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Objectives: The province of Ontario, Canada banned menthol in cigarettes and other tobacco products effective January 1, 2017 thereby adding to an existing flavor ban. However, there was an exemption for all flavored e-cigarettes, flavored cigars larger than 6 grams, and alcohol flavored cigars without filters over 1.4 grams. In this paper, we examine the association between use of flavored non-cigarette products and self-reported cigarette smoking cessation after the ban. Methods: We recruited current past-30 day cigarette smokers (N = 913) who were 16 years or older and living in Ontario during September-December 2016 and re-contacted January-August 2018. Results: Both daily and occasional pre-ban menthol cigarette smokers were more likely to use flavored cigar products (adjusted relative rate, RR = 1.53, 95% confidence interval, CI = 1.01, 2.31; adjusted RR = 1.57, 95% CI = 1.06, 2.30) after the ban, while occasional pre-ban menthol cigarette smokers were more likely to use other tobacco products (adjusted RR = 1.25, 95% CI = 1.02, 1.53) or flavored other tobacco products (adjusted RR = 1.56, 95% CI = 1.09, 2.24), conditional on prior use. Conclusions: Menthol smokers prior to the ban were more likely to use other tobacco products, or flavored tobacco products, after the ban. These results suggest that comprehensive menthol bans could be more effective without the option of using flavored tobacco or nicotine products as substitutes.

Background/purpose: Streptococcus mutans is an important pathogen in the development of dental caries. Many studies have focused on the relationship between nicotine and S. mutans in vitro. The aim of this study was to investigate the effect of nicotine on the growth of S. mutans and its cariogenic potential in vivo. Materials and methods: Sixteen male Specific-pathogen-free Wistar rats were divided into 2 groups (nicotine-treated and nicotine-untreated group) and infected with S. mutans. The S. mutans suspension was treated with 1 mg/mL nicotine in the nicotine-treated group. The Keyes method was used to evaluate sulcal caries of rats, and dental plaque on molar teeth was observed by scanning electron microscopy (SEM). Results: Incidence of sulcal caries was higher in nicotine-treated group compared to nicotine-untreated group (42.7 ± 1.7 vs 37.3 ± 4.9, P = 0.009). Severity of caries increased with nicotine treatment. The slightly dentinal caries scores and moderate dentinal caries scores were higher in the presence of nicotine (P

The dopamine level in the brain and the mesolimbick dopaminergic system are responsible for nicotine addiction. In the present study, extracellular dopamine in nucleus accumbens was collected by a brain microdialysis technique. Also a sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method with a gradient elution procedure was developed for a precise determination of dopamine in brain dialysate. The retention time of dopamine was about 11.32 min. The linear range was 20 - 1000 pg/mL. The limit of detection (LOD) and the limit of qualification (LOQ) were 5 and 20 pg/mL, respectively. The recovery ranged from 98.2 to 109.0%, and both the intra-RSD and inter-RSD were below

Background Nicotinic acetylcholine receptors (nAChRs) play an important role in cellular physiology and human nicotine dependence, and are closely associated with many human diseases including cancer. For example, previous studies suggest that nAChRs can re-wire gene regulatory networks in lung cancer cell lines. However, the tissue specificity of nAChRs genes and their regulation remain unexplored. Result In this study, we integrated data from multiple large genomic consortiums, including ENCODE, Roadmap Epigenomics, GTEx, and FANTOM, to define the transcriptomic and epigenomic landscape of all nicotinic receptor genes across many different human tissues and cell types. We found that many important nAChRs, including CHRNA3, CHRNA4, CHRNA5, and CHRNB4, exhibited strong non-neuronal tissue-specific expression patterns. CHRNA3, CHRNA5, and CHRNB4 were highly expressed in human colon and small intestine, and CHRNA4 was highly expressed in human liver. By comparing the epigenetic marks of CHRNA4 in human liver and hippocampus, we identified a novel liver-specific transcription start site (TSS) of CHRNA4. We further demonstrated that CHRNA4 was specifically transcribed in hepatocytes but not transcribed in hepatic sinusoids and stellate cells, and that transcription factors HNF4A and RXRA were likely upstream regulators of CHRNA4. Our findings suggest that CHRNA4 has distinct transcriptional regulatory mechanisms in human liver and brain, and that this tissue-specific expression pattern is evolutionarily conserved in mouse. Finally, we found that liver-specific CHRNA4 transcription was highly correlated with genes involved in the nicotine metabolism, including CYP2A6, UGT2B7, and FMO3. These genes were significantly down-regulated in liver cancer patients, whereas CHRNA4 is also significantly down-regulated in cancer-matched normal livers. Conclusions Our results suggest important non-neuronally expressed nicotinic acetylcholine receptors in the human body. These non-neuronal expression patterns are highly tissue-specific, and are epigenetically conserved during evolution in the context of non-conserved DNA sequence. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3813-4) contains supplementary material, which is available to authorized users.

