Nicotine Intake Research Articles

The Novel CYP2A6 Inhibitor, DLCI-1, Decreases Nicotine Self-Administration in Mice.

During tobacco and e-cigarette use, nicotine is mainly metabolized in the human liver by cytochrome P450 2A6 (CYP2A6). Given that a slower CYP2A6 metabolism has been associated with less vulnerability to develop nicotine dependence, the current studies sought to validate a novel CYP2A6 inhibitor, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), for its effects on intravenous nicotine self-administration. Male and female mice were trained to self-administer nicotine across daily sessions. Once stable responding was achieved, DLCI-1 or vehicle control was administered prior to nicotine sessions. We found that the lower 25 mg/kg and moderate 50 mg/kg doses of DLCI-1 induced a significant decrease in nicotine intake for both males and females. DLCI-1 was further shown to be more effective than a moderate 1 mg/kg dose of bupropion on reducing nicotine intake and did not exert the adverse behavioral effects found with a high 75 mg/kg dose of bupropion. Although mice treated with DLCI-1 self-administered significantly less nicotine, similar nicotine-mediated behavioral effects on locomotion were observed. Together, along with the analysis of nicotine metabolites during self-administration, these findings support the contention that blocking hepatic nicotine metabolism would allow for similar activation of nicotinic acetylcholine receptors at lower nicotine doses. Moreover, these effects of DLCI-1 were specific to nicotine self-administration, as DLCI-1 did not result in any behavioral changes during food self-administration. Taken together, these studies validate DLCI-1 as a novel compound to decrease nicotine consumption, which may thereby promote tobacco and nicotine product cessation. SIGNIFICANCE STATEMENT: Current pharmacological approaches for nicotine and tobacco cessation have only been able to achieve limited efficaciousness in promoting long-term abstinence. In this work, we characterize the effects of a novel compound, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), which inhibits the main enzyme that metabolizes nicotine, and we report a significant decrease in intravenous nicotine self-administration in male and female mice, supporting the potential of DLCI-1 as a novel tobacco cessation pharmacotherapeutic.

Habenular TCF7L2 links nicotine addiction to diabetes.

Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.

Are hazardous drinkers more impulsive than light drinkers? A comprehensive assessment in young adults.

Those with alcohol dependence are characteristically impulsive. It is unclear whether the same is true of hazardous drinkers (i.e., women routinely drinking more than 14 units in a typical week but fewer than 35, and men drinking more than 14 units but fewer than 50). Yet, it is important to understand the mechanisms involved in such drinking, since it places the drinker at risk for future harm. The present study thus comprehensively assessed whether impulsivity was elevated in hazardous drinkers, compared to lighter drinkers. An opportunity sample of 57 light and 49 hazardous drinkers was assessed on the following impulsivity subdomains (via the measures in parentheses): (i) trait impulsivity (the Barratt Impulsiveness Scale, Version 11); (ii) temporal impulsivity (the Monetary Choice Questionnaire); (iii) stopping impulsivity (the Stop-Signal Task); (iv) waiting impulsivity (the Continuous Performance Task or CPT); (v) reward-sensitivity (the Behavioural Activation Scales); and (vi) risk-taking (the Balloon Analogue Risk Task). Alcohol- and other drug-dependent individuals were excluded from the study, while socio-demographics (age, gender, and socio-economic status), mood, binge drinking, and nicotine intake were all controlled for. The groups were compared via a series of Bonferroni-corrected, independent-measures t tests. The results revealed that hazardous drinkers were more impulsive than light drinkers on the CPT; there were no other statistically significant group differences. Consistent with the above, a logistic regression, with drinking group as the dependent variable and the impulsivity indices as independent variables, revealed that only CPT performance was a significant predictor of drinking status. Other than gender, none of the control variables significantly correlated with CPT performance. A sequential linear regression revealed that drinking status continued to predict CPT performance, after first accounting for gender. Thus, from a battery of impulsivity measures, only waiting impulsivity (i.e., CPT score) was elevated in hazardous drinkers, relative to lighter drinkers. Waiting impulsivity may thus be important in the maintenance of hazardous drinking.

Differential patterns of alcohol and nicotine intake: Combined alcohol and nicotine binge consumption behaviors in mice.

