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Sample records for 4-mg nicotine lozenge

  1. Nicotine Lozenges

    MedlinePlus

    Nicotine lozenges are used to help people stop smoking. Nicotine lozenges are in a class of medications called smoking cessation aids. They work by providing nicotine to your body to decrease the withdrawal symptoms ...

  2. Pharmacokinetics of a nicotine polacrilex lozenge.

    PubMed

    Choi, Jae H; Dresler, Carolyn M; Norton, Michele R; Strahs, Kenneth R

    2003-10-01

    To evaluate the pharmacokinetic characteristics of the 2-mg and 4-mg nicotine polacrilex lozenges, the following four separate studies were conducted in healthy adult smokers: (a) A single-dose, four-way crossover (replicate design) study to compare the 4-mg lozenge and the 4-mg nicotine polacrilex gum, (b) a single-dose, two-way crossover study to compare the 2-mg lozenge and the 2-mg gum, (c) a multiple-dose, four-way crossover study to compare the lozenges administered every 90 min and the gums administered every 60 min at 2- and 4-mg dose levels, and (d) a single-dose, three-way crossover study to compare the pharmacokinetic profiles of the 4-mg lozenge when administered in three different ways: (i) Used as directed, (ii) chewed and immediately swallowed, and (iii) chewed, retained in the mouth for 5 min, and then swallowed. The single-dose studies consistently demonstrated 8%-10% higher maximal plasma concentrations and 25%-27% higher AUC values (area under the concentration-time curve) from the lozenges compared with the gums at the 2- and 4-mg dose levels, probably owing to the residual nicotine retained in the gum. The multiple-dose study applying different dosing intervals (i.e., every 90 min for the lozenges and every 60 min for the gums) resulted in approximately 30% lower AUC(0-t) values for the lozenges compared with those for the gums. Administration of the lozenge contrary to the label-specified instructions for use did not lead to a faster or higher absorption of nicotine. These pharmacokinetic characteristics should allow the lozenge to become an effective and safe therapeutic alternative for smoking cessation.

  3. Pharmacokinetics of a nicotine polacrilex lozenge.

    PubMed

    Choi, Jae H; Dresler, Carolyn M; Norton, Michele R; Strahs, Kenneth R

    2003-10-01

    To evaluate the pharmacokinetic characteristics of the 2-mg and 4-mg nicotine polacrilex lozenges, the following four separate studies were conducted in healthy adult smokers: (a) A single-dose, four-way crossover (replicate design) study to compare the 4-mg lozenge and the 4-mg nicotine polacrilex gum, (b) a single-dose, two-way crossover study to compare the 2-mg lozenge and the 2-mg gum, (c) a multiple-dose, four-way crossover study to compare the lozenges administered every 90 min and the gums administered every 60 min at 2- and 4-mg dose levels, and (d) a single-dose, three-way crossover study to compare the pharmacokinetic profiles of the 4-mg lozenge when administered in three different ways: (i) Used as directed, (ii) chewed and immediately swallowed, and (iii) chewed, retained in the mouth for 5 min, and then swallowed. The single-dose studies consistently demonstrated 8%-10% higher maximal plasma concentrations and 25%-27% higher AUC values (area under the concentration-time curve) from the lozenges compared with the gums at the 2- and 4-mg dose levels, probably owing to the residual nicotine retained in the gum. The multiple-dose study applying different dosing intervals (i.e., every 90 min for the lozenges and every 60 min for the gums) resulted in approximately 30% lower AUC(0-t) values for the lozenges compared with those for the gums. Administration of the lozenge contrary to the label-specified instructions for use did not lead to a faster or higher absorption of nicotine. These pharmacokinetic characteristics should allow the lozenge to become an effective and safe therapeutic alternative for smoking cessation. PMID:14577980

  4. Nicotine patch and lozenge are effective for women.

    PubMed

    Shiffman, Saul; Sweeney, Christine T; Dresler, Carolyn M

    2005-02-01

    It has been hypothesized that women may be less likely to obtain therapeutic benefit from nicotine replacement therapy (NRT). The present study tested this hypothesis, using two different types of NRT medications. A secondary analysis of two randomized clinical trials was performed: One compared active 21-mg nicotine patch with placebo among 193 men and 309 women, and the other compared active 2-mg or 4-mg nicotine lozenge with placebo among 788 men and 1,030 women. Using logistic regression analysis of 6-month continuous abstinence and survival analysis, we assessed the efficacy of patch and lozenge among women and tested for a gender x treatment interaction. Active NRT was more effective than placebo among women, for both patch and lozenge. In the lozenge trial, women were less successful than men. The gender x treatment interaction was not significant in either study, whether assessed by logistic regression or survival analysis. In the lozenge trial, gender moderated the effects of smoking rate and dependence (but not treatment) on outcome: These variables affected success rates only among women. Treatment with nicotine patch or lozenge is effective for women, and the analysis did not reveal significant gender differences in efficacy. Gender differences in outcome may be moderated by nicotine dependence. PMID:15804684

  5. The effectiveness of nicotine patch and nicotine lozenge in very heavy smokers.

    PubMed

    Shiffman, Saul; Di Marino, Michael E; Pillitteri, Janine L

    2005-01-01

    The efficacy of nicotine replacement therapy (NRT) among very heavy and highly dependent smokers was examined in a secondary analysis of two randomized clinical trials of NRT. In the first trial, smokers were assigned to active patch (n=249) or placebo (n=253) plus intensive behavioral treatment. In the second trial, smokers were assigned to active 4-mg nicotine lozenge (n=450) or placebo (n=451) plus brief behavioral treatment. Nicotine patch and lozenge significantly increased 6-month continuous abstinence quit rates in both very heavy (>or=40 cigarettes per day) and highly dependent (Fagerström Tolerance Questionnaire or Fagerström Test for Nicotine Dependence score >7) smokers. The effect of active NRT treatment did not differ significantly by smoking rate or nicotine dependence, with the exception that the nicotine patch was significantly more effective than placebo in highly dependent smokers. The nicotine patch and lozenge are effective (vs. placebo) even in heavy and highly dependent smokers. PMID:15723732

  6. Comparative Effectiveness of the Nicotine Lozenge and Tobacco-Free Snuff for Smokeless Tobacco Reduction

    PubMed Central

    Ebbert, Jon O.; Severson, Herbert H.; Croghan, Ivana T.; Danaher, Brian G.; Schroeder, Darrell R.

    2013-01-01

    Long-term smokeless tobacco (ST) use is associated with cardiovascular disease and cancer, but not all ST users want to quit. Previous studies have evaluated the effectiveness of nicotine lozenges and tobacco-free snuff for reducing ST use among ST users not ready to quit, but no comparative effectiveness trials of these two products have been conducted. We conducted a multicenter, randomized clinical pilot study evaluating the comparative effectiveness of the 4-mg nicotine lozenge and tobacco-free snuff for reducing ST use and increasing tobacco abstinence among ST users with no intention of quitting in the next 30 days. Participants received 8 weeks of treatment and behavioral counseling on tobacco reduction strategies with follow-up to 26 weeks. We randomized 81 participants (40 nicotine lozenges, 41 tobacco-free snuff). No significant differences in reduction were observed between the two groups at weeks 8, 12, and 26. No signficant differences were observed between groups in nicotine withdrawal or tobacco craving. However, both groups significantly reduced (p < .001) ST use in cans/week and dips/day from baseline which was sustained through the end-of-study. The observed biochemically-confirmed abstinence rates at week 26 were similar between groups (12% vs. 12%, one-tailed p = .615). The 4-mg nicotine lozenge and the tobacco-free snuff both appear to be effective and comparable for reducing ST use among ST users not ready to quit in the next 30 days. PMID:23454876

  7. Comparative effectiveness of the nicotine lozenge and tobacco-free snuff for smokeless tobacco reduction.

    PubMed

    Ebbert, Jon O; Severson, Herbert H; Croghan, Ivana T; Danaher, Brian G; Schroeder, Darrell R

    2013-05-01

    Long-term smokeless tobacco (ST) use is associated with cardiovascular disease and cancer, but not all ST users want to quit. Previous studies have evaluated the effectiveness of nicotine lozenges and tobacco-free snuff for reducing ST use among ST users not ready to quit, but no comparative effectiveness trials of these two products have been conducted. We conducted a multicenter, randomized clinical pilot study evaluating the comparative effectiveness of the 4-mg nicotine lozenge and tobacco-free snuff for reducing ST use and increasing tobacco abstinence among ST users with no intention of quitting in the next 30 days. Participants received 8 weeks of treatment and behavioral counseling on tobacco reduction strategies with follow-up to 26 weeks. We randomized 81 participants (40 nicotine lozenges, 41 tobacco-free snuff). No significant differences in reduction were observed between the two groups at weeks 8, 12, and 26. No significant differences were observed between groups in nicotine withdrawal or tobacco craving. However, both groups significantly reduced (p<.001) ST use in cans/week and dips/day from baseline which was sustained through the end-of-study. The observed biochemically-confirmed abstinence rates at week 26 were similar between groups (12% vs. 12%, one-tailed p=.615). The 4-mg nicotine lozenge and the tobacco-free snuff both appear to be effective and comparable for reducing ST use among ST users not ready to quit in the next 30 days.

  8. Comparative effectiveness of the nicotine lozenge and tobacco-free snuff for smokeless tobacco reduction.

    PubMed

    Ebbert, Jon O; Severson, Herbert H; Croghan, Ivana T; Danaher, Brian G; Schroeder, Darrell R

    2013-05-01

    Long-term smokeless tobacco (ST) use is associated with cardiovascular disease and cancer, but not all ST users want to quit. Previous studies have evaluated the effectiveness of nicotine lozenges and tobacco-free snuff for reducing ST use among ST users not ready to quit, but no comparative effectiveness trials of these two products have been conducted. We conducted a multicenter, randomized clinical pilot study evaluating the comparative effectiveness of the 4-mg nicotine lozenge and tobacco-free snuff for reducing ST use and increasing tobacco abstinence among ST users with no intention of quitting in the next 30 days. Participants received 8 weeks of treatment and behavioral counseling on tobacco reduction strategies with follow-up to 26 weeks. We randomized 81 participants (40 nicotine lozenges, 41 tobacco-free snuff). No significant differences in reduction were observed between the two groups at weeks 8, 12, and 26. No significant differences were observed between groups in nicotine withdrawal or tobacco craving. However, both groups significantly reduced (p<.001) ST use in cans/week and dips/day from baseline which was sustained through the end-of-study. The observed biochemically-confirmed abstinence rates at week 26 were similar between groups (12% vs. 12%, one-tailed p=.615). The 4-mg nicotine lozenge and the tobacco-free snuff both appear to be effective and comparable for reducing ST use among ST users not ready to quit in the next 30 days. PMID:23454876

  9. The impact of nicotine lozenges and stimulus expectancies on cigarette craving.

    PubMed

    Schlagintweit, Hera E; Good, Kimberley P; Barrett, Sean P

    2014-08-01

    Reduced craving associated with nicotine replacement therapy use is frequently attributed to the effects of nicotine pharmacology, however non-pharmacological factors may also play a role. This study examined the impact of nicotine pharmacology and non-pharmacological components of an acute nicotine lozenge (4 mg) on cigarette craving, mood and heart rate in 70 daily smokers (36 male). Smoking-related stimuli were used to assess cue-induced craving. Participants were randomly assigned to one of four conditions in a balanced placebo design where half the participants were provided deceptive information regarding the nicotine content of a lozenge. Subjective ratings of craving and mood were collected and heart rate was assessed before and after neutral and smoking cues. Nicotine expectancy reduced withdrawal-related craving (p = 0.006) regardless of actual nicotine administration while combined nicotine expectancy and administration reduced intentions to smoke (p = 0.046) relative to each of the other conditions. Exposure to smoking-related stimuli increased cigarette craving (p ≤ 0.001) and negative affect (p ≤ 0.001) regardless of expectancy or pharmacology. Following the smoking cue, women reported a greater increase in withdrawal-related craving than men (p = 0.027). Findings suggest that both pharmacological and non-pharmacological components of nicotine lozenge administration contribute to its acute effects on craving, yet neither appears effective in preventing craving triggered by exposure to environmental smoking stimuli.

  10. The impact of nicotine lozenges and stimulus expectancies on cigarette craving.

    PubMed

    Schlagintweit, Hera E; Good, Kimberley P; Barrett, Sean P

    2014-08-01

    Reduced craving associated with nicotine replacement therapy use is frequently attributed to the effects of nicotine pharmacology, however non-pharmacological factors may also play a role. This study examined the impact of nicotine pharmacology and non-pharmacological components of an acute nicotine lozenge (4 mg) on cigarette craving, mood and heart rate in 70 daily smokers (36 male). Smoking-related stimuli were used to assess cue-induced craving. Participants were randomly assigned to one of four conditions in a balanced placebo design where half the participants were provided deceptive information regarding the nicotine content of a lozenge. Subjective ratings of craving and mood were collected and heart rate was assessed before and after neutral and smoking cues. Nicotine expectancy reduced withdrawal-related craving (p = 0.006) regardless of actual nicotine administration while combined nicotine expectancy and administration reduced intentions to smoke (p = 0.046) relative to each of the other conditions. Exposure to smoking-related stimuli increased cigarette craving (p ≤ 0.001) and negative affect (p ≤ 0.001) regardless of expectancy or pharmacology. Following the smoking cue, women reported a greater increase in withdrawal-related craving than men (p = 0.027). Findings suggest that both pharmacological and non-pharmacological components of nicotine lozenge administration contribute to its acute effects on craving, yet neither appears effective in preventing craving triggered by exposure to environmental smoking stimuli. PMID:24476987

  11. A pilot study of mailed nicotine lozenges with assisted self-help for the treatment of smokeless tobacco users.

    PubMed

    Ebbert, Jon O; Severson, Herbert H; Croghan, Ivana T; Danaher, Brian G; Schroeder, Darrell R

    2010-05-01

    Smokeless tobacco (ST) is associated with adverse health consequences yet treatment resources for ST are not widely available. Cost-effective behavioral interventions incorporating self-help materials and counseling calls have been demonstrated to reduce ST use rates and can be easily disseminated, but the feasibility and effectiveness of incorporating pharmacotherapy into this approach have not been evaluated. We conducted a clinical pilot study randomizing 60 patients to 12 weeks of the 4-mg nicotine lozenge or placebo delivered through the mail. All subjects received an assisted self-help intervention (ASH) with telephone support. At the end of the medication phase, lozenges were being used by 63% of subjects in the 4-mg nicotine lozenge group and 43% in placebo. The nicotine lozenge decreased composite withdrawal symptoms and adverse events were minimal. No significant differences were observed in abstinence rates between the two groups at 3 or 6 months. We conclude that the mailing of nicotine lozenges to ST users is a feasible and safe strategy the efficacy of which needs to be evaluated.

  12. A pilot study of mailed nicotine lozenges with assisted self-help for the treatment of smokeless tobacco users.

    PubMed

    Ebbert, Jon O; Severson, Herbert H; Croghan, Ivana T; Danaher, Brian G; Schroeder, Darrell R

    2010-05-01

    Smokeless tobacco (ST) is associated with adverse health consequences yet treatment resources for ST are not widely available. Cost-effective behavioral interventions incorporating self-help materials and counseling calls have been demonstrated to reduce ST use rates and can be easily disseminated, but the feasibility and effectiveness of incorporating pharmacotherapy into this approach have not been evaluated. We conducted a clinical pilot study randomizing 60 patients to 12 weeks of the 4-mg nicotine lozenge or placebo delivered through the mail. All subjects received an assisted self-help intervention (ASH) with telephone support. At the end of the medication phase, lozenges were being used by 63% of subjects in the 4-mg nicotine lozenge group and 43% in placebo. The nicotine lozenge decreased composite withdrawal symptoms and adverse events were minimal. No significant differences were observed in abstinence rates between the two groups at 3 or 6 months. We conclude that the mailing of nicotine lozenges to ST users is a feasible and safe strategy the efficacy of which needs to be evaluated. PMID:20060229

  13. Nicotine replacement lozenges: abuse-related hyperkeratosis of the lateral border of the tongue. A case report.

    PubMed

    Naudi, K B; Felix, D H

    2007-09-22

    A case of a white patch on the right lateral border of the tongue, found to be hyperkeratosis induced by long-term habitual placement of nicotine replacement lozenges (NiQuitin CQ) in the right lingual sulcus, is presented. The lesion became less evident once the patient varied the intraoral location and reduced his consumption of these tablets.

  14. Adrenergic blocker carvedilol attenuates the cardiovascular and aversive effects of nicotine in abstinent smokers.

    PubMed

    Sofuoglu, Mehmet; Mouratidis, Maria; Yoo, Sonah; Kosten, Thomas

    2006-12-01

    The cardiovascular response to nicotine is mediated mainly by noradrenergic activation. Whether noradrenergic activation mediates other effects of nicotine has not been well documented in humans. In this study, we examined the effects of an alpha and beta-adrenergic receptor blocker: carvedilol, on cardiovascular and subjective responses to nicotine lozenge and on the ability of nicotine lozenge to suppress tobacco withdrawal symptoms in overnight abstinent smokers. Fifteen smokers, nine men and six women, participated in a double-blind, placebo-controlled, crossover study. In each of the three experimental sessions, participants were treated orally with a single 25 or 50 mg dose of carvedilol or placebo. Two hours and 10 min following the medication treatment, participants received a single 4 mg nicotine lozenge. Carvedilol treatment attenuated the nicotine-induced heart rate, systolic and diastolic blood pressure increases. Carvedilol also attenuated the self-report rating of 'bad effects' in response to nicotine. Carvedilol, alone or in combination with nicotine lozenge, did not affect tobacco withdrawal symptoms. Carvedilol treatment did not affect performance on the Stroop Test. These results support the effectiveness of carvedilol for attenuating the cardiovascular effects of nicotine. Attenuation of the rating of 'bad effects' by carvedilol suggests that noradrenergic activation may also mediate the aversive effects of nicotine. PMID:17110799

  15. Acute effects of nicotine on alcohol cue-reactivity in nondependent and dependent smokers.

    PubMed

    McGrath, Daniel S; Peloquin, Marcel P; Ferdinand, Justin C; Barrett, Sean P

    2015-02-01

    Evidence from alcohol self-administration studies suggests that nicotine replacement therapy may influence subjective and behavioral responses to alcohol. However, its effect on alcohol cue-reactivity is unknown. The present study examined the impact of acutely administered nicotine on subjective responses to alcohol-focused pictorial stimuli. In a mixed within/between-subjects design, nondependent smokers (n = 51) and dependent smokers (n = 45) who socially drink were assigned to either a nicotine (4 mg) or placebo lozenge condition following overnight tobacco abstinence. Following lozenge absorption, participants viewed neutral images followed by alcohol-focused pictures. Craving measures for alcohol and tobacco were completed at baseline, following lozenge absorption, following neutral cues, and following alcohol cues. The presentation of alcohol cues increased alcohol-related craving relative to neutral cues, especially among men, but the administration of nicotine did not influence the magnitude of these effects. Nicotine lozenges were found to decrease intentions to smoke and withdrawal-related craving in dependent but not in nondependent smokers. Finally, the presentation of alcohol cues was found to increase intentions to smoke relative to neutral cues across participants regardless of lozenge condition. Findings suggest that although the presentation of alcohol cues can increase alcohol- and tobacco-related cravings in smokers, such effects do not appear to be affected by acute nicotine administration. PMID:25643027

  16. The acute effects of nicotine on the subjective and behavioural responses to denicotinized tobacco in dependent smokers.