Background Nicotine craving and relapse often occurs after reactivation of nicotine reward memories. We recently developed a memory retrieval-reconsolidation interference procedure in which reactivation of nicotine reward memories by acute exposure to nicotine (the unconditioned stimulus, UCS) and then pharmacologically interfering with memory reconsolidation decreased relapse to nicotine seeking in rats and nicotine craving in smokers. Here we investigated underlying mechanisms. Methods In the first series of experiments, we trained rats for nicotine-induced conditioned place preference (CPP) or nicotine self-administration and ventricularly microinjected them with the protein synthesis inhibitor anisomycin immediately after UCS-induced memory retrieval. In the second series of experiments, we used TAI-FISH (tyramide-amplified immunohistochemistry–fluorescence in situ hybridization) to examine neural ensembles in basolateral amygdala (BLA) reactivated by nicotine conditioned stimulus (CS)- or UCS-induced memory retrieval. We then used the Daun02 chemogenetic inactivation procedure to selectively inhibit the nicotine UCS-reactivated BLA neuronal ensembles. Results Ventricular injections of the anisomycin immediately after nicotine UCS memory retrieval inhibited subsequent nicotine CPP and relapse to operant nicotine seeking after short or prolonged abstinence. More importantly, within the BLA, distinct neuronal ensembles encoded Pavlovian CPP and operant self-administration reward memories and nicotine (the UCS) injections in the homecage reactivated both neuronal ensembles. Daun02 chemogenetic inactivation of the nicotine-reactivated ensembles prevented both nicotine CPP and relapse to nicotine seeking. Conclusions Results demonstrate that the nicotine UCS-induced memory retrieval manipulation reactivates multiple nicotine reward memories that are encoded by distinct BLA neuronal ensembles that play a role in nicotine preference and relapse.

Smoking cessation reduces the risk of cardiovascular disease (CVD) and improves clinical outcomes in public health. We studied the effect of smoking cessation on high-density lipoprotein (HDL) functionality. METHODS AND RESULTS: We randomly treated 32 smokers with varenicline or a transdermal nicotine patch as part of a 12-week smoking cessation program (The VN-SEESAW Study). The plasma lipid profiles, plasma and HDL malondialdehyde (MDA) levels, HDL subfractions as analyzed by capillary isotachophoresis, cholesterol efflux capacity, and antiinflammatory activity of HDL were measured before and after the anti-smoking intervention. After smoking cessation, HDL-C, apoA-I levels and HDL subfractions were not significantly different from the respective baseline values. However, cholesterol efflux capacity and the HDL inflammatory index (HII) were significantly improved after smoking cessation. The changes in both parameters (%∆ cholesterol efflux capacity and ∆HII) were also significantly improved in the successful smoking cessation group compared with the unsuccessful group. The changes in cholesterol efflux capacity and HII also correlated with those in end-expiratory CO concentration and MDA in HDL, respectively.Our findings indicate that smoking cessation leads to improved HDL functionality, increased cholesterol efflux capacity and decreased HII, without changing HDL-C or apoA-I levels or HDL subfractions. This may be one of the mechanisms by which smoking cessation improves the risk of CVD.