Late adolescence and young adulthood, corresponding to the high school and college years, are vulnerable periods for increased alcohol and nicotine use. The dramatic increase in the prevalence of electronic cigarette use is particularly concerning in these age groups. Late adolescents and young adults are more likely to engage in cycles of binge drug consumption, and alcohol and nicotine are frequently used together. However, there are few data examining the combination of alcohol and nicotine in binge models in animal models. In this study, our objectives were to determine how voluntary nicotine consumption beginning in late adolescence influenced subsequent binge alcohol consumption in young adulthood, how a combination of alcohol and nicotine binge consumption differed from alcohol-only binge consumption, and whether nicotine would be consumed when presented in a binge procedure. Male C57BL/6J mice voluntarily consumed unsweetened alcohol and nicotine in continuous-access bottle-choice procedures in combination with cycles of drinking-in-the-dark. Our results show that experience with voluntary nicotine consumption in late adolescence did not affect subsequent binge alcohol consumption in early adulthood. However, mice that consumed nicotine in adolescence showed an initial decrease in alcohol preference, and consequently increase in nicotine preference, on the first session of combined ethanol and nicotine binge consumption in adulthood compared with mice that drank only water during late adolescence. Lastly, we found that mice readily consumed unsweetened nicotine when presented in a binge procedure, and the level of consumption exceeded the nicotine consumption observed in the combination alcohol and nicotine binge. Our data show that expansion of the patterns of alcohol and nicotine co-consumption in a mouse models is possible, which will enable us to dissect relevant molecular targets underlying these consumption patterns and better inform drug development efforts.

Evening intake of alcohol, caffeine, and nicotine: night-to-night associations with sleep duration and continuity among African Americans in the Jackson Heart Sleep Study.

We examined the night-to-night associations of evening use of alcohol, caffeine, and nicotine with actigraphically estimated sleep duration, sleep efficiency, and wake after sleep onset (WASO) among a large cohort of African American adults. Participants in the Jackson Heart Sleep Study underwent wrist actigraphy for an average of 6.7 nights and completed concurrent daily sleep diary assessments to record any consumption of alcohol, caffeine, and nicotine within 4 hours of bedtime. Linear mixed-effect models were fit and adjusted for age, sex, educational attainment, body mass index, depression, anxiety, stress, and having work/school the next day. Eligible participants (n = 785) were an average of 63.7 years (SD: 10.6), and were predominantly female (67.9%). There were 5164 days of concurrent actigraphy and sleep diary data. Evening alcohol use was associated with that night's lower sleep efficiency (-0.98% [95% CI: -1.67% to -0.29%], p = 0.005), but not with WASO or sleep duration. Evening nicotine use was associated with that night's lower sleep efficiency [1.74% (95% CI: -2.79 to -0.68), p = 0.001] and 6.09 minutes higher WASO ([95% CI: 0.82 to 11.35], p = 0.02), but was not associated with sleep duration. Evening caffeine use was not associated with any of the sleep parameters. Nicotine and alcohol use within 4 hours of bedtime were associated with increased sleep fragmentation in the associated night, even after controlling for multiple potential confounders. These findings support the importance of sleep health recommendations that promote the restriction of evening alcohol and nicotine use to improve sleep continuity.

Smoking is associated with greater pain intensity and pain-related occupational disability in Japanese workers.

Pain symptom, such as that caused by musculoskeletal disorders, is a major cause of occupational disability. As nicotine intake from smoking increases pain sensitivity, smokers may experience stronger pain and be more likely to experience pain-related disability than non-smokers. The study aim was to examine whether smoking was associated with pain-related occupational disability via pain intensity. Participants were 1189 workers with pain aged 20-74years in Japan. Participants completed a self-report questionnaire, which included a question to measure pain-related occupational disability with ordinal-option: (1) without pain-related disability, (2) pain-related presenteeism, and (3) pain-related absenteeism. An ordinal logistic regression model was used to calculate multivariable-adjusted proportional odds ratios (OR) with 95% confidence intervals (CI) for the prevalence of pain-related occupational disability according to smoking status. A multiple mediation analysis was also conducted to assess whether pain sensitivity mediated the association between smoking and pain-related occupational disability. Adjusted variables were demographic variables, socioeconomic status, work-related psychosocial factors, general psychological factors, and pain duration. Current smoking and pain were associated with pain-related occupational disability compared with non-smoking and pain (multivariable OR 1.78; 95% CI 1.26-2.52). Greater pain intensity partially mediated the association of current smoking and pain with pain-related occupational disability. The mediation rate (indirect/total effect) was 25%. Smoking and pain were associated with pain-related occupational disability, partially through greater pain intensity, among Japanese workers.