    PubMed

    Barrett, Sean P; Darredeau, Christine

    2012-06-01

    Both nicotine and various non-nicotine smoking factors are believed to contribute to tobacco addiction but their relative roles remain incompletely understood. This study aimed to help clarify these roles by examining acute interactions between nicotine and denicotinized tobacco (DT). During two randomized blinded sessions, the effects of a quick-release 4 mg nicotine lozenge (NL) versus placebo lozenge (PL) on the subjective and behavioural responses to DT were examined in 27 (14 men) dependent, daily smokers. Participants were administered NL or PL for 30 min before receiving one initial DT cigarette. Participants could then earn additional DT cigarette puffs over the following 60 min. Subjective state was assessed using the Questionnaire of Smoking Urges-Brief and visual analogue scales at baseline, postlozenge and postinitial DT cigarette. Relative to PL, NL was associated with increased alertness as well as with reduced levels of DT self-administration (P<0.01). The administration of a single DT cigarette was followed by a reduction in craving under both lozenge conditions (P<0.001), an effect that was significantly greater in women (P<0.01). Moreover, DT administration was associated with increased ratings of 'pleasant', 'satisfied', 'stimulated' and 'relaxed', as well as with decreased ratings of 'anxious' (P's<0.01), independent of lozenge condition. The findings suggest that both nicotine and non-nicotine smoking factors may make important contributions towards the addictive properties of tobacco. PMID:22470104

  17. The influence of acutely administered nicotine on cue-induced craving for gambling in at-risk video lottery terminal gamblers who smoke.

    PubMed

    McGrath, Daniel S; Dorbeck, Anders; Barrett, Sean P

    2013-04-01

    Evidence indicates that tobacco use and gambling often co-occur. Despite this association, little is known about how tobacco use affects the propensity to gamble. Nicotine, the putative addictive component of tobacco, has been reported to potentiate the hedonic value of other nonsmoking stimuli. Environmental cues have been identified as an important contributor to relapse in addictive behavior; however, the extent to which nicotine can affect the strength of gambling cues remains unknown. This study examined whether nicotine influences subjective ratings for gambling following gambling cues. In a mixed within/between-subjects design, 30 (20 men) video lottery terminal (VLT) gamblers ('moderate-risk' or 'problem' gamblers) who smoke daily were assigned to nicotine (4 mg deliverable) or placebo lozenge conditions. Subjective and behavioral responses were assessed at baseline, following lozenge, following neutral cues, and following presentation of gambling cues. Nicotine lozenge was found to significantly reduce tobacco-related cravings (P<0.05) but did not affect gambling-related cravings, the choice to play a VLT, or other subjective responses. These results suggest that a low dose of acutely administered nicotine does not increase cue-induced craving for gambling in at-risk VLT gamblers who smoke.

  18. The influence of acutely administered nicotine on cue-induced craving for gambling in at-risk video lottery terminal gamblers who smoke.

    PubMed

    McGrath, Daniel S; Dorbeck, Anders; Barrett, Sean P

    2013-04-01

    Evidence indicates that tobacco use and gambling often co-occur. Despite this association, little is known about how tobacco use affects the propensity to gamble. Nicotine, the putative addictive component of tobacco, has been reported to potentiate the hedonic value of other nonsmoking stimuli. Environmental cues have been identified as an important contributor to relapse in addictive behavior; however, the extent to which nicotine can affect the strength of gambling cues remains unknown. This study examined whether nicotine influences subjective ratings for gambling following gambling cues. In a mixed within/between-subjects design, 30 (20 men) video lottery terminal (VLT) gamblers ('moderate-risk' or 'problem' gamblers) who smoke daily were assigned to nicotine (4 mg deliverable) or placebo lozenge conditions. Subjective and behavioral responses were assessed at baseline, following lozenge, following neutral cues, and following presentation of gambling cues. Nicotine lozenge was found to significantly reduce tobacco-related cravings (P<0.05) but did not affect gambling-related cravings, the choice to play a VLT, or other subjective responses. These results suggest that a low dose of acutely administered nicotine does not increase cue-induced craving for gambling in at-risk VLT gamblers who smoke. PMID:23412113

  19. Lozenge Tilings with Free Boundaries

    NASA Astrophysics Data System (ADS)

    Panova, Greta

    2015-11-01

    We study lozenge tilings of a domain with partially free boundary. In particular, we consider a trapezoidal domain (half-hexagon), s.t. the horizontal lozenges on the long side can intersect it anywhere to protrude halfway across. We show that the positions of the horizontal lozenges near the opposite flat vertical boundary have the same joint distribution as the eigenvalues from a Gaussian Unitary Ensemble (the GUE-corners/minors process). We also prove the existence of a limit shape of the height function, which is also a vertically symmetric plane partition. Both behaviors are shown to coincide with those of the corresponding doubled fixed boundary hexagonal domain. We also consider domains where the different sides converge to {∞} at different rates and recover again the GUE-corners process near the boundary.

  20. Modafinil and nicotine interactions in abstinent smokers.

    PubMed

    Sofuoglu, Mehmet; Waters, Andrew J; Mooney, Marc

    2008-01-01

    In this study, we examined the effects of a wakefulness-promoting medication, modafinil, alone and with the nicotine lozenge, on subjective, physiological and cognitive measures as well as on nicotine withdrawal in overnight abstinent cigarette smokers. Nineteen smokers, 13 male and 6 female, participated in a double-blind, placebo-controlled, crossover study. In each of three experimental sessions, subjects were treated orally with a single 200 mg or 400 mg dose of modafinil or placebo. Two hours and 10 min following the medication treatment, subjects received a single 2 mg nicotine lozenge. Both doses of modafinil alone increased the rating of elated-depressed on the Profile of Mood States (POMS) subscale in the direction of depressed and increased ratings of negative affect on the Positive and Negative Affect Schedule (PANAS). In contrast, the 200 mg modafinil dose combined with a 2 mg nicotine lozenge, increased the rating of energetic-tired in the direction of energetic on the POMS subscale. Modafinil attenuated self-reported rating of 'drug strength' in response to the nicotine lozenge. Modafinil, alone or in combination with the nicotine lozenge, did not affect tobacco withdrawal symptoms. There was an increase in baseline heart rate and systolic blood pressure under modafinil treatment. In addition, modafinil speeded reaction times on a modified Stroop task. The clinical utility of modafinil for smoking cessation needs to be determined in future studies. PMID:17868195

  1. Salivary levels of gramicidin after use of a tyrothricin-containing gargle/mouth-wash and tyrothricin lozenges.

    PubMed

    Matula, C; Nahler, G; Kreuzig, F

    1988-01-01

    Three pharmaceutical preparations for the disinfection of the oropharynx were tested with regard to the gramicidin concentration obtained in the saliva after their appropriate application. Peak values followed a dose-concentration relationship and were highest after sucking a lozenge containing 10 mg tyrothricin (mean 109.3 mg/L) followed by that of a gargle/mouth-wash containing 667 mg tyrothricin/L (mean 21.1 mg/L) and of a lozenge containing 4 mg tyrothricin (mean 14.4 mg/L). PMID:2460410

  2. Lozenge Tilings and Hurwitz Numbers

    NASA Astrophysics Data System (ADS)

    Novak, Jonathan

    2015-10-01

    We give a new proof of the fact that, near a turning point of the frozen boundary, the vertical tiles in a uniformly random lozenge tiling of a large sawtooth domain are distributed like the eigenvalues of a GUE random matrix. Our argument uses none of the standard tools of integrable probability. In their place, it uses a combinatorial interpretation of the Harish-Chandra/Itzykson-Zuber integral as a generating function for desymmetrized Hurwitz numbers.

  3. Preferences among five nicotine treatments based on information versus sampling.

    PubMed

    Schneider, Nina G; Cortner, Chris; Justice, Melanie; Gould, Jessica L; Amor, Courtney; Hartman, Neil; Kleinman, Leonard; Olmstead, Richard E

    2008-01-01

    Smokers' minimal exposure to nicotine replacement treatments (NRTs) may account for poor compliance and outcome with these treatments. This study tested effects of information versus sampling of NRTs on smokers' preferences and expectations. The study was a crossover comparing information-only (INF) with sampling (SMP) methods for five NRTs: gum (2 and 4 mg), lozenges (2 and 4 mg), and inhalers. Subjects were given computer-based presentations on NRTs (INF) and rated and ranked use variables (e.g., ease, sensory/ritual, perceived relief, embarrassment) and overall choice for "use to quit." After INF testing, subjects sampled each NRT (SMP) and again rated and ranked drugs. SMP was brief (4 min) to mimic potential use in practice. Results showed changes in perceptions and preferences post-SMP. NRT preferences shifted for overall "use to quit" (59%) and most use variables (43%-63%) post-SMP. Inhalers (generally top choice) showed a 20% drop in choice to quit (p<.04) and a 24% drop in anticipated "relief of withdrawal" (p<.04) post-SMP; 4-mg lozenge ratings increased for "relief of withdrawal" (p<.02). Ratings improved post-SMP for three of the five NRTs ("ease of use," p<.05) but were reduced overall for liking "sensory action" (p<.003) and reduced for all but 2-mg gum for "use to quit" (p<.03). Positive changes were seen in improved ratings of NRTs chosen post-SMP. Given that reactions to NRTs change with experience, sampling should allow for a more realistic choice of NRT (self-tailoring) and better compliance versus current trial-and-error methods.

  4. Ability of a new oral nicotine substitute to reduce smoking urge in moderate smokers.

    PubMed

    Demazières, A; Luthringer, R; Coppel, E; Gilles, C; Fleury, C; Roegel, J C; Delarue, A; Laur, C; Lagrue, G

    2006-03-01

    The aim of this study was to assess the effectiveness of a new nicotine lozenge ( Nicopass 1.5 mg) in reducing smoking urge after an overnight abstinence. Twenty-four moderate smokers participated in a randomized, double-blind, placebo-controlled, 2-period crossover trial. The results showed that 1.5 mg-nicotine lozenge is superior to placebo in reducing smoking urge (p = 0.0001). In addition, nicotine lozenge, but not placebo, significantly improved vigilance and psychomotor performances (p < 0.05) and displayed a cardiac chronotropic effect. Thus, the 1.5-mg nicotine lozenge appears as an effective aid to alleviate acute tobacco withdrawal symptoms in moderate smokers. PMID:15964703

  5. New Product Marketing Blurs the Line Between Nicotine Replacement Therapy and Smokeless Tobacco Products.

    PubMed

    Kostygina, Ganna; England, Lucinda; Ling, Pamela

    2016-07-01

    Tobacco companies have begun to acquire pharmaceutical subsidiaries and recently started to market nicotine replacement therapies, such as Zonnic nicotine gum, in convenience stores. Conversely, tobacco companies are producing tobacco products such as tobacco chewing gum and lozenges that resemble pharmaceutical nicotine replacement products, including a nicotine pouch product that resembles snus pouches. This convergence of nicotine and tobacco product marketing has implications for regulation and tobacco cessation. PMID:27077338

  6. New Product Marketing Blurs the Line Between Nicotine Replacement Therapy and Smokeless Tobacco Products.

    PubMed

    Kostygina, Ganna; England, Lucinda; Ling, Pamela

    2016-07-01

    Tobacco companies have begun to acquire pharmaceutical subsidiaries and recently started to market nicotine replacement therapies, such as Zonnic nicotine gum, in convenience stores. Conversely, tobacco companies are producing tobacco products such as tobacco chewing gum and lozenges that resemble pharmaceutical nicotine replacement products, including a nicotine pouch product that resembles snus pouches. This convergence of nicotine and tobacco product marketing has implications for regulation and tobacco cessation.

  7. Nicotine Replacement Therapy: An Overview

    PubMed Central

    Wadgave, Umesh; Nagesh, L

    2016-01-01

    Today tobacco use is the single greatest preventable cause of death in the world. Tobacco use is often incorrectly perceived to be solely a personal choice. This is contradicted by the fact that when fully aware of the health impact, most tobacco users want to quit but find it difficult to stop due to the addictiveness of nicotine. Henceforth, Nicotine replacement therapy (NRT) came into existence which temporarily replaces much of the nicotine from tobacco to reduce motivation to consume tobacco and nicotine withdrawal symptoms, thus easing the transition from cigarette smoking to complete abstinence. Various alternative nicotine sources (gum, transdermal patch, nasal spray, inhaler and sublingual tablets/lozenges) have been incorporated into tobacco cessation programs. Recent research is more focusing on rapid delivery of nicotine (Nicotine preloading, true pulmonary inhaler) and immunological approaches (nicotine vaccine) to tackle nicotine dependence. These NRTs are in general well tolerated and have minimal adverse effects. The review aims to summarize literature on various modes of nicotine replacement therapy methods currently used to treat nicotine dependence, and to give an overview about future possible approaches to treat tobacco use disorder. PMID:27610066

  8. Nicotine Replacement Therapy: An Overview.

    PubMed

    Wadgave, Umesh; Nagesh, L

    2016-07-01

    Today tobacco use is the single greatest preventable cause of death in the world. Tobacco use is often incorrectly perceived to be solely a personal choice. This is contradicted by the fact that when fully aware of the health impact, most tobacco users want to quit but find it difficult to stop due to the addictiveness of nicotine. Henceforth, Nicotine replacement therapy (NRT) came into existence which temporarily replaces much of the nicotine from tobacco to reduce motivation to consume tobacco and nicotine withdrawal symptoms, thus easing the transition from cigarette smoking to complete abstinence. Various alternative nicotine sources (gum, transdermal patch, nasal spray, inhaler and sublingual tablets/lozenges) have been incorporated into tobacco cessation programs. Recent research is more focusing on rapid delivery of nicotine (Nicotine preloading, true pulmonary inhaler) and immunological approaches (nicotine vaccine) to tackle nicotine dependence. These NRTs are in general well tolerated and have minimal adverse effects. The review aims to summarize literature on various modes of nicotine replacement therapy methods currently used to treat nicotine dependence, and to give an overview about future possible approaches to treat tobacco use disorder.

  9. Nicotine Replacement Therapy: An Overview.

    PubMed

    Wadgave, Umesh; Nagesh, L

    2016-07-01

    Today tobacco use is the single greatest preventable cause of death in the world. Tobacco use is often incorrectly perceived to be solely a personal choice. This is contradicted by the fact that when fully aware of the health impact, most tobacco users want to quit but find it difficult to stop due to the addictiveness of nicotine. Henceforth, Nicotine replacement therapy (NRT) came into existence which temporarily replaces much of the nicotine from tobacco to reduce motivation to consume tobacco and nicotine withdrawal symptoms, thus easing the transition from cigarette smoking to complete abstinence. Various alternative nicotine sources (gum, transdermal patch, nasal spray, inhaler and sublingual tablets/lozenges) have been incorporated into tobacco cessation programs. Recent research is more focusing on rapid delivery of nicotine (Nicotine preloading, true pulmonary inhaler) and immunological approaches (nicotine vaccine) to tackle nicotine dependence. These NRTs are in general well tolerated and have minimal adverse effects. The review aims to summarize literature on various modes of nicotine replacement therapy methods currently used to treat nicotine dependence, and to give an overview about future possible approaches to treat tobacco use disorder. PMID:27610066

  10. Nicotine Replacement Therapy: An Overview

    PubMed Central

    Wadgave, Umesh; Nagesh, L

    2016-01-01

    Today tobacco use is the single greatest preventable cause of death in the world. Tobacco use is often incorrectly perceived to be solely a personal choice. This is contradicted by the fact that when fully aware of the health impact, most tobacco users want to quit but find it difficult to stop due to the addictiveness of nicotine. Henceforth, Nicotine replacement therapy (NRT) came into existence which temporarily replaces much of the nicotine from tobacco to reduce motivation to consume tobacco and nicotine withdrawal symptoms, thus easing the transition from cigarette smoking to complete abstinence. Various alternative nicotine sources (gum, transdermal patch, nasal spray, inhaler and sublingual tablets/lozenges) have been incorporated into tobacco cessation programs. Recent research is more focusing on rapid delivery of nicotine (Nicotine preloading, true pulmonary inhaler) and immunological approaches (nicotine vaccine) to tackle nicotine dependence. These NRTs are in general well tolerated and have minimal adverse effects. The review aims to summarize literature on various modes of nicotine replacement therapy methods currently used to treat nicotine dependence, and to give an overview about future possible approaches to treat tobacco use disorder.

  11. 77 FR 70955 - FDA Actions Related to Nicotine Replacement Therapies and Smoking-Cessation Products; Report to...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-28

    ... HUMAN SERVICES Food and Drug Administration 21 CFR Part 15 FDA Actions Related to Nicotine Replacement... public on FDA consideration of applicable approval mechanisms and additional indications for nicotine..., including nicotine-containing gums, patches, and lozenges, are already marketed for smoking cessation....

  12. The future of nicotine replacement.

    PubMed

    Russell, M A

    1991-05-01

    Following in the wake of progress forged by nicotine chewing gum, a new generation of nicotine replacement products will soon be available as aids to giving up smoking. These range from nicotine skin patches, which take 6-8 hrs to give very flat steady-state peak blood levels, to nicotine vapour inhalers which mimic the transient high-nicotine boli that follow within a few seconds of each inhaled puff of cigarette smoke. Other products undergoing clinical trials include a nasal nicotine spray and nicotine lozenges. It is argued here that it is not so much the efficacy of new nicotine delivery systems as temporary aids to cessation, but their potential as long-term alternatives to tobacco that makes the virtual elimination of tobacco a realistic future target. Their relative safety compared with tobacco is discussed. A case is advanced for selected nicotine replacement products to be made as palatable and acceptable as possible and actively promoted on the open market to enable them to compete with tobacco products. They will also need health authority endorsement, tax advantages and support from the anti-smoking movement if tobacco use is to be gradually phased out altogether.

  13. ``Lozenge'' Contour Plots in Scattering from Polymer Networks

    NASA Astrophysics Data System (ADS)

    Read, D. J.; McLeish, T. C. B.

    1997-07-01

    We present a consistent explanation for the appearance of ``lozenge'' shapes in contour plots of the two dimensional scattering intensity from stretched polymer networks. By explicitly averaging over quenched variables in a tube model, we show that lozenge patterns arise as a result of chain material that is not directly deformed by the stretch. We obtain excellent agreement with experimental data.

  14. Nicotine poisoning

    MedlinePlus

    Nicotine is found in: Chewing tobacco Cigarettes E-cigarettes Liquid nicotine Nicotine gum (Nicorette) Nicotine patches (Habitrol, Nicoderm) Pipe tobacco Some insecticides Tobacco leaves Note: This list may not be all-inclusive.

  15. Absorption of orally administered amphotericin B lozenges.

    PubMed

    Ching, M S; Raymond, K; Bury, R W; Mashford, M L; Morgan, D J

    1983-07-01

    The systemic absorption of amphotericin B, administered as a 10 mg lozenge, was investigated in 14 patients with malignancies, who received three or four doses daily during chronic administration. The mean plasma amphotericin B concentration, measured 3 h after the morning dose on from 1-20 occasions over a 1-80 day period, ranged among subjects from 46 +/- 13 ng/ml (s.d., n = 20) to 136 +/- 25 ng/ml (n = 19). Using the previously reported intravenous clearance of the drug, the fraction of the dose absorbed was estimated at 8.3-9.9%. This is considerably greater than that estimated from earlier reports (0.2-0.9%), which used much higher oral doses (2-10 g/day). PMID:6882617

  16. [Safety of nicotine addiction treatment].

    PubMed

    Korzeniowska, Katarzyna; Cieślewicz, Artur; Jabłecka, Anna

    2013-01-01

    Not all smoking addicts can succeed in quitting smoking with willpower only. These people may use nicotine replacement therapy (patches, gums, lozenges, sublingual tablets, inhalers), medicines (bupropion, varenicline and cytisine) and psychological aid. Each drug, besides its therapeutic effect, creates the risk of adverse reactions which number and severity is not always accepted by the patient. The aim of the study was to analyze adverse effects of bupropion, varenicline and cytisine formulations reported by patients. From July 2011 to June 2013 Regional Centre for Monitoring Adverse Drug Reactions (Department of Clinical Pharmacology, Department of Cardiology, Poznan University of Medical Sciences) recorded 32 suspected adverse reactions to the use of drugs for the treatment of nicotine addiction (12 after the preparation of cytisine and varenicline, 8 after preparations of bupropion). High determination caused that none of the patients withdrew from the therapy because of adverse effects.