Importance A relapse into nicotine addiction during abstinence often occurs after the reactivation of nicotine reward memories, either by acute exposure to nicotine (a smoking episode) or by smoking-associated conditioned stimuli (CS). Preclinical studies suggest that drug reward memories can undergo memory reconsolidation after being reactivated, during which they can be weakened or erased by pharmacological or behavioral manipulations. However, translational clinical studies using CS-induced memory retrieval-reconsolidation procedures to decrease drug craving reported inconsistent results. Objective To develop and test an unconditioned stimulus (UCS)-induced retrieval-reconsolidation procedure to decrease nicotine craving among people who smoke. Design, Setting, and Participants A translational rat study and human study in an academic outpatient medical center among 96 male smokers (aged 18- 45 years) to determine the association of propranolol administration within the time window of memory reconsolidation (after retrieval of the nicotine-associated memories by nicotine UCS exposure) with relapse to nicotine-conditioned place preference (CPP) and operant nicotine seeking in rats, and measures of preference to nicotine-associated CS and nicotine craving among people who smoke. Intervention The study rats were injected noncontingently with the UCS (nicotine 0.15 mg/kg, subcutaneous) in their home cage, and the human study participants administered a dose of propranolol (40 mg, per os; Zhongnuo Pharma). Main Outcomes and Measures Nicotine CPP and operant nicotine seeking in rats, and preference and craving ratings for newly learned and preexisting real-life nicotine-associated CS among people who smoke. Results Sixty-nine male smokers completed the experiment and were included for statistical analysis: 24 in the group that received placebo plus 1 hour plus UCS, 23 who received propranolol plus 1 hour plus UCS, and 22 who received UCS plus 6 hours plus propranolol. In rat relapse models, propranolol injections administered immediately after nicotine UCS-induced memory retrieval inhibited subsequent nicotine CPP and operant nicotine seeking after short (CPP, d = 1.72, 95% CI, 0.63-2.77; operant seeking, d = 1.61, 95% CI, 0.59-2.60) or prolonged abstinence (CPP, d = 1.46, 95% CI, 0.42-2.47; operant seeking: d = 1.69, 95% CI, 0.66-2.69), as well as nicotine priming-induced reinstatement of nicotine CPP ( d = 1.28, 95% CI, 0.27-2.26) and operant nicotine seeking ( d = 1.61, 95% CI, 0.59-2.60) after extinction. Among the smokers, oral propranolol administered prior to nicotine UCS-induced memory retrieval decreased subsequent nicotine preference induced by newly learned nicotine CS (CS1, Cohen d = 0.61, 95% CI, 0.02-1.19 and CS2, d = 0.69, 95% CI, 0.10-1.28, respectively), preexisting nicotine CS ( d = 0.57, 95% CI, −0.02 to 1.15), and nicotine priming (CS1, d = 0.82, 95% CI, 0.22-1.41 and CS2, d = 0.78, 95% CI, 0.18-1.37, respectively; preexisting nicotine CS, d = 0.92, 95% CI, 0.31-1.52), as well as nicotine craving induced by the preexisting nicotine CS ( d = 0.64, 95% CI, 0.05-1.22), and nicotine priming ( d = 1.15, 95% CI, 0.52-1.76). Conclusions and Relevance In rat-to-human translational study, a novel UCS-induced memory retrieval-reconsolidation interference procedure inhibited nicotine craving induced by exposure to diverse nicotine-associated CS and nicotine itself. This procedure should be studied further in clinical trials.