Alcohol in the Aging Brain - The Interplay Between Alcohol Consumption, Cognitive Decline and the Cardiovascular System.

As our society grows older new challenges for medicine and healthcare emerge. Age-related changes of the body have been observed in essential body functions, particularly in the loco-motor system, in the cardiovascular system and in cognitive functions concerning both brain plasticity and changes in behavior. Nutrition and lifestyle, such as nicotine intake and chronic alcohol consumption, also contribute to biological changes in the brain. This review addresses the effect of alcohol consumption on cognitive decline, changes in brain plasticity in the aging brain and on cardiovascular health in aging. Thus, studies on the interplay of chronic alcohol intake and either cognitive decline or cognitive preservation are outlined. Because of the inconsistency in the literature of whether alcohol consumption preserves cognitive functions in the aging brain or whether it accelerates cognitive decline, it is crucial to consider individual contributing factors such as culture, health and lifestyle in future studies.

Urinary Cotinine and Expired CO Concentrations in Women Exposed to Environmental Tobacco Smoke at Home

Introduction: The health effects of exposure to environmental tobacco smoke (ETS) using cotinine was a nicotine metabolite detected in urine. This should be recommended as a quantitative measurement of nicotine intake and as biomarker for ETS exposure in humans. 
 Method: We performed a cross-sectional study to 60 ETS-exposed and 58 non ETS exposed adult women in Pasar Rebo area, Jakarta. The urinary cotinine concentrations were measured and analyzed using ELISA method, other informations were collected such as expired CO data, questionnaire regarding smoking habits of the subjects’ family members at home and respiratory health effects occured to subjects. 
 Results: Median of urinary cotinine concentrations in ETS-exposed group were 24.65 ng/ml and 7.30 ng/ml in non-exposed group (P=0.0001). Median of expired CO in ETS-exposed group were 5.00 ppm and 3.00 ppm in non-exposed to ETS group (P=0.0001). Total amount of time (hours/day) in women exposed to ETS in their house was significantly correlated to urinary cotinine concentrations (P=0.037). The respiratory symptoms showed significant correlation with ETS exposure status (P=0.01). Time duration of last exposed to ETS had significant correlation with expired CO (P=0.004). The urinary cotinine concentrations cut-off point was 14.4 ng/ml (sensitivity=75%, specificity=74%, P=0.0001). The expired CO cut-off point was 3.5 ppm (sensitivity=75%, specificity=81%, p=0.0001). Strong and significant correlation was found between expired CO and urinary cotinine (r=0.641, P=0.0001).
 Conclusion: The urinary cotinine and expired CO concentration were significantly higher in women exposed to tobacco smoke at home than the non-exposed group. Urinary cotinine measurement was a sensitive, non-invasive and effective method to correlate with ETS exposure. (J Respir Indo. 2019; 39(3):140-53)

Economic demand analysis of within-session dose-reduction during nicotine self-administration

BackgroundThis study determined if a within-session dose-reduction design sufficiently captures elasticity of demand for nicotine in male and female rats using environmental enrichment to manipulate demand elasticity. MethodsMale and female Sprague-Dawley rats were trained to self-administer nicotine (60 μg/kg/infusion). In Experiment 1, rats began daily dose-reduction for nine sessions following acquisition. Rats then underwent a minimum of five within-session dose-reduction sessions where each dose was available for 10 min. In Experiment 2, rats were reared in isolated, social, or enriched housing followed by acquisition of nicotine self-administration. Rats then underwent within-session dose-reduction. Housing environments were then switched, followed by additional testing sessions. Consumption was calculated for each dose and exponential demand curves were fit. ResultsNo sex differences in acquisition of nicotine self-administration were detected for either experiment. In experiment 1, demand intensity (Q0; estimated intake if nicotine were freely available), was higher with between- compared to within-session dose-reduction, although elasticity of demand (α; rate of decline in nicotine intake as a function of increasing unit price), was lower. In Experiment 2, animals reared in enrichment had fewer infusions during acquisition compared to animals in isolation. Enriched males had reduced demand intensity compared to both isolated and social males, whereas isolated females had reduced intensity compared to enriched females. ConclusionsThe within-session dose-reduction procedure for nicotine self-administration replicated effects of environmental enrichment on consumption behaviors. Additionally, this procedure captured differences in nicotine demand due to sex, laying important groundwork for future translational research on mechanisms of nicotine dependence.