  17. Lozenge Tilings, Glauber Dynamics and Macroscopic Shape

    NASA Astrophysics Data System (ADS)

    Laslier, Benoît; Toninelli, Fabio Lucio

    2015-09-01

    We study the Glauber dynamics on the set of tilings of a finite domain of the plane with lozenges of side 1/ L. Under the invariant measure of the process (the uniform measure over all tilings), it is well known (Cohn et al. J Am Math Soc 14:297-346, 2001) that the random height function associated to the tiling converges in probability, in the scaling limit , to a non-trivial macroscopic shape minimizing a certain surface tension functional. According to the boundary conditions, the macroscopic shape can be either analytic or contain "frozen regions" (Arctic Circle phenomenon Cohn et al. N Y J Math 4:137-165, 1998; Jockusch et al. Random domino tilings and the arctic circle theorem, arXiv:math/9801068, 1998). It is widely conjectured, on the basis of theoretical considerations (Henley J Statist Phys 89:483-507, 1997; Spohn J Stat Phys 71:1081-1132, 1993), partial mathematical results (Caputo et al. Commun Math Phys 311:157-189, 2012; Wilson Ann Appl Probab 14:274-325, 2004) and numerical simulations for similar models (Destainville Phys Rev Lett 88:030601, 2002; cf. also the bibliography in Henley (J Statist Phys 89:483-507, 1997) and Wilson (Ann Appl Probab 14:274-325, 2004), that the Glauber dynamics approaches the equilibrium macroscopic shape in a time of order L 2+ o(1). In this work we prove this conjecture, under the assumption that the macroscopic equilibrium shape contains no "frozen region".

  18. Development of shear zone-related lozenges in foliated rocks

    NASA Astrophysics Data System (ADS)

    Ponce, Carlos; Druguet, Elena; Carreras, Jordi

    2013-05-01

    Tectonic lozenges are elongate bodies bounded by relatively more deformed rocks. The focus of this study is on the 2-D structure of tectonic lozenges developed during ductile shear in rocks with a pre-existing mechanical anisotropy. On the basis of a detailed analysis of shear zones in foliated rocks from the Cap de Creus area (Variscan of the eastern Pyrenees), five mechanisms to explain the development of different types of lozenges in foliated rocks are suggested. These mechanisms are explained on the basis of the orientation of the previous foliation relative to the bulk shearing direction. It is shown that the prevailing mechanism does not majorly depend on the bulk kinematics but on the angular relationship between the pre-existing foliation and the bulk kinematic axes, and on shear zone interaction. This has implications on the use of lozenge shapes in tectonic interpretations. The fact that there is a wide range of initial orientations, propagation modes and coalescence types implies that the final lozenge geometry is not univocally related neither to the type of strain nor to the kinematic regime.

  19. Role of nicotine pharmacokinetics in nicotine addiction and nicotine replacement therapy: a review.

    PubMed

    Le Houezec, J

    2003-09-01

    Smoking is a complex behaviour involving both pharmacological and psychological components. Nicotine is the main alkaloid found in tobacco, and is responsible for its addictive potential. Nicotine-positive effects on mood and cognition are strong reinforcements for smokers that contribute to their addiction, and cigarette smoking is particularly addictive because inhaled nicotine is absorbed through the pulmonary venous rather than the systemic venous system, and thus reaches the brain in 10-20 seconds. As the likelihood that a substance will be abused depends on the time between administration and central reinforcement, tobacco smoking can easily become addictive. Nicotine replacement therapy (NRT) is available in different forms (gum, transdermal patch, nasal spray, inhaler, sublingual tablet and lozenge), and has been shown to relieve withdrawal symptoms and to double abstinence rates compared to placebo. Most NRT forms deliver nicotine more slowly than smoking, and the increase in nicotine blood levels is more gradual. Compared to tobacco smoking or even tobacco chewing, few positive (reinforcing) effects are obtained from NRT use. Nasal spray provides faster withdrawal relief than other NRT, but compared to smoking absorption is slower and nicotine blood levels obtained are lower than with smoking. These differences in pharmacokinetic profiles compared with smoking may explain that some smokers still have difficulties quitting smoking even when using NRT (apart from psychological and/or social factors). Combination therapy (e.g., patch+gum, patch+inhaler), higher dosage, temporary abstinence or smoking reduction (using NRT to reduce smoke intake) may be needed to help more smokers to quit. PMID:12971663

  20. Cannabinoid receptor stimulation increases motivation for nicotine and nicotine seeking.

    PubMed

    Gamaleddin, Islam; Wertheim, Carrie; Zhu, Andy Z X; Coen, Kathleen M; Vemuri, Kiran; Makryannis, Alex; Goldberg, Steven R; Le Foll, Bernard

    2012-01-01

    The cannabinoid system appears to play a critical facilitative role in mediating the reinforcing effects of nicotine and relapse to nicotine-seeking behaviour in abstinent subjects based on the actions of cannabinoid (CB) receptor antagonists. However, the effects of CB receptor stimulation on nicotine self-administration and reinstatement have not been systematically studied. Here, we studied the effects of WIN 55,212-2, a CB1/2 agonist, on intravenous nicotine self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement in rats. The effects of WIN 55,212-2 on responding for food under similar schedules were also studied. In addition, the effects of WIN 55,212-2 on nicotine- and cue-induced reinstatement of nicotine seeking were also studied, as well as the effects of WIN 55,212-2 on nicotine discrimination. WIN 55,212-2 decreased nicotine self-administration under the FR schedule. However, co-administration of WIN 55,212-2 with nicotine decreased responding for food, which suggests that this effect was non-selective. In contrast, WIN 55,212-2 increased both nicotine self-administration and responding for food under the PR schedule, produced dose-dependent reinstatement of nicotine seeking, and enhanced the reinstatement effects of nicotine-associated cues. Some of these effects were reversed by the CB1 antagonist rimonabant, but not by the CB2 antagonist AM630. In the drug discrimination tests between saline and 0.4 mg/kg nicotine, WIN 55,212-2 produced no nicotine-like discriminative effects but significantly potentiated discriminative stimulus effects of nicotine at the low dose through a CB1-receptor-dependent mechanism. These findings indicate that cannabinoid CB1-receptor stimulation increases the reinforcing effects of nicotine and precipitates relapse to nicotine-seeking behaviour in abstinent subjects. Thus, modulating CB1-receptor signalling might have therapeutic value for treating nicotine dependence. PMID:21521420

  1. The effects of nicotine on intrusive memories in nonsmokers.

    PubMed

    Hawkins, Kirsten A; Cougle, Jesse R

    2013-12-01

    Correlational research suggests that smoking increases risk of posttraumatic stress disorder (PTSD), though such research by nature cannot rule out third variable explanations for this relationship. The present study used an analogue trauma film design to experimentally test the effects of nicotine on the occurrence of intrusive memories. Fifty-four healthy nonsmokers were randomly assigned to ingest either a nicotine or placebo lozenge before viewing a film depicting motor vehicle accidents. Participants recorded intrusive memories immediately after the film and for a week via diary. Participants in the nicotine condition reported significantly more intrusive memories immediately after watching the film, yet no group differences emerged on intrusions or intrusion-related distress reported during the following week. Among participants low in dispositional rumination, those who had ingested a nicotine lozenge reported more intrusions in the subsequent week than those in the placebo condition. These findings provide novel experimental evidence for the role of nicotine in increasing risk of PTSD and suggest that nicotine may contribute to trauma-related rumination but not heightened reactivity to trauma cues. PMID:24099352

  2. Chewing nicotine gum for 3 months: what happens to plasma nicotine levels?

    PubMed Central

    McNabb, M E

    1984-01-01

    Techniques that help patients stop smoking should also reduce their exposure to agents such as nicotine. The mean plasma nicotine levels in 50 subjects while they were still smoking and then while they were chewing pieces of gum containing either 2 or 4 mg of nicotine over a 12-week period of abstinence were 35, 9 and 23 ng/mL (217, 56 and 143 nmol/L) respectively. A small number of subjects given an unlimited supply of gum used 14 to 24 pieces of 4-mg gum daily and had plasma nicotine levels exceeding the levels achieved while smoking. There were no acute symptoms necessitating medical intervention associated with these excessive levels. Side effects were uncommon and usually controllable. When simple dosage rules are followed people who chew nicotine gum for a few months to stop smoking lower their exposure to nicotine. PMID:6478344

  3. Nicotine dependence and smoking cessation.

    PubMed

    Tan, Linxiang; Tang, Quansheng; Hao, Wei

    2009-11-01

    Tobacco use is the single most preventable cause of death, disability and disease in the world and is projected to be the leading cause of death and disability across all developed and developing countries by 2020. Nicotine, the primary active ingredient of cigarettes that contributes to physical dependence, acts on nicotine receptors in the central nervous system and leads to the release of neurotransmitters (such as dopamine). Like other drugs of abuse, nicotine is thought to produce reinforcing effect by activating the mesocorticolimbic dopamine system. A wide variety of cessation treatments of nicotine dependence is commercially available, yet only 2 general approaches have received empirical validation: behavioral intervention (including 5 As brief intervention) and pharmacotherapy. The evidences show that 5 As brief intervention is one of the most cost-effective treatments in clinical work for busy physicians. Three types of medications have been available in market for smoking cessation treatment: nicotine replacement treatment (NRT, i.e., transdermal patch, gum, inhaler, nasal spray, and lozenge), sustained release bupropion and varenicline. Varenicline, a novel alpha4beta2 nicotinic receptor partial agonist, is effective for tobacco dependence. Phase III trials suggest that it is more effective than NRT and bupropion SR. The safety profile of varenicline is excellent, with the most commonly occurring adverse events, nausea, typically mild and well tolerated. However, new safety warnings are added to the varenicline label because of post-marketing report including agitation, depression and suicidality. A causal connection between varenicline use and these symptoms has not been established. PMID:19952392

  4. Nicotine replacement therapy as a treatment for complex aphthosis.

    PubMed

    Hill, Samantha C; Stavrakoglou, Anastasios; Coutts, Ian R

    2010-09-01

    Complex aphthosis, the occurrence of recurrent oral and genital aphthous ulceration without manifestations of systemic disease, is relatively uncommon and of unknown aetiology. We describe a case of complex aphthosis which began within weeks of stopping smoking. After failing to respond to conventional agents, the patient was successfully treated with nicotine lozenges. Recurrent aphthous stomatitis (RAS) is known to be less common in smokers and there have been previous reports of nicotine being used as successful treatments for RAS and Behçet's disease. We discuss the mechanisms of action of nicotine whereby nicotine could influence the natural history of aphthous ulceration. We recommend considering its use when conventional management has failed, particularly in ex-smokers.

  5. [Nicotine dependence].

    PubMed

    Kawazoe, Shingo; Shinkai, Takahiro

    2015-09-01

    Smoking is the most widespread addictive behavior in the world, and it causes physical and psychological dependence on nicotine. As for physical nicotine dependence, nicotine produces rewarding effects by interacting with nicotinic acetylcholine receptors on neurons in the brain's reward system. Psychological dependence on nicotine comes with a complex psychological procedure that is based on distorted cognition which justifies their smoking behavior. Clinicians should support smokers with willingness to quit smoking comprehensively with this knowledge, although the success rate of smoking cessation is no ideal in general. PMID:26394514

  6. [Anaphylactic shock after sucking on a throat lozenge].

    PubMed

    Hesselbach, C; Böhning, W; Wettengel, R

    1990-09-14

    A few minutes after sucking a lozenge for a sore throat a 68-year-old man developed an anaphylactic shock. At a heart rate of 110/min there was no palpable blood pressure. A red confluent exanthem, predominantly of the trunk, was noted. After brief intensive-care treatment the patient was completely well again and diagnostic tests for allergy were performed. The prick test for the 14 individual ingredients of the throat lozenge produced massive reddening and urticaria on the test arm with carbowax, a polyethylene glycol which serves as a vehicle in the remedy and does not have to be listed. Later there were an urge to cough and urticaria all over the trunk. There was no systemic reaction. Neither specific IgE antibodies nor any complement-consuming reaction could be demonstrated. Thus the precipitating mechanism remains unexplained. PMID:1698139

  7. [Anaphylactic shock after sucking on a throat lozenge].

    PubMed

    Hesselbach, C; Böhning, W; Wettengel, R

    1990-09-14

    A few minutes after sucking a lozenge for a sore throat a 68-year-old man developed an anaphylactic shock. At a heart rate of 110/min there was no palpable blood pressure. A red confluent exanthem, predominantly of the trunk, was noted. After brief intensive-care treatment the patient was completely well again and diagnostic tests for allergy were performed. The prick test for the 14 individual ingredients of the throat lozenge produced massive reddening and urticaria on the test arm with carbowax, a polyethylene glycol which serves as a vehicle in the remedy and does not have to be listed. Later there were an urge to cough and urticaria all over the trunk. There was no systemic reaction. Neither specific IgE antibodies nor any complement-consuming reaction could be demonstrated. Thus the precipitating mechanism remains unexplained.

  8. Methemoglobinemia and acute hemolysis after tetracaine lozenge use.

    PubMed

    Lavergne, Sandrine; Darmon, Michael; Levy, Vincent; Azoulay, Elie

    2006-03-01

    Acquired methemoglobinemia is a rare but severe condition associated with oxidizing stressors, most notably medications. Although the symptoms can be life threatening, they usually respond promptly to exposure cessation and methylene blue injection. We describe the first case of methemoglobinemia associated with tetracaine lozenge use. A previously healthy 33-year-old man was admitted with fever, respiratory distress, cyanosis, and acute hemolysis. Physical findings and chest radiograph were normal. Low pulse oximetry readings contrasted with normal partial pressure of oxygen and calculated oxygen saturation. The methemoglobin level was 10.8%. The patient recovered with methylene blue injection and blood transfusions. He reported recent self-medication with tetracaine lozenges for a sore throat during a flu-like illness. No other cause of methemoglobinemia was found.

  9. Development and evaluation of novel lozenges containing marshmallow root extract.

    PubMed

    Benbassat, Niko; Kostova, Bistra; Nikolova, Irina; Rachev, Dimitar

    2013-11-01

    Lozenges (tablets intended to be dissolved slowly in the mouth) were evaluated as delivery system for polysaccharides extract from Althaea officinalis L. (marshmallow) root. The aim of investigation was to improve of the efficacy of convenient preparations for the treatment of irritated oropharyngeal mucosa and associated dry irritable cough. The formulations studied were prepared with water extract of roots of Althaea officinalis L. The polysaccharides extract was obtained by ultrasonification. Acute oral toxicity (LD 50 p.o.) of the obtained extract was estimated in mice. Four models of lozenges based on different excipients were formulated. The characteristics of the preparations: resistance to crushing, friability testing, disintegration time and drug release properties were evaluated.

  10. Nicotine replacement products: poisoning in children.

    PubMed

    2014-05-01

    Nicotine is widely used in smoking cessation aids. They are marketed in many forms, including: chewing gum, sublingual tablets, lozenges, transdermal patches, cartridges for oral inhalation, and mouth spray. French poison control and toxico-vigilance centres identified 318 cases of exposure to nicotine replacement products in children under the age of 10 years between 2000 and 2010. The exposure provoked symptoms in 62 of these children, about two-thirds of whom were under the age of 4 years. A U.S. analysis identified 1768 cases of poisoning in children under the age of 6 years involving smokeless tobacco products, reported between 2006 and 2008.84% of these cases occurred in children under the age of 3 years. The first signs of nicotine poisoning are gastrointestinal (vomiting, diarrhoea), cardiovascular (tachycardia, hypertension) and neuropsychological (tremor of the extremities). With higher doses, these effects are rapidly followed by loss of consciousness, convulsions or respiratory failure. In children, poisoning can occur after ingestion of 1 mg of nicotine per kilogram of body weight. A dose of this magnitude is sometimes fatal in adults. Most cases of poisoning involving transdermal patches occur when a child finds an unused patch, or a used patch that an adult has discarded in a bin without taking proper precautions. Sometimes they involve patches that have become detached from an adult's skin. In practice, it is important to warn adults using smoking cessation aids containing nicotine that these products are dangerous

  11. Efficacy of Ambroxol lozenges for pharyngitis: a meta-analysis

    PubMed Central

    2014-01-01

    Background Ambroxol has a local anaesthetic action and is marketed for pain relief for sore throat. The objective is to examine the efficacy and safety of ambroxol for the relief of pain associated with acute uncomplicated sore throat. Methods A systematic review of the literature and meta-analysis. Selection criteria consisted of randomized controlled trials which compared ambroxol to placebo or any other treatment for sore throat. Two reviewers independently assessed for relevance, inclusion, and risk of bias. Weighted mean differences (WMDs) were calculated and are reported with corresponding 95% confidence intervals (CIs). Results and conclusion From 14 potentially relevant citations, five trials reported in three publications met the inclusion criteria, three of them were published twice. Ambroxol lozenges were compared in different dosages (5–30 mg) with mint flavoured lozenges and once with benzocaine. Main outcome was a ratio of pain reduction measured repeatedly over 3 h compared to baseline on 6-item verbal rating scale. A total of 1.772 adult patients participated in the trials. Pain intensity decreased in both study arms. A meta-analysis of the 5 controlled trials resulted in a difference in pain reduction compared to placebo of -0.11 (95% CI [-0.15, -0.07]; p < 0.0001) favouring ambroxol 20 mg. Quality of reporting of the studies was low. Ambroxol is slightly more effective in relieving pain in acute sore throat than mint flavoured lozenges over a period of 3 h. However, the additional benefits of ambroxol beyond three hours, remain unclear given that more than 50% of patients using mint flavoured lozenges for pain relief reported good or very good efficacy after 1 day compared to 69% with ambroxol. Ambroxol is a safe option for individual patients with mainly local symptoms asking for treatment. PMID:24621446

  12. [Clinical study on Qinghouyan lozenge in treatment of acute pharyngitis].

    PubMed

    Yu, Jiao-iiao; Xuan, Zhen-yu; Ruan, Yan; Zhang, Hui-yong; Shi, Ke-hua; Guo, Yu

    2015-01-01

    To evaluate the clinical efficacy and safety of Qinghouyan lozenge in the treatment of acute pharyngitis due to Lung-heat and Yin-deficiency, and compare with Qinghouyan oral Liquid. Totally 144 subjects were enrolled and randomly divided into two groups (72 in the test group and 72 in the control group). The participants in the test group were given Qinghouyan lozenge for 5 days, and those in the control group were given Qinghouyan oral Liquid for 5 days. The effectiveness evaluation indexes were pharyngalgia/odynophagia disappearance rate, overall efficacy of TCM syndromes, TCM syndrome scores, and single syndrome and sign disappearance rate. During the test, the safety was evaluated by vital sign, lab examination indexes and adverse events. The results for the full analysis set showed that the couth disappearance rate, the incidence rate of TCM syndromes, and the throat/uvula congestion disappearance rate of the test group were higher than that of the control group (P < 0.05), with significant differences in the changes in syndrome scores between the two groups (P < 0.05). Altogether 3 adverse events were observed in the test group while 6 adverse events in the control group, without significant differences in the adverse event rate between the two groups (P < 0.05), serious abnormal laboratory examinations and vital signs. In conclusion, Qinghouyan lozenge has better efficacy in treatment of acute pharyngitis due to Lung-heat and Yin-deficiency than Qinghouyan oral liquid, with good safety. PMID:26080572

  13. Virucidal action of sore throat lozenges against respiratory viruses parainfluenza type 3 and cytomegalovirus.

    PubMed

    Shephard, Adrian; Zybeshari, Stela

    2015-11-01

    Most respiratory tract infections are self-limiting and caused by viruses, and do not warrant antibiotic treatment. Despite this, patients with respiratory tract infections often receive antibiotics, fuelling the rise of antibiotic resistance. Therefore, there is a need to encourage patients to try alternative non-antibiotic therapies, which ideally treat the symptoms and the cause. Lozenges containing amylmetacresol and 2,4-dichlorobenzyl alcohol (AMC/DCBA lozenges) as well as lozenges containing hexylresorcinol have been shown to provide effective symptomatic relief for sore throat. In this study, we investigated whether these lozenges also have virucidal effects in vitro against two viruses associated with respiratory tract infections, parainfluenza virus type 3 and cytomegalovirus. Both viruses were incubated with AMC/DCBA lozenge, placebo lozenge or the active ingredients (AMC/DCBA) as free substances, and parainfluenza virus type 3 was incubated with hexylresorcinol lozenge, placebo lozenge or hexylresorcinol as a free substance. Virucidal effects were observed with the active lozenges and the active ingredients as free substances against both parainfluenza virus type 3 and cytomegalovirus. Mean reductions in viral titre were significantly greater compared with placebo lozenge and peak effects were observed for the shortest incubation time, 1min. These findings suggest that AMC/DCBA lozenge and hexylresorcinol lozenge have the potential to have local antiviral effects in patients with sore throat due to viral respiratory tract infections. Use of such over-the-counter treatments for self-limiting respiratory tract infections may satisfy patients' desire for an anti-infective medication and reduce the demand for antibiotics. PMID:26408353

  14. Virucidal action of sore throat lozenges against respiratory viruses parainfluenza type 3 and cytomegalovirus.

    PubMed

    Shephard, Adrian; Zybeshari, Stela

    2015-11-01

    Most respiratory tract infections are self-limiting and caused by viruses, and do not warrant antibiotic treatment. Despite this, patients with respiratory tract infections often receive antibiotics, fuelling the rise of antibiotic resistance. Therefore, there is a need to encourage patients to try alternative non-antibiotic therapies, which ideally treat the symptoms and the cause. Lozenges containing amylmetacresol and 2,4-dichlorobenzyl alcohol (AMC/DCBA lozenges) as well as lozenges containing hexylresorcinol have been shown to provide effective symptomatic relief for sore throat. In this study, we investigated whether these lozenges also have virucidal effects in vitro against two viruses associated with respiratory tract infections, parainfluenza virus type 3 and cytomegalovirus. Both viruses were incubated with AMC/DCBA lozenge, placebo lozenge or the active ingredients (AMC/DCBA) as free substances, and parainfluenza virus type 3 was incubated with hexylresorcinol lozenge, placebo lozenge or hexylresorcinol as a free substance. Virucidal effects were observed with the active lozenges and the active ingredients as free substances against both parainfluenza virus type 3 and cytomegalovirus. Mean reductions in viral titre were significantly greater compared with placebo lozenge and peak effects were observed for the shortest incubation time, 1min. These findings suggest that AMC/DCBA lozenge and hexylresorcinol lozenge have the potential to have local antiviral effects in patients with sore throat due to viral respiratory tract infections. Use of such over-the-counter treatments for self-limiting respiratory tract infections may satisfy patients' desire for an anti-infective medication and reduce the demand for antibiotics.

