotes smoking partly by binding to ?2-containing nicotinic acetylcholine receptors (?2*-nAChRs) in the brain. Smoking one tobacco cigarette results in occupation of 80% of ?2*-nAChRs for more than 6 hours. This likely contributes to maintenance of smoking dependence and cessation difficulty. Developing nicotine vaccines could improve treatments. The authors used [123I]5-I-A-85380 single photon emission computed tomography (SPECT) to evaluate the effect of 3'-AmNic-rEPA on the amount of nicotine that binds to ?2*-nAChRs in smokers' brain cortical and subcortical regions.Eleven smokers who smoked an average of 19 cigarettes per day, had smoked for 10 years on average, and met criteria for nicotine dependence were given SPECT scans on two days: before and after immunization with 4-400 ?g of 3'-AmNic-rEPA. On scan days, three 30-minute baseline emission scans were followed by intravenous administration of nicotine (1.5 mg/70 kg body weight) and up to nine 30-minute emission scans.?2*-nAChR availability was quantified as VT/fP (total distribution volume divided by free plasma concentration), and nicotine binding was derived by the Lassen plot approach. Immunization led to a 12.5% reduction in nicotine binding. Nicotine bound to ?2*-nAChRs correlated positively with nicotine injected before but not after vaccination. The daily number of cigarettes and desire for a cigarette decreased after vaccination.This proof-of-concept study demonstrates that immunization with nicotine vaccine can reduce the amount of nicotine binding to ?2*-nAChRs and disrupt the relationship between administered nicotine and nicotine available to occupy ?2*-nAChRs.
Project description:This study investigates 1) the relationship between menthol cigarette smoking and obesity and 2) the association of body mass index with the nicotine metabolite ratio among menthol and non-menthol daily smokers aged 18-35 (n = 175). A brief survey on smoking and measures of height and weight, carbon monoxide, and saliva samples were collected from participants from May to December 2013 in Honolulu, Hawaii. Multiple regression was used to estimate differences in body mass index among menthol and non-menthol smokers and the association of menthol smoking with obesity. We calculated the log of the nicotine metabolite ratio to examine differences in the nicotine metabolite ratio among normal, overweight, and obese smokers. Sixty-eight percent of smokers used menthol cigarettes. Results showed that 62% of normal, 54% of overweight, and 91% of obese smokers used menthol cigarettes (p = .000). The mean body mass index was significantly higher among menthol compared with non-menthol smokers (29.4 versus 24.5, p = .000). After controlling for gender, marital status, educational attainment, employment status, and race/ethnicity, menthol smokers were more than 3 times as likely as non-menthol smokers to be obese (p = .04). The nicotine metabolite ratio was significantly lower for overweight menthol smokers compared with non-menthol smokers (.16 versus .26, p = .02) in the unadjusted model, but was not significant after adjusting for the covariates. Consistent with prior studies, our data show that menthol smokers are more likely to be obese compared with non-menthol smokers. Future studies are needed to determine how flavored tobacco products influence obesity among smokers.
Project description:Electronic cigarettes (e-cigarettes) are being increasingly used. We examined the correlates associated with e-cigarette awareness, use and perceived effectiveness in smoking cessation among Chinese daily smokers in Hong Kong.Daily smokers (N = 1,307) were recruited to a community-based randomised controlled trial ('Quit to Win') in 2014. Socio-demographic characteristics, conventional cigarette smoking status, nicotine addiction level, quit attempts, quit intention, e-cigarette awareness, use and perceived effectiveness on quitting were reported at baseline and 1-week follow-up. Multivariate logistic regression was used to identify factors associated with e-cigarette awareness, use and perceived effectiveness in quitting.Most smokers (82.6%, 95% CI 80.2%-84.9%) had heard about e-cigarettes, and 13.3% (11.3%-15.5%) ever used e-cigarettes. Most users (74.1%) and non-users (91.2%) did not perceive e-cigarettes as effective in quitting. Being younger and having a larger family income were associated with e-cigarette awareness. Being younger, a tertiary education and a stronger addiction to nicotine were associated with e-cigarette use, which was itself associated with lower levels of intention to quit and had no association with attempts to quit (P for trend 0.45). E-cigarette use, the last quit attempt being a month earlier, having made a quit attempt lasting 24 hours or longer and perceiving quitting as important were all associated with the perceived effectiveness of e-cigarettes in quitting (all P <0.05).Among community-recruited smokers who intended to quit, awareness of e-cigarettes was high, but most did not perceive e-cigarettes as effective in quitting. Correlates concerning e-cigarette perceptions and use will help to inform prospective studies, public education and policy on controlling e-cigarettes.