Assessing nicotine dependence using an oral nicotine free-choice paradigm in mice

Models to assess the addictive-like properties of nicotine in mice are limited. Therefore, we aimed to characterize and validate an addiction index by using an oral nicotine free-choice paradigm in mice.Adult C57BL/6J, DBA/2J, or genetically modified mice carrying deletions for nicotinic acetylcholine receptor (nAChR) subunits, (n = 8–10/sex/group) were given a choice of water or nicotine (10–960 μg/ml) solution using a two-bottle free-choice (2BC) paradigm. In general, oral nicotine intake and preference were higher in female mice compared to males. Absence of nicotine led to withdrawal, and intermittent access resulted in an escalation in consumption and greater nicotine withdrawal than continuous exposure. Additionally, oral nicotine consumption increased nucleus accumbens tyrosine hydroxylase levels. While β2 and α6 KO mice showed a significant decrease in nicotine intake, deletion of α5 nAChRs increased nicotine consumption at high concentrations. Deletion of the α7 subunit altered the observed sex difference in nicotine consumption, with females consuming less than males. The α4β2 partial agonist varenicline decreased oral nicotine consumption. Although addition of quinine to the nicotine solution lowered nicotine intake, mice primed with nicotine did not lower their intake after quinine addition. Nicotine deprivation followed by re-exposure showed increased nicotine consumption, and DBA/2J mice consumed less nicotine compared to C57BL/6J.We validated the mouse 2BC paradigm to study nicotine's addictive-like properties including nicotine intake, preference, withdrawal, and escalation of nicotine consumption during binge drinking or after reinstatement of a deprivation period.

Black Light Smokers: How Nicotine Intake and Carcinogen Exposure Differ Across Various Biobehavioral Factors

ObjectiveThe study objective was to identify biobehavioral variables associated with greater intake of nicotine and a tobacco carcinogen among Black light smokers who smoke 1 to 10 cigarettes per day (CPD). MethodsWe analyzed baseline data collected from 426 Black light smokers enrolled in Kick It at Swope III (KIS III), a smoking cessation trial for Black smokers. We examined differences in concentrations of tobacco biomarkers, including urinary total nicotine equivalents (TNE) and total 4-(methylnitrosamino)-1-(3)pyridyl-1-butanonol (NNAL; a human carcinogen), across gender, age, plasma nicotine metabolite ratio (NMR), CPD, and measures of tobacco dependence, including time to first cigarette (TFC), using ANOVA. ResultsTobacco biomarker levels were significantly higher among those who smoked more CPD (6–10 vs 1–5 CPD) and those with greater reported physical dependence on tobacco. Concurrently, those who smoked 1–5 CPD smoked each cigarette more intensely than those who smoked 6–10 CPD. While we found no gender differences overall, among those who smoked 1–5 CPD, women had higher NNAL levels compared to men. The rate of nicotine metabolism, measured by the nicotine metabolite ratio, was not significantly related to TNE or NNAL levels. ConclusionAmong Black Light smokers, higher cigarette consumption and greater physical dependence—but not rate of nicotine metabolism, menthol use, or socioeconomic status—were associated with greater toxicant exposure and thus a likely increased risk of tobacco-related diseases. The lack of data on light smokers, and specifically on Blacks, make this observation important given the disproportionate burden of lung cancer in this population.

Differences in Magnitude of Cue Reactivity Across Durations of Smoking History: A Meta-analysis.