  15. Silver acetate interactions with nicotine and non-nicotine smoke components.

    PubMed

    Rose, Jed E; Behm, Frédérique M; Murugesan, Thangaraju; McClernon, F Joseph

    2010-12-01

    Oral topical silver-containing formulations were marketed in the 1970s and 1980s as smoking deterrents, based on the finding that when using such formulations, an unpleasant taste occurs upon smoking. This approach has not been widely adopted, however, in part because of a lack of efficacy data. The advent of new pharmacologic treatments for smoking cessation renews the possibility that such a taste aversion approach may be a useful adjunct to smoking cessation treatment. This study explored the basic mechanistic question of whether topical oral silver acetate solution interacts with nicotine as opposed to non-nicotine smoke constituents. We recruited 20 smoking volunteers to rate nicotine-containing or denicotinized cigarettes, as well as the Nicotrol nicotine vapor inhaler and sham (air) puffs. In two sessions, subjects rated the sensory and hedonic qualities of puffs after rinsing their mouths with either silver acetate solution or deionized water (placebo). Silver acetate relative to placebo solution substantially reduced liking and satisfaction ratings for the usual brand and denicotinized cigarettes; in contrast, for the nicotine inhaler these ratings were unaffected by the silver-based treatment. These results support the conclusion that silver acetate not only renders the taste of cigarette smoke less appealing, but also that the compound appears to interact selectively with non-nicotine smoke constituents. Moreover, these data suggest silver acetate would be compatible with buccal nicotine delivery systems (e.g., nicotine lozenge or gum). Combined use of taste aversion with nicotine replacement therapy could provide the smoker with additional assistance to resist relapse. Further exploration is warranted of the use of silver-based preparations as a short-term adjunct to smoking cessation treatment. PMID:21186921

  16. Enhanced attenuation of nicotine discrimination in rats by combining nicotine-specific antibodies with a nicotinic receptor antagonist.

    PubMed

    LeSage, Mark G; Shelley, David; Pravetoni, Marco; Pentel, Paul R

    2012-07-01

    Tobacco addiction requires activation by nicotine of a variety of central nicotinic acetylcholine receptors (nAChRs). In animals, both nAChR antagonists and immunization against nicotine can reduce nAChR activation by nicotine and block a variety of addiction-relevant behaviors. However, clinical use of nAChR antagonists for smoking cessation is limited by dose-related side effects, and immunization does not reliably produce sufficient antibody levels in smokers to enhance smoking cessation rates. Combining these approaches may be one way of addressing the limitations of each while enhancing overall efficacy. This study examined the individual and combined effects of passive immunization with the monoclonal nicotine-specific antibody Nic311 and the nicotinic receptor antagonist mecamylamine (MEC) on nicotine's discriminative stimulus effects. Rats were trained to discriminate 0.4 mg/kg of nicotine from saline using a two-lever operant discrimination procedure. Antagonism of nicotine discrimination by Nic311 (160 mg/kg i.v.) and ascending doses of MEC (0.03, 0.1, 0.3, and 1.0 mg/kg s.c.) was assessed across four consecutive daily 2-min extinction test sessions using a 2×2 design. Nic311 alone produced a 24-48% reduction in % nicotine-lever responding (%NLR) across all four test sessions. MEC produced a dose-dependent decrease in %NLR, with no effect at the two lowest doses and 80-93% attenuation at the two highest doses. Nic311 combined with MEC significantly suppressed %NLR at every MEC dose (85-92% reduction across all four test sessions). Very low doses of MEC that were ineffective alone completely blocked nicotine discrimination when combined with Nic311. These data demonstrate that nicotine-specific antibodies and MEC can work synergistically to suppress the subjective effects of nicotine and suggest that low doses of MEC may significantly enhance the efficacy of immunotherapy.

  17. Exposure to nicotine enhances its subsequent self-administration: contribution of nicotine-associated contextual stimuli.

    PubMed

    Neugebauer, Nichole M; Cortright, James J; Sampedro, Georgia R; Vezina, Paul

    2014-03-01

    Contextual stimuli present during nicotine exposure can come to act as conditioned stimuli and have been shown to play an important role in ongoing nicotine self-administration. In the present study, we characterized the effects of contextual stimuli previously paired with non-contingent nicotine exposure injections on subsequent nicotine self-administration. Rats were exposed to five injections of either saline or nicotine (0.4 mg/kg, i.p.) in either their home cage or a self-administration chamber with the levers retracted. Two weeks later, they were allowed to self-administer nicotine (30 μg/kg/infusion, IV) under fixed ratio (FR) schedules of reinforcement across 12 consecutive sessions. Lastly, responding under a progressive ratio (PR) schedule was assessed. Rats exposed to nicotine in the self-administration chamber subsequently increased their intake of nicotine across the FR test days, obtaining more infusions on average by days 7-12 compared to their saline exposed controls. This increase was not due to nicotine exposure alone as rats exposed to nicotine in the home cage did not show this effect. It was also not due to differences in the final ratio achieved between nicotine and saline exposed rats. Although rats exposed to nicotine in the self-administration chambers displayed reduced discrimination between the active and inactive levers during FR testing, they showed increased motivation to self-administer nicotine under the PR schedule. These results indicate that exposure to nicotine can enhance its subsequent self-administration and highlight the contribution of nicotine-associated contextual stimuli to the work output rats ultimately emit to obtain the drug. PMID:24295728

  18. The fentanyl 'lozenge' story: from books to battlefield.

    PubMed

    Aldington, Dominic; Jagdish, S

    2014-06-01

    This article outlines the process that led to the introduction of the fentanyl lozenge for acute pain management. It starts with the historical context before discussing the recognition of an ongoing problem and then identifies the options that were considered. There follows a description of the pharmacology of fentanyl before describing the trial of concept that was conducted. This leads into an outline of the meetings and committees that had to be engaged with before the final acceptance and subsequent ushering in. The final section describes an option that was unsuccessful. PMID:24413475

  19. Nicotine replacement therapy

    MedlinePlus

    Smoking cessation - nicotine replacement; Tobacco - nicotine replacement therapy ... Bullen C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2012 Nov 14;11: ...

  20. In vitro evaluation of the antimicrobial activities of selected lozenges.

    PubMed

    Richards, R M; Xing, D K

    1993-12-01

    The in vitro antimicrobial activities of 10 lozenges (Merothol, Merocets, Merocaine, Strepsils (two varieties), Dequacaine, Dequacets, Zensyls, Tyrozets, and Labosept) were determined by use of a microtiter counting method with Streptococcus pyogenes, Staphylococcus aureus, and Candida albicans as the test organisms. Merothol, Merocets, Merocaine, and both Strepsils formulations all reduced the counts of both S. aureus and S. pyogenes suspensions by approximately 6 log cycles within 5 and 20 min, respectively. Merothol, Merocets, and Merocaine also caused a reduction in the counts of the C. albicans suspension approximately 5 log cycles within 40 min, but no other lozenge formulation showed rapid and marked activity against C. albicans. Dequacaine and Dequacets showed marked but much slower activities against this yeast. Zensyls caused an approximately 6-log-cycle reduction in bacterial counts within 40 min, and Dequacaine, Dequacets, and Tyrozets showed marked but slower antibacterial activities. This work confirmed by a statistically sound in vitro method the in vivo antibacterial activities reported for Merothol, Merocets, and Merocaine, demonstrated equivalent antibacterial activities for Strepsils, and indicated that Merothol, Merocets, and Merocaine also showed marked activities against C. albicans. PMID:8308699

  1. Nicotine Withdrawal

    PubMed Central

    McLaughlin, Ian; Dani, John A.; De Biasi, Mariella

    2015-01-01

    An aversive abstinence syndrome manifests 4–24 h following cessation of chronic use of nicotine-containing products. Symptoms peak on approximately the 3rd day and taper off over the course of the following 3–4 weeks. While the severity of withdrawal symptoms is largely determined by how nicotine is consumed, certain short nucleotide polymorphisms (SNPs) have been shown to predispose individuals to consume larger amounts of nicotine more frequently—as well as to more severe symptoms of withdrawal when trying to quit. Additionally, rodent behavioral models and transgenic mouse models have revealed that specific nicotinic acetylcholine receptor (nAChR) subunits, cellular components, and neuronal circuits are critical to the expression of withdrawal symptoms. Consequently, by continuing to map neuronal circuits and nAChR subpopulations that underlie the nicotine withdrawal syndrome—and by continuing to enumerate genes that predispose carriers to nicotine addiction and exacerbated withdrawal symptoms—it will be possible to pursue personalized therapeutics that more effectively treat nicotine addiction. PMID:25638335

  2. Geometrical analysis of deformation band lozenges and their scaling relationships to fault lenses

    NASA Astrophysics Data System (ADS)

    Awdal, Abdullah; Healy, David; Alsop, G. Ian

    2014-09-01

    Deformation bands can influence fluid flow in sandstone hydrocarbon reservoirs and therefore, understanding the geometrical attributes of individual bands and their patterns is a critical step in quantifying their connectivity. We present a geometrical study of deformation band lozenges, which are rock volumes contained between deformation bands, and fault lenses, which are rock volumes bounded by slip surfaces in fault cores. We investigate the statistical trends among data sets for deformation band lozenges and fault lenses in sandstones from the Moray Firth (Scotland) and southeastern Utah (USA), and explore their potential correlation to other attributes of the fracture pattern and petrophysical properties. The aspect ratio of lozenges, that represents the ratio of length or height to the maximum thickness of a lozenge, displays an oblate-shaped geometry in relation to fault-zone orientation. The length-thickness scaling relationships of lozenges are statistically similar to lenses. The scaling relationships show a slope break between lozenges bounded by deformation bands and lenses bounded by slip surfaces in the fault core. This break is inferred to mark the boundary between the lozenge domain and lens domain, and is likely due to a deformation transition from distributed strain for deformation bands to localised strain for slip surfaces. Furthermore, the integration of geometrical analysis with an understanding of scaling properties can help to make better predictions of fractures and fault properties in subsurface reservoirs.

  3. Nicotine Gum

    MedlinePlus

    ... program, which may include support groups, counseling, or specific behavioral change techniques. Nicotine gum is in a ... at room temperature and away from light, excess heat and moisture (not in the bathroom). Throw away ...

  4. Salivary concentrations of amphotericin B following its use as an oral lozenge.

    PubMed

    de Vries-Hospers, H G; van der Waaij, D

    1980-01-01

    Amphotericin B concentrations were measured in the saliva of ten healthy volunteers who had sucked on lozenges with this drug. It appeared that high amphotericin B concentrations can be achieved in this way in the saliva. Even half an hour after swallowing the last remnant of a lozenge, the amphotericin B concentration was found to be high enough to suppress the growth of sensitive Candida albicans strains. The possible usefulness of amphotericin B lozenges in the selective decontamination of the oropharynx of yeasts and other fungi is discussed and compared with the application of this drug in orabase. PMID:6993365

  5. Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study.

    PubMed Central

    Eby, G A; Davis, D R; Halcomb, W W

    1984-01-01

    As a possible treatment for common colds, we tested zinc gluconate lozenges in a double-blind, placebo-controlled, clinical trial. One 23-mg zinc lozenge or matched placebo was dissolved in the mouth every 2 wakeful h after an initial double dose. After 7 days, 86% of 37 zinc-treated subjects were asymptomatic, compared with only 46% of 28 placebo-treated subjects (P = 0.0005). Side effects or complaints were usually minor and consisted mainly of objectionable taste and mouth irritation. Zinc lozenges shortened the average duration of common colds by about 7 days. PMID:6367635

  6. Spin-lozenge thermodynamics and magnetic excitations in Na3RuO4

    NASA Astrophysics Data System (ADS)

    Haraldsen, J. T.; Stone, M. B.; Lumsden, M. D.; Barnes, T.; Jin, R.; Taylor, J. W.; Fernandez-Alonso, F.

    2009-12-01

    We report inelastic and elastic neutron scattering, magnetic susceptibility, and heat capacity measurements for polycrystalline sodium ruthenate (Na3RuO4). Previous work suggests that this material consists of isolated tetramers of S = 3/2 Ru5+ ions in a so-called lozenge configuration. Comparisons of magnetic susceptibility and inelastic and elastic neutron scattering results with analytic calculations for several cluster models show that although there may be significant spin-spin correlations within the lozenge cluster, a simple isolated lozenge model is not appropriate for Na3RuO4.

  7. Spin-lozenge thermodynamics and magnetic excitations in Na(3)RuO(4).

    PubMed

    Haraldsen, J T; Stone, M B; Lumsden, M D; Barnes, T; Jin, R; Taylor, J W; Fernandez-Alonso, F

    2009-12-16

    We report inelastic and elastic neutron scattering, magnetic susceptibility, and heat capacity measurements for polycrystalline sodium ruthenate (Na(3)RuO(4)). Previous work suggests that this material consists of isolated tetramers of S = 3/2  Ru(5+) ions in a so-called lozenge configuration. Comparisons of magnetic susceptibility and inelastic and elastic neutron scattering results with analytic calculations for several cluster models show that although there may be significant spin-spin correlations within the lozenge cluster, a simple isolated lozenge model is not appropriate for Na(3)RuO(4). PMID:21836228

  8. Relationships of PROP Taste Phenotype, Taste Receptor Genotype, and Oral Nicotine Replacement Use

    PubMed Central

    Tepper, Beverly J.; Graham, Margaret C.; Holloman, Christopher; Matcham, William A.

    2015-01-01

    Introduction: Recommended dosage of oral nicotine replacement therapy (NRT) product is often not achieved in smoking cessation attempts. n-6-propylthiouracil (PROP) bitter taste phenotype may be a potential risk factor for non-adherence to oral NRT products due to their bitter taste. There is limited literature on this phenotype in the context of smoking and none in relation to oral NRT pharmacotherapy. Methods: The association of PROP taste phenotype with NRT usage and sensory response to products was examined. In a cross-over experimental design, 120 participants received a 1 week supply of nicotine inhalers and 1 week of nicotine lozenges with random assignment to order. Mixed effects linear model analyses were conducted. Results: PROP taste phenotype and taste receptor genotype were not associated with NRT usage or sensory response to NRT, after adjusting for other factors. However, PROP non-tasters used a higher number of lozenges per day (continuous exposure) than nicotine cartridges (intermittent exposure). Unexpectedly, half of baseline PROP non-tasters shifted to taster phenotype 2 weeks after smoking cessation or reduction. Menthol cigarette smokers identified higher NRT strength of sensation scores than nonmenthol smokers. Taste receptor genotype was related to PROP taste phenotype (Kendall τ = .591, p = .0001). Conclusions: A nonsignificant relationship of PROP phenotype and NRT usage may be associated with NRT under-dosing and limited variance in the outcome variable. PROP non-tasters’ greater use of lozenges is consistent with nicotine exposure being less aversive to non-tasters. Further research of this and other factors impacting NRT usage are warranted to effectively inform smoking cessation pharmacotherapy. PMID:25542917

  9. Efficacy of a benzocaine lozenge in the treatment of uncomplicated sore throat.

    PubMed

    Chrubasik, Sigrun; Beime, Beate; Magora, Florella

    2012-02-01

    Benzocaine lozenges are popular in symptomatic treatment of acute sore throat. The aim of this study was to evaluate if sucking a benzocaine lozenge was superior to a placebo lozenge in patients with pain while swallowing. Volunteers with acute, uncomplicated sore throat received randomly and double-blind either a benzocaine 8 mg or a placebo lozenge. Pain was assessed on a numerical visual rating scale. The primary outcome measure was the sum of the pain intensity differences (SPID) over 2 h. Secondary outcome measures included the number of patients who reported 50% or more of their baseline pain score (responders) and those with worthwhile and complete pain relief, the times to worthwhile/complete pain relief and to pain recurrence and the occurrence of any adverse effects. A predefined interim analysis after including 50 patients revealed the superiority of benzocaine versus placebo in the SPID (p = 0.0086). At this time, a total of 165 patients had been recruited (full analysis set, FAS) and underwent statistical analysis. In the FAS, median SPID had significantly more decreased in patients receiving benzocaine compared to placebo (-12 vs. - 5, p = 0.001). There were significantly more responders and patients with worthwhile pain relief in group benzocaine. The number of patients with complete pain relief was very small. Median time to worthwhile pain relief was 20 min (benzocaine) and >45 min (placebo). Adverse events were not observed. Benzocaine lozenges are superior to placebo lozenges and a useful, well-tolerated treatment option to reduce painful pharyngeal discomfort.