Background Tobacco and non-tobacco-based waterpipe smoking has increased exponentially in many countries in recent decades, particularly among youth and young adults. Although tobacco smoking is banned in many indoor public places, waterpipe smoking, ostensibly non-tobacco, continues in Ontario and other jurisdictions where only tobacco smoking is prohibited. This study assessed air quality and exposure in waterpipe cafes using multiple methods and markers. Methods Indoor (n=12) and outdoor (n=5) air quality was assessed in Toronto, Canada waterpipe cafes from 30 August to 11 October 2012. Real-time measurements of air nicotine, fine particulate matter less than 2.5 microns in diameter (PM 2.5 ) and ambient carbon monoxide (CO) were collected in 2 h sessions. Levels of CO in breath were collected in non-smoking field staff before entering and upon leaving venues. Observations of occupant behaviour, environmental changes and venue characteristics were also recorded. Results In indoor venues, mean values were 1419 µg/m 3 for PM 2.5 , 17.7 ppm for ambient CO, and 3.3 µg/m 3 for air nicotine. Levels increased with increasing number of active waterpipes. On outdoor patios, mean values were 80.5 µg/m 3 for PM 2.5 , 0.5 ppm for ambient CO, and 0.6 µg/m 3 for air nicotine. Air quality levels in indoor waterpipe cafes are hazardous for human health. Outdoor waterpipe cafes showed less harmful particulate levels than indoors, but mean PM 2.5 levels (80.5 µg/m 3 ) were still ‘poor’. Conclusions Staff and patrons of waterpipe cafes are exposed to air quality levels considered hazardous to human health. Results support eliminating waterpipe smoking in hospitality venues indoors and out.

High titers of serum IgG2 reactive with Actinobacillus actinomycetemcomitans are present in early-onset periodontitis (EOP) patients and it appears that anti-A. actinomycetemcomitans may be protective. Smoking is associated with increased periodontal disease severity in generalized early-onset periodontitis (G-EOP) patients, but is not associated with periodontal disease severity in patients with localized juvenile periodontitis (LJP). Furthermore, smoking is associated with reduced serum IgG2 levels in black patients with G-EOP but not in those with LJP. Based on this selective effect of smoking, we hypothesized that smoking would be associated with a reduction of specific IgG2 reactive with A. actinomycetemcomitans in black G-EOP patients but not black LJP patients. In addition, we examined IgG2 responses to carbohydrate antigens from non-periodontal pathogens including Haemophilus influenzae b oligosaccharide antigen (Hib) and the Streptococcus pneumoniae antigen phosphocholine (PC). Smoking status was assessed from serum cotinine levels, and IgG2 specific for A. actinomycetemcomitans, Hib, and PC was assessed by ELISA. Our study revealed that smoking was correlated with a dramatic reduction in serum IgG2 anti-A. actinomycetemcomitans in G-EOP smokers but not in LJP smokers. In contrast, anti-Hib IgG2 and anti-PC IgG2 were not affected in either G-EOP or LJP patients. In short, these results indicate that smoking is associated with a reduction in serum IgG2 anti-A. actinomycetemcomitans in black G-EOP subjects, but IgG2 reactive with other antigens may not be reduced in G-EOP smokers.

Nicotine binds to nicotinic acetylcholine receptors on dopaminergic terminals to evoke dopamine (DA) release. The clearance of released DA occurs rapidly through reuptake into nerve terminals through the DA transporter (DAT). However, whether nicotine modulates DAT function in vivo is still not well understood. In the present study, we determined the effect of nicotine on DA clearance using in vivo amperometric recording in the striatum of urethane-anesthetized rats. Stable DA release was evoked by electrical stimulation of the medial forebrain bundle (MFB). Subsequently, nicotine or saline was administered with MFB stimulation at 10-min intervals for 60 min. Kinetic analysis revealed that nicotine decreased the amplitude of DA overflow and the maximal DA clearance rate (Vmax) in response to stimulation of 96 pulses at 80 Hz. Surprisingly, nicotine enhanced the maximal DA clearance rate (Vmax) by stimulation of 768 pulses at 80 Hz. Furthermore, we found that this paradoxical effect of nicotine on Vmax depended on the stimulation pattern. These results suggest that nicotine may exert its addictive role by dynamically modulating DAT function in vivo.