Cue-elicited craving may vary due to duration of smoking history, increasing as more years of smoking strengthen associations between nicotine intake and cues. However, research on this relationship is virtually absent. This project assessed the relationship between cue reactivity and years of smoking. Data from 53 studies (68 effect sizes) were analyzed. Eligible studies were those measuring self-reported craving following cue exposure in nontreatment seeking smokers and reporting mean years smoking. Preliminary subgroup analyses identified methodological factors influencing cue-reactivity effect sizes; primary meta-regression analysis assessed differences across years smoking; exploratory analyses assessed potential for ceiling effects. Effect sizes varied due to abstinence requirement and cue presentation modality, but not dependence severity. Unexpectedly, meta-regression analysis revealed a decline in effect sizes across years smoking. Exploratory analyses suggested declines may have been due to a ceiling effect in craving measurement for those with longer smoking histories-more experienced smokers reported higher levels of craving at baseline or following neutral cue exposure, but all reported similar levels of craving after smoking cue exposure. Methodological factors and duration of smoking history influenced measurement of cue reactivity. Highlighted were important relationships between years smoking and magnitude of cue reactivity, depending on use of baseline or neutral cue comparisons. Further research is needed to assess differences in cue reactivity due to duration of smoking history using participant-level data, directly testing for ceiling effects. In addition, cue-reactivity studies are needed across young adults to assess onset of associations between nicotine intake and cues. This meta-analysis project contributes to the cue-reactivity literature by reporting on the previously ignored relationship between duration of smoking history and magnitude of cue-elicited craving. Results suggest that declines in cue-reactivity effect sizes across years of smoking may have been due to study-level methodological factors, but not due to differences in sample-level dependence severity. Cue-reactivity effect sizes were stable across years of smoking in studies using a neutral cue comparison but declined sharply in studies when baseline assessment (typically coupled with an abstinence requirement) was used.

Marketing communications from the tobacco industry for nicotine intake: “Old habits die hard”

Marketing communications from the tobacco industry for nicotine intake: “Old habits die hard”

Chronic Nicotine Exposure Alters the Neurophysiology of Habenulo-Interpeduncular Circuitry.

Antagonism of nicotinic acetylcholine receptors (nAChRs) in the medial habenula (MHb) or interpeduncular nucleus (IPN) triggers withdrawal-like behaviors in mice chronically exposed to nicotine, implying that nicotine dependence involves the sensitization of nicotinic signaling. Identification of receptor and/or neurophysiological mechanisms underlying this sensitization is important, as it could promote novel therapeutic strategies to reduce tobacco use. Using an approach involving photoactivatable nicotine, we previously demonstrated that chronic nicotine (cNIC) potently enhances nAChR function in dendrites of MHb neurons. However, whether cNIC modulates downstream components of the habenulo-interpeduncular (Hb-IP) circuit is unknown. In this study, cNIC-mediated changes to Hb-IP nAChR function were examined in mouse (male and female) brain slices using molecular, electrophysiological, and optical techniques. cNIC enhanced action potential firing and modified spike waveform characteristics in MHb neurons. Nicotine uncaging revealed nAChR functional enhancement by cNIC on proximal axonal membranes. Similarly, nAChR-driven glutamate release from MHb axons was enhanced by cNIC. In IPN, the target structure of MHb axons, neuronal morphology, and nAChR expression is complex, with stronger nAChR function in the rostral subnucleus [rostral IPN (IPR)]. As in MHb, cNIC induced strong upregulation of nAChR function in IPN neurons. This, coupled with cNIC-enhanced nicotine-stimulated glutamate release, was associated with stronger depolarization responses to brief (1 ms) nicotine uncaging adjacent to IPR neurons. Together, these results indicate that chronic exposure to nicotine dramatically alters nicotinic cholinergic signaling and cell excitability in Hb-IP circuits, a key pathway involved in nicotine dependence.SIGNIFICANCE STATEMENT This study uncovers several neuropharmacological alterations following chronic exposure to nicotine in a key brain circuit involved in nicotine dependence. These results suggest that smokers or regular users of electronic nicotine delivery systems (i.e., "e-cigarettes") likely undergo sensitization of cholinergic circuitry in the Hb-IP system. Reducing the activity of Hb-IP nAChRs, either volitionally during smoking cessation or inadvertently via receptor desensitization during nicotine intake, may be a key trigger of withdrawal in nicotine dependence. Escalation of nicotine intake in smokers, or tolerance, may involve stimulation of these sensitized cholinergic pathways. Smoking cessation therapeutics are only marginally effective, and by identifying cellular/receptor mechanisms of nicotine dependence, our results take a step toward improved therapeutic approaches for this disorder.

Urine Metabolites for Estimating Daily Intake of Nicotine From Cigarette Smoking.