  10. The neurobiological basis for partial agonist treatment of nicotine dependence: varenicline.

    PubMed

    Foulds, J

    2006-05-01

    Smoking cessation has major health benefits for men and women of all ages. However, most smokers are addicted to nicotine and fail repeatedly in their attempts to quit. Stimulation of nicotinic receptors in the brain, particularly alpha4beta2 receptors, releases dopamine in the meso-limbic area of the brain and is reinforcing. Nicotine abstinence reduces dopamine release, and this is associated with withdrawal symptoms and craving for nicotine. Eight current pharmacotherapies--bupropion, nortriptyline, clonidine and nicotine patch, gum, inhaler, lozenge and nasal spray--are moderately effective aids to smoking cessation. Each is significantly better than placebo, but approximately 80% of patients using one of these medications return to smoking within the first year. Varenicline, a specific alpha4beta2 nicotinic receptor partial agonist, is a new pharmacotherapy that stimulates dopamine and simultaneously blocks nicotine receptors. Phase II and III trials have yielded promising results suggesting that varenicline could be an important advance in the treatment of nicotine dependence. PMID:16700857

  11. A multicentre, randomised, double-blind, single-dose study assessing the efficacy of AMC/DCBA Warm lozenge or AMC/DCBA Cool lozenge in the relief of acute sore throat

    PubMed Central

    2011-01-01

    Background Clinically proven over-the-counter (OTC) treatment options are becoming increasingly important in the self-management of acute sore throat. The aim of this study was to determine the analgesic and sensorial benefits of two different amylmetacresol/2,4-dichlorobenzyl alcohol (AMC/DCBA) throat lozenge formulation variants, AMC/DCBA Warm lozenge and AMC/DCBA Cool lozenge, compared with an unflavoured, non-medicated placebo lozenge in the relief of acute sore throat due to upper respiratory tract infections. Methods In this multicentre, randomised, double-blind, single-dose study, 225 adult patients with acute sore throat were randomly assigned to receive either one AMC/DCBA Warm lozenge (n = 77), one AMC/DCBA Cool lozenge (n = 74) or one unflavoured, non-medicated lozenge (matched for size, shape and demulcency; n = 74). After baseline assessments, patients received their assigned lozenge and completed four rating assessments at 11 timepoints from 1 to 120 minutes post dose. Analgesic properties were assessed by comparing severity of throat soreness and sore throat relief ratings. Difficulty in swallowing, throat numbness, functional, sensorial and emotional benefits were also assessed. Results Both the AMC/DCBA Warm and AMC/DCBA Cool lozenge induced significant analgesic, functional, sensorial and emotional effects compared with the unflavoured, non-medicated lozenge. Sore throat relief, improvements in throat soreness and difficulty in swallowing, and throat numbness were observed as early as 1-5 minutes, and lasted up to 2 hours post dose. Sensorial benefits of warming and cooling associated with the AMC/DCBA Warm and AMC/DCBA Cool lozenge, respectively, were experienced soon after first dose, and in the case of the latter, it lasted long after the lozenge had dissolved. Emotional benefits of feeling better, happier, less distracted and less frustrated were reported in those taking either of the AMC/DCBA throat lozenge variants, with no differences in

  12. Zinc lozenges as cure for the common cold--a review and hypothesis.

    PubMed

    Eby, George A

    2010-03-01

    A 7-day reduction in duration of common colds was shown by Eby et al. in 1984 using 23mg zinc gluconate throat lozenges. Over the following 25years, 14 double-blind, placebo-controlled, randomized clinical trials produced widely differing results with about one-half showing success and the remainder showing failure. Positively charged, ionic zinc (iZn), but not bound zinc, is strongly astringent, antirhinoviral, increases interferon-gamma (IFN-gamma) 10-fold, inhibits intercellular adhesion molecule-1 (ICAM-1) and inhibits the release of vasoactive ingredients from mast cell granules. Solution equilibrium chemistry analytical techniques showed lozenge iZn fraction varying from 0% to 100% of total lozenge zinc between trials, with zinc acetate (ZA) releasing 100% iZn, zinc gluconate (ZG) releasing 72% iZn and other zinc compounds releasing much less or none at physiologic pH 7.4. Since only iZn has in vitro benefits, iZn variations are hypothesized to have produced the widely varying clinical results. In support of the iZn hypothesis, lozenge iZn and total daily iZn in trials were found highly correlated with reductions in common cold durations with statistical significance for mean duration (P<0.001) and median duration (P<0.004), while total zinc (iZn plus bound) showed no correlation with changes in duration. Duration reductions (mean 0 days, median 0.43 days) for multi-ligand ZG and ZA lozenges differed significantly from duration reductions (mean 3.37 days, median 2.9 days) for single ligand ZA and ZG lozenges (P<0.001) showing that additive ligands as flavor-masks damaged or eliminated efficacy. Five of 6 trials with lozenges whose zinc compositions had a first stability constant of 1.7 or less succeeded, while only 2 of 9 trials of lozenges with higher stability succeeded (P<0.02). From the strong, multiple statistical relationships found, it is inferred that iZn is the active ingredient in zinc lozenges for colds, as it is in vitro against rhinoviruses, and

  13. Impact of nicotine replacement therapy on smoking behavior.

    PubMed

    Cummings, K Michael; Hyland, Andrew

    2005-01-01

    This review summarizes evidence pertaining to the role of nicotine medications in smoking cessation and focuses particularly on evaluating evidence of the impact that nicotine replacement therapies (NRT) have had on altering population trends in smoking behavior. Accumulated evidence from controlled clinical trials has demonstrated that available forms of NRT (e.g., gum, transdermal patch, nasal spray, inhaler, and lozenge) increase quit rates compared with placebos by 50%-100%. However, despite the positive results from these studies, fewer than one in five smokers making a quit attempt do so with the benefit of NRT. Because not enough smokers are using NRT, the availability of NRT has not had a measurable impact on influencing population trends in smoking behavior. Among the factors contributing to the low utilization of nicotine medications are the inadequacies of the current dosage strengths and formulations of existing medications, smokers' perceptions of the high cost of the drugs, and concerns that many smokers have about safety and efficacy of nicotine medications. PMID:15760302

  14. Efficacy of a benzocaine lozenge in the treatment of uncomplicated sore throat.

    PubMed

    Chrubasik, Sigrun; Beime, Beate; Magora, Florella

    2012-02-01

    Benzocaine lozenges are popular in symptomatic treatment of acute sore throat. The aim of this study was to evaluate if sucking a benzocaine lozenge was superior to a placebo lozenge in patients with pain while swallowing. Volunteers with acute, uncomplicated sore throat received randomly and double-blind either a benzocaine 8 mg or a placebo lozenge. Pain was assessed on a numerical visual rating scale. The primary outcome measure was the sum of the pain intensity differences (SPID) over 2 h. Secondary outcome measures included the number of patients who reported 50% or more of their baseline pain score (responders) and those with worthwhile and complete pain relief, the times to worthwhile/complete pain relief and to pain recurrence and the occurrence of any adverse effects. A predefined interim analysis after including 50 patients revealed the superiority of benzocaine versus placebo in the SPID (p = 0.0086). At this time, a total of 165 patients had been recruited (full analysis set, FAS) and underwent statistical analysis. In the FAS, median SPID had significantly more decreased in patients receiving benzocaine compared to placebo (-12 vs. - 5, p = 0.001). There were significantly more responders and patients with worthwhile pain relief in group benzocaine. The number of patients with complete pain relief was very small. Median time to worthwhile pain relief was 20 min (benzocaine) and >45 min (placebo). Adverse events were not observed. Benzocaine lozenges are superior to placebo lozenges and a useful, well-tolerated treatment option to reduce painful pharyngeal discomfort. PMID:22015737

  15. Nicotine withdrawal: a behavioral assessment using schedule controlled responding, locomotor activity, and sensorimotor reactivity.

    PubMed

    Helton, D R; Modlin, D L; Tizzano, J P; Rasmussen, K

    1993-01-01

    Three different behavioral measures were used to assess the effects of abrupt cessation of chronic nicotine treatment. Nicotine (0, 3, or 6 mg/kg per day) was continuously administered for 12 days in rats by surgically implanting Alzet osmotic mini-pumps subcutaneously. Experiment 1 employed a light/dark discrimination task. There were no significant effects on number of responses or percent correct responding either during nicotine administration, or following cessation of nicotine. Experiment 2 examined ambulatory (locomotor) and nonambulatory activity. Chronic nicotine administration produced significant dose-dependent increases in both ambulatory and nonambulatory activity during the first 3 days of exposure. However, no significant alterations were seen in activity levels following nicotine cessation. Experiment 3 examined sensorimotor reactivity using the auditory startle response. During nicotine withdrawal, significant increases were seen in startle amplitude in both nicotine groups for 4 days. Nicotine (0.4 mg/kg, IP) administered before startle testing during the withdrawal phase attenuated the increased reactivity seen during nicotine cessation. These studies indicate that 1) rats display increased sensorimotor reactivity after cessation of chronic nicotine exposure, and 2) the expression of nicotine dependence and withdrawal is dependent on the behavioral task employed. PMID:7855182

  16. Demonstration of dose response of flurbiprofen lozenges with the sore throat pain model.

    PubMed

    Schachtel, Bernard P; Homan, Harvey D; Gibb, Iain A; Christian, Jenny

    2002-05-01

    The dose response of flurbiprofen lozenges (2.5, 5.0, and 12.5 mg) was evaluated in the treatment of sore throat. A refined version of the sore throat pain model showed that 12.5 mg flurbiprofen was significantly more effective than placebo at providing total pain relief and reducing throat soreness (p <.05). Flurbiprofen, 5.0 mg, was more effective than placebo for the reduction of throat soreness and the sensation of throat swelling (P <.05). The 2.5-mg flurbiprofen lozenge was indistinguishable from placebo. For every milligram of increase in the dose of flurbiprofen, there was an approximately 0.3-unit increase in total pain relief (P <.05). Flurbiprofen lozenges in all 3 dosages were well tolerated. Flurbiprofen lozenges are effective for sore throat at a dose between 5.0 mg and 12.5 mg; the sore throat pain model is a sensitive assay for demonstration of the dose-response relationship of an analgesic agent.

  17. Two randomized controlled trials of zinc gluconate lozenge therapy of experimentally induced rhinovirus colds.

    PubMed Central

    Farr, B M; Conner, E M; Betts, R F; Oleske, J; Minnefor, A; Gwaltney, J M

    1987-01-01

    The therapeutic efficacy of zinc gluconate lozenge therapy in experimentally induced rhinovirus infection was assessed in two randomized controlled trials in susceptible adult volunteers. In trial 1, lozenges containing either zinc gluconate (23 mg of elemental zinc) or placebo were given 36 h after nasal inoculation of rhinovirus type 39 and administered eight times per day for 5 days. All of the volunteers had early cold symptoms at the time that treatment was begun. In trial 2, the same lozenge regimen was used, beginning 2 h after nasal inoculation with rhinovirus type 13, and continued for 7 days. Zinc therapy did not reduce the severity or duration of cold symptoms or the frequency or duration of viral shedding in either trial. Viral titers were measured in trial 2 and were shown to be unaffected by zinc therapy. Nasal mucus weights and the numbers of paper tissues used were slightly higher in zinc recipients. A statistically significant increase in levels of zinc in serum was documented in zinc recipients after 5 days of therapy. These data suggest that zinc gluconate lozenge therapy is not therapeutically useful in the treatment of rhinovirus colds. PMID:2820298

  18. Caffeinated nitric oxide-releasing lozenge improves cycling time trial performance.

    PubMed

    Lee, J; Kim, H T; Solares, G J; Kim, K; Ding, Z; Ivy, J L

    2015-02-01

    Boosting nitric oxide production during exercise by various means has been found to improve exercise performance. We investigated the effects of a nitric oxide releasing lozenge with added caffeine (70 mg) on oxygen consumption during steady-state exercise and cycling time trial performance using a double-blinded randomized, crossover experimental design. 15 moderately trained cyclists (7 females and 8 males) were randomly assigned to ingest the caffeinated nitric oxide lozenge or placebo 5 min before exercise. Oxygen consumption and blood lactate were assessed at rest and at 50%, 65% and 75% maximal oxygen consumption. Exercise performance was assessed by time to complete a simulated 20.15 km cycling time-trial course. No significant treatment effects for oxygen consumption or blood lactate at rest or during steady-state exercise were observed. However, time-trial performance was improved by 2.1% (p<0.01) when participants consumed the nitric oxide lozenge (2,424±69 s) compared to placebo (2,476±78 s) and without a significant difference in rating of perceived exertion. These results suggest that acute supplementation with a caffeinated nitric oxide releasing lozenge may be a practical and effective means of improving aerobic exercise performance.

  19. Caffeinated nitric oxide-releasing lozenge improves cycling time trial performance.

    PubMed

    Lee, J; Kim, H T; Solares, G J; Kim, K; Ding, Z; Ivy, J L

    2015-02-01

    Boosting nitric oxide production during exercise by various means has been found to improve exercise performance. We investigated the effects of a nitric oxide releasing lozenge with added caffeine (70 mg) on oxygen consumption during steady-state exercise and cycling time trial performance using a double-blinded randomized, crossover experimental design. 15 moderately trained cyclists (7 females and 8 males) were randomly assigned to ingest the caffeinated nitric oxide lozenge or placebo 5 min before exercise. Oxygen consumption and blood lactate were assessed at rest and at 50%, 65% and 75% maximal oxygen consumption. Exercise performance was assessed by time to complete a simulated 20.15 km cycling time-trial course. No significant treatment effects for oxygen consumption or blood lactate at rest or during steady-state exercise were observed. However, time-trial performance was improved by 2.1% (p<0.01) when participants consumed the nitric oxide lozenge (2,424±69 s) compared to placebo (2,476±78 s) and without a significant difference in rating of perceived exertion. These results suggest that acute supplementation with a caffeinated nitric oxide releasing lozenge may be a practical and effective means of improving aerobic exercise performance. PMID:25285468

  20. Demonstration of dose response of flurbiprofen lozenges with the sore throat pain model.

    PubMed

    Schachtel, Bernard P; Homan, Harvey D; Gibb, Iain A; Christian, Jenny

    2002-05-01

    The dose response of flurbiprofen lozenges (2.5, 5.0, and 12.5 mg) was evaluated in the treatment of sore throat. A refined version of the sore throat pain model showed that 12.5 mg flurbiprofen was significantly more effective than placebo at providing total pain relief and reducing throat soreness (p <.05). Flurbiprofen, 5.0 mg, was more effective than placebo for the reduction of throat soreness and the sensation of throat swelling (P <.05). The 2.5-mg flurbiprofen lozenge was indistinguishable from placebo. For every milligram of increase in the dose of flurbiprofen, there was an approximately 0.3-unit increase in total pain relief (P <.05). Flurbiprofen lozenges in all 3 dosages were well tolerated. Flurbiprofen lozenges are effective for sore throat at a dose between 5.0 mg and 12.5 mg; the sore throat pain model is a sensitive assay for demonstration of the dose-response relationship of an analgesic agent. PMID:12011823

  1. New Techniques for Augmenting Saliva Collection: Bacon Rules and Lozenge Drools

    PubMed Central

    Miočević, Olga; Warner, Melissa C.; Slowey, Paul D.; Shirtcliff, Elizabeth A.

    2015-01-01

    Purpose Saliva is a reliable, noninvasive, and cost-effective alternative to biomarkers measured in other biological fluids. Within certain populations, saliva sampling may be difficult because of insufficient saliva flow, which may compromise disease diagnosis or research integrity. Methods to improve flow rates (eg, administering citric acid, chewing gum, or collecting cotton) may compromise biomarker integrity, especially if the methods involve the presence of a collection aid in the oral cavity. Anecdotal strategies (eg, looking at pictures of food or imagining food) have not been evaluated to date. In this study, we evaluate whether 2 novel collection techniques improve saliva flow or interfere with assay of common biomarkers (ie, cortisol, dehydroepiandrosterone, and testosterone). We evaluate an over-the-counter anhydrous crystalline maltose lozenge intended to increase saliva production for patients with xerostomia long after the lozenge dissolves. We then evaluate whether the smell of freshly cooked bacon stimulates a pavlovian-type reflex. Methods Saliva was collected from 27 healthy young adults (aged 20-34 years; 12 men) on a basal day and a lozenge day, providing 5 samples at 15-minute intervals. Twenty participants then returned for the bacon day condition, providing 2 saliva samples with an interval of 15 minutes between samples. Collection times required to generate 2 mL of saliva across collection strategies were recorded, and then saliva samples were assayed for cortisol, dehydroepiandrosterone, and testosterone. Findings Repeated analysis of variance measures revealed that both the lozenges and bacon significantly decreased collection time compared with the passive drool collection on the basal day. No significant effects were found related to the quantification of cortisol, testosterone, or dehydroepiandrosterone when comparing lozenge or bacon to the basal day. In addition, bivariate correlations revealed that concentrations from time

  2. Typology of lozenges and their development in anastomosing shear zones in foliated rocks

    NASA Astrophysics Data System (ADS)

    Ponce, Carlos; Carreras, Jordi; Druguet, Elena

    2010-05-01

    Lozenges are characteristic common structures related to anastomosing networks of shear zones. They are ellipsoid-shaped bodies of undeformed (or less deformed) country rock bounded by mylonites. They have been studied since the 1980's (Bell and Rubenach 1980, Bell 1981, Simpson, 1982, Choukroune and Gapais 1987, Hudleston 1999, Fusseis 2006), and various formation processes have been proposed. However, the lack of a systematic typology has led to confronting interpretations about their origin, development and significance in the context of anastomosing shear zones. A typology of shear zone-related lozenges is proposed with regard to the pre-shearing rock properties: 1) Lozenges in rheologically heterogeneous rocks. Their development is related to the presence of volumes of rock that behave more competent than the surrounding media. These are therefore typically developed in shear zones affecting rocks with a marked competence constrast. This is the case e.g. of a sheared competent dyke in a less competent schistose matrix. 2) Lozenges in homogeneous (2a, isotropic or 2b, anisotropic) rocks that arise from the confluence of differently oriented shears. The development of this type of lozenges is at present less understood than type 1 lozenges. The present work is focused in the formation and development of type 2 lozenges. The here presented preliminary results are based on a 2D approach (sections parallel to the shear direction) and supported by the analysis of natural examples from the Cap de Creus shear belt Eastern Pyrenees). Two main variables are taken into account for the interpretation of this type of lozenges. First, the relative kinematics of the bounding shear zones, i.e., shear zones have the same shear sense or, instead, they have opposite shear sense (conjugate sets). Second, only for foliated rocks, the relative orientation of the previous foliation with regard to the lozenge major axis. Furthermore, some models are presented to explain the

  3. Salivary levels of gramicidin after use of a tyrothricin lozenge and a tyrothricin gargle/mouth-wash.

    PubMed

    Kreuzig, F; Nahler, G

    1983-01-01

    Salivary levels and total salivary recovery of gramicidin were determined by high performance liquid chromatography in healthy volunteers after administration of a tyrothricin lozenge and a tyrothricin gargle/mouth-wash. Average peak values of gramicidin after sucking the lozenge were 37.5 mg/l and were usually reached within the five minutes. After use of the lozenge mean total recovery of gramicidin in saliva was 44% within the first 30 minutes. After application of the gargle/mouth-wash about 11% was retained in the oral cavity and excreted with saliva within the following 30 minutes. The implications of these findings are discussed. PMID:6207119

  4. Comparison of pure nicotine- and smokeless tobacco extract-induced toxicities and oxidative stress.

    PubMed

    Yildiz, D; Liu, Y S; Ercal, N; Armstrong, D W

    1999-11-01

    The toxicities and oxidative stress-inducing actions of (-)-nicotine and smokeless tobacco extract (STE), containing equivalent amounts of nicotine, were studied. Toxicities were determined by colony formation assays using Chinese hamster ovary (CHO) cells. Results indicated that nicotine is less toxic than smokeless tobacco extract that contained the same amount of nicotine. The generation of reactive oxygen species, following treatment with smokeless tobacco extract and nicotine, was assessed by measurement of changes in glutathione (GSH) and malondialdehyde (MDA) levels. CHO cells (5 x 10(5) cells/5 ml media) were incubated with 4, 0.8, and 0.08 mg of nicotine and STE containing the same amounts of nicotine. All preparations of smokeless tobacco extract significantly decreased GSH levels and increased MDA generation. However, 0.08 mg of nicotine treatment did not result in a significant change in GSH level, and only 4 mg of nicotine were sufficient to increase MDA generation. Addition of free radical scavenging enzymes, superoxide dismutase (SOD) and catalase (CAT), and an intracellular GSH precursor, N-acetyl-L-cysteine (NAC), replenished the GSH levels in nicotine-treated cells. GSH levels in cells exposed to smokeless tobacco extract containing 4 and 0.8 mg nicotine remained significantly lower than the control with the addition of SOD and CAT. However, co-addition of NAC with smokeless tobacco extract preparations returned the GSH levels to the control level. Lactate dehydrogenase (LDH) activities were measured in the media to establish the membrane damage following exposure to smokeless tobacco extract and nicotine. Treatment of cells with 4 mg nicotine caused a significant increase in LDH activity, which was returned to control level in the presence of the antioxidant enzymes and NAC. Smokeless tobacco extract did not change the LDH activity. http://link.springer-ny. com/link/service/journals/00244/bibs/37n4p434.html

  5. Rescue treatment and prevention of asthma using magnesium throat lozenges: Hypothesis for a mouth-lung biologically closed electric circuit.

    PubMed

    Eby, George A

    2006-01-01

    In the rescue treatment of acute asthma, injected and inhalant magnesium are relatively weak having demonstrated value only in severe illness, although theoretical and laboratory considerations suggest that magnesium should be strongly effective as an asthma rescue agent. It was hypothesized that a mouth-lung biologically closed electric circuit (BCEC) exists capable of nearly instantly transporting positively charged magnesium ions from the mouth and throat into the lungs. One hundred milligram magnesium (magnesium chloride) 4-g throat lozenges producing 100+ mM magnesium ion concentration in saliva were tested to determine if they had beneficial effects in asthma rescue and prevention. Subjects were selected based solely on need for asthma rescue, and lozenges were used as needed. Case histories are presented showing the nearly immediate effect of magnesium chloride throat lozenges in terminating and preventing asthma attacks. Throat lozenges containing magnesium chloride produced much more rapid and stronger benefits than has been reported for inhaled and injected magnesium. An added benefit from magnesium chloride lozenge treatment of asthma was relaxation. In this first report of its kind, magnesium chloride throat lozenges appeared to provide rescue benefits in the treatment of asthma equivalent to pharmaceutical asthma drugs. Countering these benefits, strong ionic magnesium solutions greatly increase rhinovirus, herpesvirus and Candida albicans in vitro, and appear to worsen these infections in humans. Magnesium lozenges releasing concentrated magnesium ions appear contraindicated during common colds, oral herpes infections, chronic rhinosinusitis, oral and respiratory infections in general, and their use must immediately be terminated if respiratory or oral symptoms worsen. Double-blind, placebo-controlled, clinical trials in people without respiratory or oral infections are needed to determine magnesium lozenge safety, and the extent by which drug

  6. Theory for Neutron Scattering from Polymers in Tubes: Lozenges, Dangling Ends and Retraction

    NASA Astrophysics Data System (ADS)

    Read, D. J.; McLeish, T. C. B.

    1997-03-01

    We present a consistent explanation for the 'lozenge' shapes in contour plots of the two-dimensional neutron scattering intensity from stretched polymer networks. By explicitly averaging over quenched variables in a tube model, we show that lozenge patterns arise as a result of chain material that is not directly deformed by the stretch. We also present a complete theory for the calculation of neutron scattering functions in the following experimental situation: a melt of partially deuterated block copolymers is stretched and sufficient time allowed for the polymers to retract along their tubes but for no further relaxation processes to occur before quenching below the glass transition temperature. The theory is necessary for the modelling of neutron scattering experiments which test the retraction theory for strongly stretched melts. We expect to be able to comment on the success of the theory for one such experiment.

  7. Nicotine dependence as a moderator of a quitline-based message framing intervention.

    PubMed

    Fucito, Lisa M; Latimer, Amy E; Carlin-Menter, Shannon; Salovey, Peter; Cummings, K Michael; Makuch, Robert W; Toll, Benjamin A

    2011-04-01

    High nicotine dependence is a reliable predictor of difficulty quitting smoking and remaining smoke-free. Evidence also suggests that the effectiveness of various smoking cessation treatments may vary by nicotine dependence level. Nicotine dependence, as assessed by Heaviness of Smoking Index baseline total scores, was evaluated as a potential moderator of a message-framing intervention provided through the New York State Smokers' Quitline (free telephone based service). Smokers were exposed to either gain-framed (n=810) or standard-care (n=1222) counseling and printed materials. Those smoking 10 or more cigarettes per day and medically eligible were also offered a free 2-week supply of nicotine patches, gum, or lozenge. Smokers were contacted for follow-up interviews at 3 months by an independent survey group. There was no interaction of nicotine dependence scores and message condition on the likelihood of achieving 7-day point prevalence smoking abstinence at the 3-month follow-up contact. Among continuing smokers at the 3-month follow-up, smokers who reported higher nicotine dependence scores were more likely to report smoking more cigarettes per day and this effect was greater in response to standard-care messages than gain-framed messages. Smokers with higher dependence scores who received standard-care messages also were less likely to report use of nicotine medications compared with less dependent smokers, while there was no difference in those who received gain-framed messages. These findings lend support to prior research demonstrating nicotine dependence heterogeneity in response to message framing interventions and suggest that gain-framed messages may result in less variable smoking outcomes than standard-care messages. PMID:21036492

  8. Effects of nicotine gum on F waves in non-smokers.

    PubMed

    Strenge, H; Schmidt, G; Niederberger, U; Porschke, H; Schütz, H W

    1996-01-01

    The effects of chewing gum, containing 0 and 4 mg nicotine, on F waves were studied in healthy volunteers in a repeated measure design. F responses were recorded from the abductor pollicis brevis muscle following stimulation of the median nerve at the wrist. The persistence and various amplitude measures were analysed. Chewing a 4 mg nicotine gum, with a considerable rise in systemic nicotine (6.4-37.4 ng/ml), failed to produce significant effects on F wave parameters in relation to the placebo baseline. The analysis of different F wave amplitude ranges, however, revealed significant nicotine-induced changes: a dose-related decrease of F responses > or = 500 microV and an increase of F waves between 200-290 microV. This may be due to an activation of Renshaw cells in the spinal cord. PMID:8934149

  9. Theoretical model of an organic ferrimagnetic state for a bipartite lozenge chain

    NASA Astrophysics Data System (ADS)

    Duan, Y. F.; Yao, K. L.

    2001-04-01

    A model for one-dimensional bipartite lozenge chain is proposed. By unrestricted Hartree-Fock approximation, we find that the system should exhibit ferrimagnetic ordering for a half filled band. In the ground state, the energy levels of electrons will split off with respect to different spins and the electrons along the chain will form an antiferromagnetic spin-density wave. The ground state of the system will be more stable with increasing of the on-site Hubbard term.

  10. Spin-lozenge thermodynamics and magnetic excitations in Na3RuO4

    SciTech Connect

    Haraldsen, Jason T; Stone, Matthew B; Lumsden, Mark D; Barnes, Ted {F E }; Jin, Rongying; Taylor, J. W.; Fernandez-Alonso, F

    2009-01-01

    We report inelastic and elastic neutron scattering, magnetic susceptibility, and heat capacity measurements of polycrystalline sodium ruthenate (Na3RuO4). Previous work suggests this material consists of isolated tetramers of S = 3/2 Ru5+ ions in a so-called lozenge configuration. Using a Heisenberg antiferromagnet Hamiltonian, we analytically determine the energy eigenstates for general spin S. From this model, the neutron scattering cross-sections for excitations associated with spin-3/2 tetramer configurations is determined. Comparison of magnetic susceptibility and inelastic neutron scattering results shows that the proposed lozenge model is not distinctly supported, but provides evidence that the system may be better described as a pair of non-interacting inequivalent dimers, i.e double dimers. However, the existence of long-range magnetic order below Tc ≈ 28 K immediately questions such a description. Although no evidence of the lozenge model is observed, future studies on single crystals may further clarify the appropriate magnetic Hamiltonian.

  11. Double-blind comparison of two types of benzocaine lozenges for the treatment of acute pharyngitis.

    PubMed

    Busch, Regina; Graubaum, Hans-Joachim; Grünwald, Jörg; Schmidt, Mathias

    2010-01-01

    In a reference-controlled double-blind trial in patients with acute pharyngitis the effects of a newly developed lozenge containing 8 mg of benzocaine (p-aminobenzoic acid ethyl ester, CAS 94-09-7) were compared with those of an identically dosed commercial pastille. 246 patients were randomized to receive either the lozenges (group A, n = 123) or the pastilles (group B, n = 123). Each patient took a total of six doses within 12 h according to the double-dummy principle, with each single dose spaced by 2 h. The primary parameter was the assessment of the responder rate with = 50 % pain relief within 15 min post application. Further parameters included the relative relief of pain in the course of the study and the tolerability of the formulation. After application of the first unit the comparison of groups yielded very similar and statistically not differing results for efficacy in both groups, with responder rates of 25.2 % and 22.0 % in groups A and B, respectively. One adverse drug reaction was observed in group B (burning and tingling feeling on the tongue), which, however, did not lead to discontinuation of study participation. In all other cases tolerability was stated to be "good to very good". The application of the benzocaine lozenges was statistically non-inferior to the use of the pastilles. PMID:20533760

  12. The acute effects of daily nicotine intake on heart rate--a toxicokinetic and toxicodynamic modelling study.

    PubMed

    Gajewska, M; Worth, A; Urani, C; Briesen, H; Schramm, K-W

    2014-10-01

    Joint physiologically-based toxicokinetic and toxicodynamic (PBTK/TD) modelling was applied to simulate concentration-time profiles of nicotine, a well-known stimulant, in the human body following single and repeated dosing. Both kinetic and dynamic models were first calibrated by using in vivo literature data for the Caucasian population. The models were then used to estimate the blood and liver concentrations of nicotine in terms of the Area Under Curve (AUC) and the peak concentration (Cmax) for selected exposure scenarios based on inhalation (cigarette smoking), oral intake (nicotine lozenges) and dermal absorption (nicotine patches). The model simulations indicated that whereas frequent cigarette smoking gives rise to high AUC and Cmax in blood, the use of nicotine-rich dermal patches leads to high AUC and Cmax in the liver. Venous blood concentrations were used to estimate one of the most common acute effects, mean heart rate, both at rest and during exercise. These estimations showed that cigarette smoking causes a high peak heart rate, whereas dermal absorption causes a high mean heart rate over 48h. This study illustrates the potential of using PBTK/TD modelling in the safety assessment of nicotine-containing products. PMID:25066669

  13. The acute effects of daily nicotine intake on heart rate--a toxicokinetic and toxicodynamic modelling study.

    PubMed

    Gajewska, M; Worth, A; Urani, C; Briesen, H; Schramm, K-W

    2014-10-01

    Joint physiologically-based toxicokinetic and toxicodynamic (PBTK/TD) modelling was applied to simulate concentration-time profiles of nicotine, a well-known stimulant, in the human body following single and repeated dosing. Both kinetic and dynamic models were first calibrated by using in vivo literature data for the Caucasian population. The models were then used to estimate the blood and liver concentrations of nicotine in terms of the Area Under Curve (AUC) and the peak concentration (Cmax) for selected exposure scenarios based on inhalation (cigarette smoking), oral intake (nicotine lozenges) and dermal absorption (nicotine patches). The model simulations indicated that whereas frequent cigarette smoking gives rise to high AUC and Cmax in blood, the use of nicotine-rich dermal patches leads to high AUC and Cmax in the liver. Venous blood concentrations were used to estimate one of the most common acute effects, mean heart rate, both at rest and during exercise. These estimations showed that cigarette smoking causes a high peak heart rate, whereas dermal absorption causes a high mean heart rate over 48h. This study illustrates the potential of using PBTK/TD modelling in the safety assessment of nicotine-containing products.

  14. Effects of Nicotine on Streptococcus gordonii Growth, Biofilm Formation, and Cell Aggregation.

    PubMed

    Huang, R; Li, M; Ye, M; Yang, K; Xu, X; Gregory, R L

    2014-12-01

    Streptococcus gordonii is a commensal species of human oral flora. It initiates dental biofilm formation and provides binding sites for later colonizers to attach to and generate mature biofilm. Smoking is the second highest risk factor for periodontal disease, and cigarette smoke extract has been reported to facilitate Porphyromonas gingivalis-S. gordonii dual-species biofilm formation. Our hypothesis is that nicotine, one of the most important and active components of tobacco, stimulates S. gordonii multiplication and aggregation. In the present study, S. gordonii planktonic cell growth (kinetic absorbance and CFU), biofilm formation (crystal violet stain and confocal laser scanning microscopy [CLSM]), aggregation with/without sucrose, and 11 genes that encode binding proteins or regulators of gene expression were investigated. Results demonstrated planktonic cell growth was stimulated by 1 to 4 mg/ml nicotine treatment. Biofilm formation was increased at 0.5 to 4 mg/ml nicotine. CLSM indicated bacterial cell mass was increased by 2 and 4 mg/ml nicotine, but biofilm extracellular polysaccharide was not significantly affected by nicotine. Cell aggregation was upregulated by 4, 8, and 16 mg/ml nicotine with sucrose and by 16 mg/ml nicotine without sucrose. Quantitative reverse transcriptase PCR indicated S. gordonii abpA, scaA, ccpA, and srtA were upregulated in planktonic cells by 2 mg/ml nicotine. In conclusion, nicotine stimulates S. gordonii planktonic cell growth, biofilm formation, aggregation, and gene expression of binding proteins. Those effects may promote later pathogen attachment to tooth surfaces, the accumulation of tooth calculus, and the development of periodontal disease in cigarette smokers.

  15. Mechanisms of Nicotine Addiction

    SciTech Connect

    McGehee, Daniel

    2002-06-26

    Nicotine reinforces the use of tobacco products primarily through its interaction with specific receptor proteins within the brain's reward centers. A critical step in the process of addiction for many drugs, including nicotine, is the release of the neurotransmitter dopamine. A single nicotine exposure will enhance dopamine levels for hours, however, nicotinic receptors undergo both activation and then desensitization in minutes, which presents an important problem. How does the time course of receptor activity lead to the prolonged release of dopamine? We have found that persistent modulation of both inhibitory and excitatory synaptic connections by nicotine underlies the sustained increase in dopamine release. Because these inputs express different types of nicotinic receptors there is a coordinated shift in the balance of synaptic inputs toward excitation of the dopamine neurons. Excitatory inputs are turned on while inhibitory inputs are depressed, thereby boosting the brain's reward system.

  16. Mechanisms of Nicotine Addiction

    SciTech Connect

    McGehee, Daniel

    2009-06-26

    Nicotine reinforces the use of tobacco products primarily through its interaction with specific receptor proteins within the brain’s reward centers. A critical step in the process of addiction for many drugs, including nicotine, is the release of the neurotransmitter dopamine. A single nicotine exposure will enhance dopamine levels for hours, however, nicotinic receptors undergo both activation and then desensitization in minutes, which presents an important problem. How does the time course of receptor activity lead to the prolonged release of dopamine? We have found that persistent modulation of both inhibitory and excitatory synaptic connections by nicotine underlies the sustained increase in dopamine release. Because these inputs express different types of nicotinic receptors there is a coordinated shift in the balance of synaptic inputs toward excitation of the dopamine neurons. Excitatory inputs are turned on while inhibitory inputs are depressed, thereby boosting the brain’s reward system.

  17. Nicotine Therapy Sampling to Induce Quit Attempts Among Smokers Unmotivated to Quit

    PubMed Central

    Carpenter, Matthew J.; Hughes, John R.; Gray, Kevin M.; Wahlquist, Amy E.; Saladin, Michael E.; Alberg, Anthony J.

    2012-01-01

    Background Rates of smoking cessation have not changed in a decade, accentuating the need for novel approaches to prompt quit attempts. Methods Within a nationwide randomized clinical trial (N=849) to induce further quit attempts and cessation, smokers currently unmotivated to quit were randomized to a practice quit attempt (PQA) alone or to nicotine replacement therapy (hereafter referred to as nicotine therapy), sampling within the context of a PQA. Following a 6-week intervention period, participants were followed up for 6 months to assess outcomes. The PQA intervention was designed to increase motivation, confidence, and coping skills. The combination of a PQA plus nicotine therapy sampling added samples of nicotine lozenges to enhance attitudes toward pharmacotherapy and to promote the use of additional cessation resources. Primary outcomes included the incidence of any ever occurring self-defined quit attempt and 24-hour quit attempt. Secondary measures included 7-day point prevalence abstinence at any time during the study (ie, floating abstinence) and at the final follow-up assessment. Results Compared with PQA intervention, nicotine therapy sampling was associated with a significantly higher incidence of any quit attempt (49% vs 40%; relative risk [RR], 1.2; 95% CI, 1.1–1.4) and any 24-hour quit attempt (43% vs 34%; 1.3; 1.1–1.5). Nicotine therapy sampling was marginally more likely to promote floating abstinence (19% vs 15%; RR, 1.3; 95% CI, 1.0–1.7); 6-month point prevalence abstinence rates were no different between groups (16% vs 14%; 1.2; 0.9–1.6). Conclusion Nicotine therapy sampling during a PQA represents a novel strategy to motivate smokers to make a quit attempt. Trial Registration clinicaltrials.gov Identifier: NCT00706979 PMID:22123796

  18. Wistar Kyoto and Wistar rats differ in the affective and locomotor effects of nicotine.

    PubMed

    Rauhut, Anthony S; Zentner, Isaac J; Mardekian, Stacey K; Tanenbaum, Jason B

    2008-01-28

    Anhedonia is a characteristic of clinical depression and has been associated with dysfunction of the mesolimbic dopaminergic system, a system also involved in mediating nicotine reward. To further examine the relationship between anhedonia, clinical depression and nicotine reward, the present experiment determined if Wistar Kyoto (WKY) rats, an animal model of clinical depression, differed from Wistar rats in nicotine conditioned place preference (CPP). Strain differences in nicotine-induced changes in locomotor activity also were determined simultaneously. To determine if strain differences were specific to reward-based learning, nicotine or lithium chloride (LiCl) conditioned taste avoidance (CTA) experiments were conducted. Rats received vehicle or nicotine (0.4 or 0.8 mg/kg) during a multi-trial, biased CPP training procedure or received vehicle, nicotine (0.2, 0.4 or 0.8 mg/kg) or lithium chloride (LiCl; 0.0375, 0.075 or 0.15 M) during a multi-trial CTA training procedure. Whereas both nicotine doses (0.4 and 0.8 mg/kg) initially induced hypoactivity, only the moderate nicotine dose (0.4 mg/kg) induced hyperactivity with repeated administration and produced a CPP in Wistar rats. Both nicotine doses failed to alter locomotor activity or produce a CPP in WKY rats. WKY rats also acquired a LiCl CTA more slowly and less robustly compared to Wistar rats. In contrast, nicotine dose-dependently produced a CTA in both strains and WKY rats were more sensitive to the avoidance effects of nicotine compared to Wistar rats. Collectively, these results suggest that WKY rats show deficits in nicotine reward and specific aversive drug stimuli compared to Wistar rats.

  19. Interaction between intra-oral cinnamaldehyde and nicotine assessed by psychophysical and physiological responses.

    PubMed

    Jensen, Tanja K; Andersen, Michelle V; Nielsen, Kent A; Arendt-Nielsen, Lars; Boudreau, Shellie A

    2016-08-01

    Cinnamaldehyde and nicotine activate the transient receptor potential subtype A1 (TRPA1) channel, which may cause burning sensations. This study investigated whether cinnamaldehyde modulates nicotine-induced psychophysical and physiological responses in oral tissues. Healthy non-smokers (n = 22) received, in a randomized, double-blind, crossover design, three different gums containing 4 mg of nicotine, 20 mg of cinnamaldehyde, or a combination thereof. Assessments of orofacial temperature and blood flow, blood pressure, heart rate, taste experience, and intra-oral pain/irritation area and intensity were performed before, during, and after a 10-min chewing regime. Cinnamaldehyde increased the temperature of the tongue and blood flow of the lip, and was associated with pain/irritation, especially in the mouth. Nicotine increased the temperature of the tongue and blood flow of the cheek, and produced pain/irritation in the mouth and throat. The combination of cinnamaldehyde and nicotine did not overtly change the psychophysical or physiological responses. Interestingly, half of the subjects responded to cinnamaldehyde as an irritant, and these cinnamaldehyde responders reported greater nicotine-induced pain/irritation areas in the throat. Whether sensitivity to cinnamaldehyde can predict the response to nicotine-induced oral irritation remains to be determined. A better understanding of the sensory properties of nicotine in the oral mucosa has important therapeutic implications because pain and irritation represent compliance issues for nicotine replacement products.