Accurate measurement of nicotine exposure from cigarette smoke is important in studying disease risk and level of dependence. Urine total nicotine equivalents, the molar sum of nicotine and six metabolites (NE7), accounts for more than 90% of a nicotine dose and is independent of individual metabolic differences. However, measuring NE7 is technically difficult and costly. We compared NE7, the gold standard of nicotine intake, with different combinations of fewer urinary nicotine metabolites. We also examined the impact of individual differences in nicotine metabolic rate, sex, and race on strength of association with NE7. Urine samples from 796 daily smokers, who participated across five clinical studies, were assayed for nicotine and/or metabolites. Associations with NE7 were assessed by regression and Bland-Altman analyses. Overall, the molar sum of urine [cotinine + 3'-hydroxycotinine (3HC)] (NE2) and [nicotine + cotinine + 3HC] (NE3) were strongly correlated with NE7 (r=.97 and .99, respectively). However, in slow metabolizers NE2 was less predictive of NE7, whereas NE3 was equally robust. Urine total cotinine was also strongly correlated with NE7 (r=.87). Urine NE3 is a robust biomarker of daily nicotine intake, independently of individual metabolic differences, whereas NE2 is less accurate in slow metabolizers. Our findings inform the selection of more rigorous and cost-effective measures to assess nicotine exposure in tobacco research studies. The molar sum of urine total nicotine, cotinine and 3HC (NE3) is a robust biomarker of daily nicotine intake, independently of individual metabolic differences, and performs as well as measuring seven nicotine metabolites (NE7). The sum of cotinine and 3HC (NE2) is less accurate in slow metabolizers. Our findings inform the selection of more rigorous and cost-effective measures to assess nicotine exposure in tobacco research studies.

Are ‘dual users’ who smoke and use e-cigarettes interested in using varenicline to stop smoking altogether, and can they benefit from it? A cohort study of UK vapers

ObjectivesSmokers who use e-cigarettes (EC) do so mostly to stop smoking, but many continue to use both products. It is not known whether these ‘dual users’ are interested in stop-smoking...

Evaluation of a weighted genetic risk score for the prediction of biomarkers of CYP2A6 activity.

The nicotine metabolite ratio (NMR; 3-hydroxycotinine/cotinine) is an index of CYP2A6 activity. CYP2A6 is responsible for nicotine's metabolic inactivation and variation in the NMR/CYP2A6 is associated with several smoking behaviors. Our aim was to integrate established alleles and novel genome-wide association studies (GWAS) signals to create a weighted genetic risk score (wGRS) for the CYP2A6 gene for European-ancestry populations. The wGRS was compared with a previous CYP2A6 gene scoring approach designed for an alternative phenotype (C2/N2; cotinine-d2/(nicotine-d2 + cotinine-d2)). CYP2A6 genotypes and the NMR were assessed in European-ancestry participants. The wGRS training set included N=933 smokers recruited to the Pharmacogenetics of Nicotine Addiction and Treatment clinical trial [NCT01314001]. The replication cohort included N=196 smokers recruited to the Quit 2 Live clinical trial [NCT01836276]. Comparisons between the two CYP2A6 phenotypes and with fractional clearance were made in a laboratory-based pharmacokinetic study (N=92 participants). In both the training and replication sets, the wGRS, which included seven CYP2A6 variants, explained 33.8% (P<0.001) of the variance in NMR, providing improved predictive power to the NMR phenotype when compared with other CYP2A6 gene scoring approaches. NMR and C2/N2 were strongly correlated to nicotine clearance (ρ=0.70 and ρ=0.79, respectively; P<0.001), and to one another (ρ=0.82; P<0.001); however reduced function genotypes occurred in slow NMR but throughout C2/N2. The wGRS was able to predict smoking quantity and nicotine intake, to discriminate between NMR slow and normal metabolizers (AUC=0.79; P<0.001), and to replicate previous NMR-stratified cessation outcomes showing unique treatment outcomes between metabolizer groups.

Oral sazetidine-A, a selective α4β2* nicotinic receptor desensitizing agent, reduces nicotine self-administration in rats