  20. Nicotine and sympathetic neurotransmission.

    PubMed

    Haass, M; Kübler, W

    1997-01-01

    Nicotine increases heart rate, myocardial contractility, and blood pressure. These nicotine-induced cardiovascular effects are mainly due to stimulation of sympathetic neurotransmission, as nicotine stimulates catecholamine release by an activation of nicotine acetylcholine receptors localized on peripheral postganglionic sympathetic nerve endings and the adrenal medulla. The nicotinic acetylcholine receptor is a ligand-gated cation channel with a pentameric structure and a central pore with a cation gate, which is essential for ion selectivity and permeability. Binding of nicotine to its extracellular binding site leads to a conformational change of the central pore, which results in the influx of sodium and calcium ions. The resulting depolarization of the sympathetic nerve ending stimulates calcium influx through voltage-dependent N-type calcium channels, which triggers the nicotine-evoked exocytotic catecholamine release. In the isolated perfused guinea-pig heart, cardiac energy depletion sensitizes cardiac sympathetic nerves to the norepinephrine-releasing effect of nicotine, as indicated by a leftward shift of the concentration-response curve, a potentiation of maximum transmitter release, and a delay of the tachyphylaxis of nicotine-evoked catecholamine release. This sensitization was also shown to occur in the human heart under in vitro conditions. Through the intracardiac release of norepinephrine, nicotine induces a beta-adrenoceptor-mediated increase in heart rate and contractility, and an alpha-adrenoceptor-mediated increase in coronary vasomotor tone. The resulting simultaneous increase in oxygen demand and coronary resistance has a detrimental effect on the oxygen balance of the heart, especially in patients with coronary artery disease. Sensitization of the ischemic heart to the norepinephrine-releasing effect of nicotine may be a trigger for acute cardiovascular events in humans, such as acute myocardial infarction and/or life

  1. Therapeutic advances in the treatment of nicotine addiction: present and future.

    PubMed

    Casella, Giuseppina; Caponnetto, Pasquale; Polosa, Riccardo

    2010-05-01

    While the proportion of the adult population that smokes has declined steadily in several westernized societies, the rate of successful quit attempts is still low. This is because smokers develop nicotine dependence, a powerful addiction that may require multiple attempts and long-term treatment to achieve enduring abstinence. Currently available first-line agents for smoking cessation therapy include nicotine replacement therapy (available in several formulations, including transdermal patch, gum, nasal spray, inhaler, and lozenge), bupropion (an atypical antidepressant), and varenicline (a partial agonist of the α4β2 nicotinic acetylcholine receptor that was recently developed and approved specifically for smoking cessation therapy). Second-line agents are nortriptyline (a tricyclic antidepressant agent) and the antihypertensive agent clonidine. With the exception of varenicline, which has been shown to offer significant improvement in abstinence rates over bupropion, all of the available treatments appear similarly effective. The adverse event profiles of nortriptyline and clonidine make them more appropriate for second-line therapy, when first-line treatments have failed or are not tolerated. However, the currently marketed smoking cessation drugs reportedly lack high levels of efficacy, particularly in real-life settings. New medications and vaccines with significant clinical advantage are now in the advanced stage of development and offer promise. These include nicotine vaccines and monoamine type B inhibitors. In this review article we discuss current and emerging pharmacotherapies for tobacco dependence focusing on their mechanisms of action, efficacy and adverse event profiles. PMID:23251732

  2. Ferrimagnetic Ordering and Spin Density Wave of the Polymeric Organic and Inorganic Bipartite Lozenge Chain

    NASA Astrophysics Data System (ADS)

    Duan, Y. F.; Duan, Y. F.; Yao, K. L.; Yao, K. L.; Yao, K. L.; Chen, J. S.

    The ground state properties and spin-density wave of a class of quasi-one dimensional polymeric organic and inorganic chains are studied by the mean-field theory and the Hartree-Fock approximation. The topological structure of the bipartite lozenge chain possesses a flat-band structure of the energy band. In the ground state, the electrons along the chain will form an antiferromagnetic spin-density wave. Away from half filling, a very rich magnetic phase diagram has been found. The ferrimagnetic ground state of the system will be more stable with increasing of the on-site Hubbard term.

  3. Molecular Orientation of Alkyldicyanoquinonediimine and Alkyldicyanoquinonediimine-Cu Langmuir-Blodgett Films: Rod-Lozenge Model

    NASA Astrophysics Data System (ADS)

    Ikegami, Keiichi

    2001-08-01

    A simple rod-lozenge model was proposed as the first step for discussing the relationship between the orientation of the alkyl-chain part and that of the N,N\\prime-dicyanoquinonediimine (DCNQI) part of Langmuir-Blodgett (LB) films of alkylDCNQI and alkylDCNQI-Cu, which had recently been fabricated and characterized by polarized IR spectroscopy. Taking into account the reported out-of-plane order parameters of individual molecular axes, this model could depict the structures of those LB films.

  4. The incentive amplifying effects of nicotine are reduced by selective and non-selective dopamine antagonists in rats.

    PubMed

    Palmatier, Matthew I; Kellicut, Marissa R; Brianna Sheppard, A; Brown, Russell W; Robinson, Donita L

    2014-11-01

    Nicotine is a psychomotor stimulant with 'reinforcement enhancing' effects--the actions of nicotine in the brain increase responding for non-nicotine rewards. We hypothesized that this latter effect of nicotine depends on increased incentive properties of anticipatory cues; consistent with this hypothesis, multiple laboratories have reported that nicotine increases sign tracking, i.e. approach to a conditioned stimulus (CS), in Pavlovian conditioned-approach tasks. Incentive motivation and sign tracking are mediated by mesolimbic dopamine (DA) transmission and nicotine facilitates mesolimbic DA release. Therefore, we hypothesized that the incentive-promoting effects of nicotine would be impaired by DA antagonists. To test this hypothesis, separate groups of rats were injected with nicotine (0.4mg/kg base) or saline prior to Pavlovian conditioning sessions in which a CS (30s illumination of a light or presentation of a lever) was immediately followed by a sweet reward delivered in an adjacent location. Both saline and nicotine pretreated rats exhibited similar levels of conditioned approach to the reward location (goal tracking), but nicotine pretreatment significantly increased approach to the CS (sign tracking), regardless of type (lever or light). The DAD1 antagonist SCH-23390 and the DAD2/3 antagonist eticlopride reduced conditioned approach in all rats, but specifically reduced goal tracking in the saline pretreated rats and sign tracking in the nicotine pretreated rats. The non-selective DA antagonist flupenthixol reduced sign-tracking in nicotine rats at all doses tested; however, only the highest dose of flupenthixol reduced goal tracking in both nicotine and saline groups. The reductions in conditioned approach behavior, especially those by SCH-23390, were dissociated from simple motor suppressant effects of the antagonists. These experiments are the first to investigate the effects of dopaminergic drugs on the facilitation of sign-tracking engendered by

  5. Nicotine and lung development.

    PubMed

    Maritz, Gert S

    2008-03-01

    Nicotine is found in tobacco smoke. It is a habit forming substance and is prescribed by health professionals to assist smokers to quit smoking. It is rapidly absorbed from the lungs of smokers. It crosses the placenta and accumulates in the developing fetus. Nicotine induces formation of oxygen radicals and at the same time also reduces the antioxidant capacity of the lungs. Nicotine and the oxidants cause point mutations in the DNA molecule, thereby changing the program that controls lung growth and maintenance of lung structure. The data available indicate that maternal nicotine exposure induces a persistent inhibition of glycolysis and a drastically increased cAMP level. These metabolic changes are thought to contribute to the faster aging of the lungs of the offspring of mothers that are exposed to nicotine via the placenta and mother's milk. The lungs of these animals are more susceptible to damage as shown by the gradual deterioration of the lung parenchyma. The rapid metabolic and structural aging of the lungs of the animals that were exposed to nicotine via the placenta and mother's milk, and thus during phases of lung development characterized by rapid cell division, is likely due to "programming" induced by nicotine. It is, therefore, not advisable to use nicotine during gestation and lactation. PMID:18383131

  6. Pavlovian-Instrumental Transfer of the Discriminative Stimulus Effects of Nicotine and Ethanol in Rats

    ERIC Educational Resources Information Center

    Troisi, Joseph R., II

    2006-01-01

    To date, only 1 study has evaluated the impact of a Pavlovian drug conditional stimulus (CS) on operant responding. A within-subject operant 1-lever go/no-go (across sessions) design was used to evaluate the impact of Pavlovian contingencies on the discriminative stimulus effects of nicotine (0.4 mg/kg) and ethanol (800 mg/kg) in male Sprague…

  7. Dose-dependent protective effect of nicotine in a murine model of viral myocarditis induced by coxsackievirus B3.

    PubMed

    Li-Sha, Ge; Jing-Lin, Zhao; Guang-Yi, Chen; Li, Liu; De-Pu, Zhou; Yue-Chun, Li

    2015-10-28

    The alpha 7 nicotinic acetylcholine receptor (alpha7 nAChR) was recently described as an anti-inflammatory target in various inflammatory diseases. The aim of this study was to investigate the dose-related effects of nicotine, an alpha7 nAChR agonist, in murine model of viral myocarditis. BALB/C mice were infected by an intraperitoneally injection with coxsackievirus B3. Nicotine was administered at doses of 0.1, 0.2 or 0.4 mg/kg three times per day for 7 or 14 consecutive days. The effects of nicotine on survival, myocardial histopathological changes, cardiac function, and cytokine levels were studied. The survival rate on day 14 increased in a dose-dependent fashion and was markedly higher in the 0.2 and 0.4 mg/kg nicotine groups than in the infected untreated group. Treatment with high-dose nicotine reduced the myocardial inflammation and improved the impaired left ventricular function in infected mice. The mRNA expressions and protein levels of TNF-α, IL-1β, IL-6, and IL-17A were significantly downregulated in dose-dependent manners in the nicotine treatment groups compared to the infected untreated group. Nicotine dose-dependently reduced the severity of viral myocarditis through inhibiting the production of proinflammatory cytokines. The findings suggest that alpha7 nAChR agonists may be a promising new strategy for patients with viral myocarditis.

  8. Lozenge Tilings with Gaps in a 90° Wedge Domain with Mixed Boundary Conditions

    NASA Astrophysics Data System (ADS)

    Ciucu, Mihai

    2015-02-01

    We consider a triangular gap of side two in a 90° angle on the triangular lattice with mixed boundary conditions: a constrained, zig-zag boundary along one side, and a free lattice line boundary along the other. We study the interaction of the gap with the corner as the rest of the angle is completely filled with lozenges. We show that the resulting correlation is governed by the product of the distances between the gap and its three images in the sides of the angle. This provides evidence for a unified way of understanding the interaction of gaps with the boundary under mixed boundary conditions, which we present as a conjecture. Our conjecture is phrased in terms of the steady state heat flow problem in a uniform block of material in which there are a finite number of heat sources and sinks. This new physical analogy is equivalent in the bulk to the electrostatic analogy we developed in previous work, but arises as the correct one for the correlation with the boundary. The starting point for our analysis is an exact formula we prove for the number of lozenge tilings of certain trapezoidal regions with mixed boundary conditions, which is equivalent to a new, multi-parameter generalization of a classical plane partition enumeration problem (that of enumerating symmetric, self-complementary plane partitions).

  9. Caffeine and amphetamine produce cross-sensitization to nicotine-induced locomotor activity in mice.

    PubMed

    Celik, Eylem; Uzbay, I Tayfun; Karakas, Sirel

    2006-01-01

    Sensitization development is linked to the addictive potential of the drugs. The same mechanisms might play a role in sensitization development to the different addictive drugs. The aim of the study was to investigate the development of cross-sensitization to caffeine and amphetamine in nicotine-induced locomotor sensitization in mice. Caffeine (2.5-20 mg/kg), amphetamine (1-16 mg/kg) or saline were injected to Swiss-Webster mice and locomotor activity was recorded for 30 min. Nicotine (0.5-2 mg/kg) or saline were injected to mice and locomotor activity was recorded for 30 min. Process was applied for 19 days, every other day (10 sessions). Caffeine (5 mg/kg), amphetamine (4 mg/kg) or saline were challenged to the different groups of nicotine-sensitized mice 2 days later on the last nicotine injection, and locomotor activity was recorded. Repetitive injections of nicotine (0.5-2 mg) produced locomotor sensitization in mice. After caffeine and amphetamine challenge injections, locomotor activity of the nicotine-sensitized mice was found to be significantly higher than saline-pretreated mice. Saline challenge did not produce any significant effect in nicotine- or saline-pretreated mice. Our results suggest that a cross-sensitization developed to both caffeine and amphetamine in nicotine-sensitized mice. In conclusion, similar central mechanisms may be responsible for the development of addiction to these substances.

  10. Chronic nicotine exposure exacerbates transient focal cerebral ischemia-induced brain injury.

    PubMed

    Li, Chun; Sun, Hong; Arrick, Denise M; Mayhan, William G

    2016-02-01

    Tobacco smoking is a risk factor contributing to the development and progression of ischemic stroke. Among many chemicals in tobacco, nicotine may be a key contributor. We hypothesized that nicotine alters the balance between oxidant and antioxidant networks leading to an increase in brain injury following transient focal cerebral ischemia. Male Sprague-Dawley were treated with nicotine (2 or 4 mg·kg(-1)·day(-1)) for 4 wk via an implanted subcutaneous osmotic minipump and subjected to a 2-h middle cerebral artery occlusion (MCAO). Infarct size and neurological deficits were evaluated at 24 h of reperfusion. Superoxide levels were determined by lucigenin-enhanced chemiluminescence. Expression of oxidant and antioxidant proteins was measured using Western blot analysis. We found that chronic nicotine exposure significantly increased infarct size and worsened neurological deficits. In addition, nicotine significantly elevated superoxide levels of cerebral cortex under basal conditions. Transient focal cerebral ischemia produced an increase in superoxide levels of cerebral cortex in control group, but no further increase was found in the nicotine group. Furthermore, chronic nicotine exposure did not alter protein expression of NADPH oxidase but significantly decreased MnSOD and uncoupling protein-2 (UCP-2) in the cerebral cortex and cerebral arteries. Our findings suggest that nicotine-induced exacerbation in brain damage following transient focal cerebral ischemia may be related to a preexisting oxidative stress via decreasing of MnSOD and UCP-2.

  11. Development of a lozenge for oral transmucosal delivery of trans-resveratrol in humans: proof of concept.

    PubMed

    Blanchard, Otis L; Friesenhahn, Gregory; Javors, Martin A; Smoliga, James M

    2014-01-01

    Resveratrol provides multiple physiologic benefits which promote healthspan in various model species and clinical trials support continued exploration of resveratrol treatment in humans. However, there remains concern regarding low bioavailability and wide inter-individual differences in absorption and metabolism in humans, which suggests a great need to develop novel methods for resveratrol delivery. We hypothesized that oral transmucosal delivery, using a lozenge composed of a resveratrol-excipient matrix, would allow resveratrol to be absorbed rapidly into the bloodstream. We pursued proof of concept through two experiments. In the first experiment, the solubility of trans-resveratrol (tRES) in water and 2.0 M solutions of dextrose, fructose, ribose, sucrose, and xylitol was determined using HPLC. Independent t-tests with a Bonferroni correction were used to compare the solubility of tRES in each of the solutions to that in water. tRES was significantly more soluble in the ribose solution (p = 0.0013) than in the other four solutions. Given the enhanced solubility of tRES in a ribose solution, a resveratrol-ribose matrix was developed into a lozenge suitable for human consumption. Lozenges were prepared, each containing 146±5.5 mg tRES per 2000 mg of lozenge mass. Two healthy human participants consumed one of the prepared lozenges following an overnight fast. Venipuncture was performed immediately before and 15, 30, 45, and 60 minutes following lozenge administration. Maximal plasma concentrations (Cmax) for tRES alone (i.e., resveratrol metabolites not included) were 325 and 332 ng⋅mL(-1) for the two participants at 15 minute post-administration for both individuals. These results suggest a resveratrol-ribose matrix lozenge can achieve greater Cmax and enter the bloodstream faster than previously reported dosage forms for gastrointestinal absorption. While this study is limited by small sample size and only one method of resveratrol delivery, it does

  12. Nicotine Nasal Spray

    MedlinePlus

    ... program, which may include support groups, counseling, or specific behavior change techniques. Nicotine nasal spray is in ... bottles at room temperature and away from excess heat and moisture (not in the bathroom). Discard used ...

  13. Nicotine and tobacco

    MedlinePlus

    ... ease your withdrawal symptoms. Health experts warn that e-cigarettes are not a replacement therapy for cigarette smoking. ... not known exactly how much nicotine is in e-cigarette cartridges, because information on labels is often wrong. ...

  14. IPTAKALIM ATTENUATES SELF-ADMINISTRATION AND ACQUIRED GOAL-TRACKING BEHAVIOR CONTROLLED BY NICOTINE

    PubMed Central

    Charntikov, S.; Swalve, N.; Pittenger, S.; Fink, K.; Schepers, S.; Hadlock, G. C.; Fleckenstein, A. E.; Hu, G.; Li, M.; Bevins, R. A.

    2013-01-01

    Iptakalim is an ATP-sensitive potassium channel opener, as well as an α4β2-containing nicotinic acetylcholine receptor (nAChR) antagonist. Pretreatment with iptakalim diminishes nicotine-induced dopamine (DA) and glutamate release in the nucleus accumbens. This neuropharmacological profile suggests that iptakalim may be useful for treatment of nicotine dependence. Thus, we examined the effects of iptakalim in two preclinical models. First, the impact of iptakalim on the interoceptive stimulus effect of nicotine was evaluated by training rats in a discriminated goal-tracking task that included intermixed nicotine (0.4 mg/kg, SC) and saline sessions. Sucrose was intermittently presented in a response-independent manner only on nicotine sessions. On intervening test days, rats were pretreated with iptakalim (10, 30, 60 mg/kg, IP). Results revealed that iptakalim attenuated nicotine-evoked responding controlled by the nicotine stimulus in a dose-dependent manner. In a separate study, the impact of iptakalim on the reinforcing effects of nicotine was investigated by training rats to lever-press to self-administer nicotine (0.03 mg/kg/infusion). Results revealed that pretreatment with iptakalim (1, 3, 6 mg/kg, IV) decreased nicotine intake (i.e., less active lever responding). Neither behavioral effect was due to a non-specific motor effect of iptakalim, nor to an ability of iptakalim to inhibit DA transporter (DAT) or serotonin transporter (SERT) function. Together, these finding support the notion that iptakalim may be an effective pharmacotherapy for increasing smoking cessation and better understanding its action could contribute medication development. PMID:23916479

  15. Iptakalim attenuates self-administration and acquired goal-tracking behavior controlled by nicotine.

    PubMed

    Charntikov, S; Swalve, N; Pittenger, S; Fink, K; Schepers, S; Hadlock, G C; Fleckenstein, A E; Hu, G; Li, M; Bevins, R A

    2013-12-01

    Iptakalim is an ATP-sensitive potassium channel opener, as well as an α4β2-containing nicotinic acetylcholine receptor (nAChR) antagonist. Pretreatment with iptakalim diminishes nicotine-induced dopamine (DA) and glutamate release in the nucleus accumbens. This neuropharmacological profile suggests that iptakalim may be useful for treatment of nicotine dependence. Thus, we examined the effects of iptakalim in two preclinical models. First, the impact of iptakalim on the interoceptive stimulus effect of nicotine was evaluated by training rats in a discriminated goal-tracking task that included intermixed nicotine (0.4 mg/kg, SC) and saline sessions. Sucrose was intermittently presented in a response-independent manner only on nicotine sessions. On intervening test days, rats were pretreated with iptakalim (10, 30, 60 mg/kg, IP). Results revealed that iptakalim attenuated nicotine-evoked responding controlled by the nicotine stimulus in a dose-dependent manner. In a separate study, the impact of iptakalim on the reinforcing effects of nicotine was investigated by training rats to lever-press to self-administer nicotine (0.01 mg/kg/infusion) [Dosage error corrected]. Results revealed that pretreatment with iptakalim (1, 3, 6 mg/kg, IV) decreased nicotine intake (i.e., less active lever responding). Neither behavioral effect was due to a non-specific motor effect of iptakalim, nor to an ability of iptakalim to inhibit DA transporter (DAT) or serotonin transporter (SERT) function. Together, these finding support the notion that iptakalim may be an effective pharmacotherapy for increasing smoking cessation and a better understanding of its action could contribute to medication development.

  16. Spin Configurations of π Electrons and Dimerization in Quasi-One-Dimensional Organic Bipartite Lozenge Chains

    NASA Astrophysics Data System (ADS)

    Duan, Y. F.; Yao, K. L.; Yi, L.

    Based on a theoretical model proposed for an organic bipartite lozenge ferrimagnetic chain, the spin configuration of π electrons and the dimerization are investigated. With the Hartree-Fock approximation, the strong electron-phonon coupling and the electron-electron interaction in the one-dimensional system are taken into account self-consistently. It is shown that around the middle of the chain appears a π electron spin polarization cloud with alternation of sign and amplitude of the spin density extending over a certain distance, which extends all over the chain with no decay when the e-e interaction is larger than a critical value. In the stable ferrimagnetic state, the antiferromagnetic exchange interaction between electrons at site A and site B along the chain will become very strong, and almost zero dimerization happens for the chain.