Sazetidine-A selectively desensitizes α4β2 nicotinic receptors and also has partial agonist effects. We have shown that subcutaneous acute and repeated injections as well as chronic infusions of sazetidine-A significantly reduce intravenous (IV) nicotine self-administration in rats. To further investigate the promise of sazetidine-A as a smoking cessation aid, it is important to determine sazetidine-A effects with oral administration and the time-effect function for its action on nicotine self-administration. Young adult female Sprague-Dawley rats were trained to self-administer IV nicotine at the benchmark dose of 0.03 mg/kg/infusion dose in an operant FR1 schedule in 45-min sessions. After five sessions of training, they were tested for the effects of acute oral doses of sazetidine-A (0, 0.3, 1 and 3 mg/kg) given 30 min before testing. To determine the time-effect function, these rats were administered 0 or 3 mg/kg of sazetidine-A 1, 2, 4 or 23 h before the onset of testing. Our previous study showed that with subcutaneous injections, only 3 mg/kg of sazetidine-A significantly reduced nicotine self-administration, however, with oral administration of sazetidine-A lower dose of 1 mg/kg was also effective in reducing nicotine intake. A similar effect was seen in the time-effect study with 3 mg/kg of oral sazetidine-A causing a significant reduction in nicotine self-administration across all the time points of 1, 2, 4 or 23 h after oral administration. These results advance the development of sazetidine-A as a possible aid for smoking cessation by showing effectiveness with oral administration and persistence of the effect over the course of a day.

Therapeutic challenges for concurrent ethanol and nicotine consumption: naltrexone and varenicline fail to alter simultaneous ethanol and nicotine intake by female alcohol-preferring (P) rats.

Simultaneous alcohol and nicotine consumption occurs in the majority of individuals with alcohol use disorder (AUD) and nicotine dependence. Varenicline (Var) is used to assist in the cessation of nicotine use, while naltrexone (Nal) is the standard treatment for AUD. Despite evidence that ethanol (EtOH) and nicotine (NIC) co-use produces unique neuroadaptations, preclinical research has focused on the effects of pharmacotherapeutics on a single reinforcer. The current experiments examined the effects of Var and Nal on EtOH, NIC, or EtOH+NIC intake. Animals were randomly assigned to one of four drinking conditions of 24-h access to a three-bottle choice paradigm, one of which always contained water. Drinking conditions were water only, 0.07 and 0.14mg/mL NIC (NIC only), 15% and 30% EtOH (EtOH only), or 15% and 30% EtOH with 0.14mg/mL NIC (EtOH+NIC). The effects of Var (0, 1, or 2mg/kg) or Nal (0, 1, or 10mg/kg) injections on maintenance and relapse consumption were determined during four consecutive days. Var reduced maintenance and relapse NIC intake but had no effect on EtOH or EtOH+NIC drinking. Conversely, Nal reduced EtOH maintenance and relapse drinking, but had no effect on NIC or EtOH+NIC drinking. The results indicate the standard pharmacological treatments for nicotine dependence and AUD were effective at reducing consumption of the targeted reinforcer but neither reduced EtOH+NIC co-use/abuse. These findings suggest that co-abuse may promote unique neuroadaptations that require models of polysubstance abuse to develop pharmacotherapeutics to treat AUD and nicotine dependence.

Impact of Menthol on Oral Nicotine Consumption in Female and Male Sprague Dawley Rats.

One of the preferable flavors in oral nicotine delivery systems is menthol which masks the harshness of tobacco. However, possible interactions between oral menthol and nicotine on intake and preference remain unclear. Therefore, we aimed to determine the impact of menthol on oral nicotine consumption. Adult Sprague Dawley female and male rats (n = 8 per group) were given a choice of water or drug solution by using two-bottle free choice paradigm for 2 weeks: vehicle (5% ethanol), nicotine (20 mg/L), menthol (1 g/L) and mentholated nicotine groups. At the end of the study, plasma nicotine levels were determined. When rats were given a choice of nicotine or water, nicotine intake was similar between female and male rats. Menthol addition to nicotine solution significantly increased nicotine intake and preference in male but not female rats without a considerable effect on total fluid intake and body weight change in either sex. The average nicotine intake in male rats was 0.5 ± 0.05 and 1.4 ± 0.12 mg/kg/day for nicotine and menthol-nicotine combination (p < .05), respectively. The average nicotine intake in female rats was 0.6 ± 0.05 and 0.6 ± 0.03 mg/kg/day for nicotine and menthol-nicotine combination (p > .05), respectively. Plasma nicotine levels were not significantly different between the groups in either male (nicotine group: 20.8 ± 4.9, mentholated nicotine group: 31.9 ± 3.2 ng/mL) or female (nicotine group: 24.0 ± 3.3, mentholated nicotine group: 17.8 ± 2.9 ng/mL) rats (p > .05). Menthol increases oral nicotine consumption in male, but not female, rats. This study may provide data on the co-use of menthol and nicotine in smokeless tobacco, particularly oral dissolvable tobacco products.