  17. Cigarette nicotine yields and nicotine intake among Japanese male workers

    PubMed Central

    Ueda, K; Kawachi, I; Nakamura, M; Nogami, H; Shirokawa, N; Masui, S; Okayama, A; Oshima, A

    2002-01-01

    Objectives: To analyse brand nicotine yield including "ultra low" brands (that is, cigarettes yielding ≤ 0.1 mg of nicotine by Federal Trade Commission (FTC) methods) in relation to nicotine intake (urinary nicotine, cotinine and trans-3'-hydroxycotinine) among 246 Japanese male smokers. Design: Cross sectional study. Setting: Two companies in Osaka, Japan. Subjects: 130 Japanese male workers selected randomly during their annual regular health check up and 116 Japanese male volunteers taking part in a smoking cessation programme. Main outcome measurements: Subjects answered a questionnaire about smoking habits. Following the interview, each participant was asked to smoke his own cigarette and, after extinguishing it, to blow expired air into an apparatus for measuring carbon monoxide concentration. Urine was also collected for the assays of nicotine metabolites. Results: We found wide variation in urinary nicotine metabolite concentrations at any given nicotine yield. Based on one way analysis of variance (ANOVA), the urinary nicotine metabolite concentrations of ultra low yield cigarette smokers were significantly lower compared to smokers of high (p = 0.002) and medium yield cigarettes (p = 0.017). On the other hand, the estimated nicotine intake per ultra low yield cigarette smoked (0.59 mg) was much higher than the 0.1 mg indicated by machine. Conclusions: In this study of Japanese male smokers, actual levels of nicotine intake bore little relation to advertised nicotine yield levels. Our study reinforces the need to warn consumers of inappropriate advertisements of nicotine yields, especially low yield brands. PMID:11891369

  18. Presence of the carcinogen N'-nitrosonornicotine in the urine of some users of oral nicotine replacement therapy products.

    PubMed

    Stepanov, Irina; Carmella, Steven G; Briggs, Anna; Hertsgaard, Louise; Lindgren, Bruce; Hatsukami, Dorothy; Hecht, Stephen S

    2009-11-01

    N'-nitrosonornicotine (NNN) is a strong carcinogen present in unburned tobacco and cigarette smoke. We here analyze data obtained in two studies, in which a biomarker of exposure to NNN--the sum of NNN and its pyridine-N-glucuronide, called total NNN--was quantified in the urine of people who had stopped smoking and used various nicotine replacement therapy (NRT) products. In 13 of 34 nicotine gum or lozenge users from both studies, total NNN at one or more time points after biochemically confirmed smoking cessation was comparable with, or considerably higher than, the baseline levels. For most of the subjects who used the nicotine patch as a smoking cessation aid, urinary total NNN at all post-quit time points was <37% of their mean baseline levels. These results indicate that endogenous formation of significant amounts of NNN may occur sporadically in some users of oral NRT. Given the carcinogenicity of NNN and the frequent use of nicotine gum as a smoking cessation aid, further studies are needed so that preventive measures can be developed. PMID:19843845

  19. Effectiveness of zinc gluconate glycine lozenges (Cold-Eeze) against the common cold in school-aged subjects: a retrospective chart review.

    PubMed

    McElroy, Betty Howell; Miller, Shelley Porter

    2002-01-01

    Of the 62 million common colds requiring medical attention in the United States each year, more than 80% affect school-aged children. Controlled clinical trials have demonstrated the effectiveness of zinc gluconate glycine lozenges (Cold-Eeze) in reducing cold duration. The objective of this study was to determine the effectiveness of zinc gluconate glycine lozenges in reducing the duration and severity of colds in school-aged subjects and to identify the benefits of prophylactic administration of zinc gluconate glycine lozenges in reducing the occurrence of colds. The medical charts of subjects enrolled at Utah's Heritage Center before and after the introduction of zinc gluconate glycine lozenges (between January 1998 and August 2001) were reviewed to identify those who experienced cold signs or symptoms. Two or more prespecified signs or symptoms on the same day identified a cold and, along with patient or medical staff reports and use of cold medications, were used to determine cold start and resolution dates. Results from subjects who did or did not take study treatment were compared statistically to determine the prophylactic effects of lozenge use. Effects of zinc gluconate glycine lozenges on the need for antibiotic therapy were also analyzed. The review encompassed 496 records. Treatment with zinc gluconate glycine lozenges significantly decreased cold duration (7.5 versus 9.0 days for nonuse; P < 0.0001). Prophylaxis also significantly reduced the median number of colds per year (0.0 versus 1.3; P < 0.001) and concomitant antibiotic use to manage colds (4.1% versus 36.2%; P < 0.0001). Therapy with zinc gluconate glycine lozenges significantly reduced cold duration and antibiotic use in school-aged subjects. Prophylactic administration also significantly decreased cold frequency. PMID:12424502

  20. Nicotine elicits methamphetamine-seeking in rats previously administered nicotine.

    PubMed

    Neugebauer, N M; Harrod, S B; Bardo, M T

    2010-01-01

    Research has indicated a high correlation between psychostimulant use and tobacco cigarette smoking in human substance abusers. The objective of the current study was to examine the effects of acute and repeated nicotine administration on responding for intravenous methamphetamine (0.03 mg/kg/infusion) in a rodent model of self-administration, as well as the potential of nicotine to induce reinstatement of previously extinguished drug-taking behavior in male Sprague-Dawley rats. In addition, it was assessed whether nicotine-induced reinstatement of methamphetamine-seeking behavior and nicotine-induced locomotor sensitization require that nicotine be temporally paired with the methamphetamine self-administration session or the locomotor activity chamber. Nicotine acutely decreased methamphetamine self-administration, but did not persistently alter responding during the maintenance of methamphetamine self-administration. However, following extinction of methamphetamine self-administration, nicotine administration reinstated methamphetamine-seeking behavior only in rats that had previously been administered nicotine. Nicotine-induced reinstatement and expression of locomotor sensitization were not dependent on a temporal pairing of nicotine with either the methamphetamine self-administration session or the locomotor activity chamber, respectively. These results indicate that nicotine may be acting, at least in part, through a non-associative mechanism to reinstate methamphetamine-seeking behavior.

  1. Pavlovian Extinction of the Discriminative Stimulus Effects of Nicotine and Ethanol in Rats Varies as a Function of Context

    ERIC Educational Resources Information Center

    Troisi, Joseph R., II

    2011-01-01

    Operant extinction contingencies can undermine the discriminative stimulus effects of drugs. Here, nicotine (0.4 mg/kg) and ethanol (0.8 g/kg) first functioned as either an S[superscript D] or S[superscript Delta], in a counterbalanced one-lever go/no-go (across sessions) operant drug discrimination procedure. Pavlovian extinction in the training…

  2. Mecamylamine, dihydro-beta-erythroidine, and dextromethorphan block conditioned responding evoked by the conditional stimulus effects of nicotine.

    PubMed

    Struthers, Amanda M; Wilkinson, Jamie L; Dwoskin, Linda P; Crooks, Peter A; Bevins, Rick A

    2009-12-01

    Current smokers express the desire to quit. However, the majority find it difficult to remain abstinent. As such, research efforts continually seek to develop more effective treatment. One such area of research involves the interoceptive stimulus effects of nicotine as either a discriminative stimulus in an operant drug discrimination task, or more recently as a conditional stimulus (CS) in a discriminated goal-tracking task. The present work investigated the potential role nicotinic acetylcholine receptors play in the CS effects of nicotine (0.4mg/kg) using antagonists with differential selectivity for beta2*, alpha7*, alpha6beta2*, and alpha3beta4* receptors. Methyllycaconitine (MLA) had no effect on nicotine-evoked conditioned responding. Mecamylamine and dihydro-beta-erythroidine (DHbetaE) dose-dependently blocked responding evoked by the nicotine CS. In a time-course assessment of mecamylamine and DHbetaE, each blocked conditioned responding when given 5min before testing and still blocked conditioned responding when administered 200min before testing. Two novel bis-picolinium analogs (N, N'-(3, 3'-(dodecan-1,12-diyl)-bis-picolinium dibromide [bPiDDB], and N, N'-(decan-1,10-diyl)-bis-picolinium diiodide [bPiDI]) did not block nicotine-evoked conditioned responding. Finally, pretreatment with low dose combinations of mecamylamine, dextromethorphan, and/or bupropion was used to target alpha3beta4* receptors. No combination blocked conditioned responding evoked by the training dose of nicotine. However, a combination of mecamylamine and dextromethorphan partially blocked nicotine-evoked conditioned responding to a lower dose of nicotine (0.1mg/kg). These results indicate that beta2* and potentially alpha3beta4* nicotinic acetylcholine receptors play a role in the CS effects of nicotine and are potential targets for the development of nicotine cessation aids.

  3. Effects of chronic nicotine administration on body weight, food intake and nitric oxide concentration in female and male rats.

    PubMed

    Ijomone, Omamuyovwi Meashack; Olaibi, Olayemi Kafilat; Nwoha, Polycarp Umunna

    2014-09-01

    Nicotine is readily consumed through cigarettes; however it is also easily consumed through the various forms of non-prescription nicotine replacement therapy. It has been shown to possess potential therapeutic value for the management of neurologic and neurodegenerative diseases in the last decade. Hence, this study examined the effects of chronic subcutaneous nicotine administration on food intake and body weight as well as on nitric oxide concentrations and total antioxidant capacity in female and male rats. Nicotine was administered to rats via subcutaneous injections at doses of 0.25, 2 and 4mg/kg body weight for 28 days. Control groups received normal saline; the vehicle for nicotine. Food intake by each group was monitored daily and body weight of the animals was measured twice weekly. At the end of drug administration, blood was obtained from each animal via cardiac puncture for biochemical determination of serum total antioxidant capacity (TAC) and nitric (NO) concentrations using standard assay kits. Results show significant loss (p<0.05) of body weight in all nicotine treated female rats. In contrast, male rats showed weight gain, though this was significantly lower (p<0.001) in nicotine treated groups compared to control. Nicotine significantly reduced (p<0.001) food consumed in both female and male rats; however dose related changes were observed in only male rats. No significant difference was observed in TAC following nicotine treatments for both female and male rats. Furthermore, only males exhibited changes in NO concentrations following nicotine treatment, as it significantly increased (p<0.01) NO concentrations in all male treated groups. In conclusion, this study has shown that modulation of body weight, food consumption and nitric oxide formation by nicotine is sexually dimorphic. Also, the study suggests that nicotine modulation of food intake and body weight and its modulation of NO may be independent of each other.

  4. Efficacy and safety of ambroxol lozenges in the treatment of acute uncomplicated sore throat. EBM-based clinical documentation.

    PubMed

    de Mey, Christian; Peil, Hubertus; Kölsch, Stephan; Bubeck, Jürgen; Vix, Jean-Michel

    2008-01-01

    Sore throat is the hallmark of acute pharyngitis. Although usually caused by viral infections, it is frequently treated with antibiotics. Such inappropriate use of antibiotics might best be challenged by offering efficacious and safe symptomatic pain relief instead. However, there is need for robust evidence to support such alternatives. Presently, the evidence from randomised, placebo-controlled, double-blind clinical trials (RCT) with the local anaesthetic ambroxol (CAS 23828-92-4) in the treatment of sore throat is being reviewed. This relates to five RCT in 1,772 patients; 1,713 were evaluable with regard to efficacy. Treatment with ambroxol lozenges was statistically significantly superior to placebo in reducing sore throat pain intensity with a high level of consistency of the estimated effect across the different studies. The effect had an early onset and lasted up to at least 3 h after a single first lozenge. The pain relief was associated with a statistically superior regression of pharyngeal redness and inflammation; with ambroxol, the overall efficacy was more frequently rated as at least "good". Treatment with the ambroxol lozenges was well tolerated. There was heterogeneity in reporting adverse events: in one later study with less severe baseline pain intensity there was more frequent reporting of hypoaesthesia of the oral cavity and tongue as an untoward phenomenon. In patients with more severe baseline pain this reflection of the medication's pharmacological action was only rarely reported as untoward. It is concluded that lozenges containing 20 mg ambroxol are a safe and efficacious treatment for acute uncomplicated sore throat of recent onset in adult patients.

  5. Effects of lozenge containing lavender oil, extracts from hops, lemon balm and oat on electrical brain activity of volunteers.

    PubMed

    Dimpfel, W; Pischel, I; Lehnfeld, R

    2004-09-29

    Within a randomized double blind, placebo controlled trial the electrical activity of the human brain has been monitored using charge mode technology (Laplacian estimates) after exposure to a lozenge containing 4 different herbal preparations (lavender oil, extracts from hops, lemon balm and oat) or a matching placebo without any active ingredients. Sixteen healthy volunteers (8 males and 8 females) were tested within a crossover design. After baseline recording each subject sucked a lozenge and 2 hours later a second one. Recording was performed immediately after finishing the lozenge and in hourly intervals thereafter. Comparison to reference periods of 10 min eyes open and 5 min eyes closed, respectively, revealed increases in alpha 1, alpha 2 and beta 1 electrical power at the electrode positions Cz, P3, T3 and T5 which were even more pronounced after a second application two hours later. Since alpha 1 changes repeatedly have been attributed to attentional states, increases of this electrical activity must be seen as indicator of a relaxational psychophysiological state. Changes in the alpha2 frequencies have been related to working memory indicating that an increase can be seen as a correlate for attenuating this circuit. Increases of beta1 activity have been seen in the presence of anxiolytic drugs including major and minor tranquilizers. The changes as observed after the application of this herbal composition are therefore in line with the idea of having induced a state of relaxation and regeneration. This interpretation suggests that one could expect from the ingestion of this lozenge to better cope with psychological and emotional stress. The data are further proof that recording computer aided quantitative EEG is a very fruitful and promising approach in psychophysiology.

  6. Efficacy and safety of ambroxol lozenges in the treatment of acute uncomplicated sore throat. EBM-based clinical documentation.

    PubMed

    de Mey, Christian; Peil, Hubertus; Kölsch, Stephan; Bubeck, Jürgen; Vix, Jean-Michel

    2008-01-01

    Sore throat is the hallmark of acute pharyngitis. Although usually caused by viral infections, it is frequently treated with antibiotics. Such inappropriate use of antibiotics might best be challenged by offering efficacious and safe symptomatic pain relief instead. However, there is need for robust evidence to support such alternatives. Presently, the evidence from randomised, placebo-controlled, double-blind clinical trials (RCT) with the local anaesthetic ambroxol (CAS 23828-92-4) in the treatment of sore throat is being reviewed. This relates to five RCT in 1,772 patients; 1,713 were evaluable with regard to efficacy. Treatment with ambroxol lozenges was statistically significantly superior to placebo in reducing sore throat pain intensity with a high level of consistency of the estimated effect across the different studies. The effect had an early onset and lasted up to at least 3 h after a single first lozenge. The pain relief was associated with a statistically superior regression of pharyngeal redness and inflammation; with ambroxol, the overall efficacy was more frequently rated as at least "good". Treatment with the ambroxol lozenges was well tolerated. There was heterogeneity in reporting adverse events: in one later study with less severe baseline pain intensity there was more frequent reporting of hypoaesthesia of the oral cavity and tongue as an untoward phenomenon. In patients with more severe baseline pain this reflection of the medication's pharmacological action was only rarely reported as untoward. It is concluded that lozenges containing 20 mg ambroxol are a safe and efficacious treatment for acute uncomplicated sore throat of recent onset in adult patients. PMID:19137906

  7. Effects of lozenge containing lavender oil, extracts from hops, lemon balm and oat on electrical brain activity of volunteers.

    PubMed

    Dimpfel, W; Pischel, I; Lehnfeld, R

    2004-09-29

    Within a randomized double blind, placebo controlled trial the electrical activity of the human brain has been monitored using charge mode technology (Laplacian estimates) after exposure to a lozenge containing 4 different herbal preparations (lavender oil, extracts from hops, lemon balm and oat) or a matching placebo without any active ingredients. Sixteen healthy volunteers (8 males and 8 females) were tested within a crossover design. After baseline recording each subject sucked a lozenge and 2 hours later a second one. Recording was performed immediately after finishing the lozenge and in hourly intervals thereafter. Comparison to reference periods of 10 min eyes open and 5 min eyes closed, respectively, revealed increases in alpha 1, alpha 2 and beta 1 electrical power at the electrode positions Cz, P3, T3 and T5 which were even more pronounced after a second application two hours later. Since alpha 1 changes repeatedly have been attributed to attentional states, increases of this electrical activity must be seen as indicator of a relaxational psychophysiological state. Changes in the alpha2 frequencies have been related to working memory indicating that an increase can be seen as a correlate for attenuating this circuit. Increases of beta1 activity have been seen in the presence of anxiolytic drugs including major and minor tranquilizers. The changes as observed after the application of this herbal composition are therefore in line with the idea of having induced a state of relaxation and regeneration. This interpretation suggests that one could expect from the ingestion of this lozenge to better cope with psychological and emotional stress. The data are further proof that recording computer aided quantitative EEG is a very fruitful and promising approach in psychophysiology. PMID:15546807

  8. Nicotine enantiomers and oxidative stress.

    PubMed

    Yildiz, D; Ercal, N; Armstrong, D W

    1998-09-15

    Nicotine affects a variety of cellular processes ranging from induction of gene expression to secretion of hormones and modulation of enzymatic activities. The objective of this study was to characterize the toxicity of nicotine enantiomers as well as their ability to induce oxidative stress in an in vitro model using Chinese hamster ovary (CHO) cells. Colony formation assay has demonstrated that (-)-nicotine is the more toxic of the enantiomers. At 6 mM concentrations, (-)-nicotine was found to be approximately 28- and 19-fold more potent than (+)-, and (+/-)-nicotine (racemic), respectively. Results also indicated that the toxicity of (+/-)-nicotine is higher than that of (+)-nicotine. (-)-Nicotine at a 10 mM concentration substantially decreased glutathione (GSH) levels (46% decrease). In addition, a 3-fold increase in malondialdehyde (MDA) level was evident in cells after exposure to 10 mM (-)-nicotine. Increased lactate dehydrogenase (LDH) activities in the media demonstrated that cellular membrane integrity was disturbed in nicotine treated cells. In the presence of superoxide dismutase (SOD) and catalase (CAT), the LDH activities returned to control value in 24 h with all concentrations of (-)-, (+)-, and (+/-)-nicotine. The decreases in LDH activities in the presence of the radical scavenging enzymes SOD and CAT suggest that membrane damage may be due to free radical generation. PMID:9865482

  9. Bioequivalence of two formulations of montelukast sodium 4 mg oral granules in healthy adults.

    PubMed

    Fey, Constanze; Thyroff-Friesinger, Ursula; Jones, Spencer

    2014-01-01

    Montelukast is an effective and well-tolerated treatment for the prophylaxis and chronic treatment of asthma, acute prevention of exercise-induced bronchoconstriction and symptomatic relief of seasonal allergic rhinitis and perennial allergic rhinitis. The aim of the study was to compare bioavailability, and characterise the pharmacokinetic profile and safety of Sandoz generic montelukast 4 mg oral granules relative to Singulair(®) mini (Merck, Sharp & Dohme). An open-label, randomised, single-dose, two-treatment, two-period, two-sequence, two-way crossover bioequivalence study was conducted in healthy male volunteers aged 18-55 years, under fasting conditions. The duration of the clinical part of the trial was ≈ 11 days. Montelukast levels in plasma were quantified using a validated liquid chromatography tandem mass spectrometry method, and pharmacokinetic parameters calculated from the drug concentration-time profile using a non-compartmental model. A total of 40 subjects completed both study periods. The ratio test/reference of geometric least squares means was calculated for both formulations of montelukast for the In-transformed pharmacokinetic parameters; the 90% confidence intervals (CIs) were within the pre-defined limits of 80.00-125.00%: 92.2% (90% CI: 87.42-97.30%) for Cmax, 98.1% (90% CI: 94.49-101.81%) for AUC0-t and 97.6% (90% CI: 94.14-101.27%) for AUC0-∞. Two study subjects each reported one mild adverse event: dyspepsia (possibly related to study medication) and throat pain (not considered related to study medication). Sandoz montelukast 4 mg oral granules are bioequivalent to Singulair(®) 4 mg mini oral granules, with a similar safety profile. This suggests that these two preparations can be considered interchangeable in clinical practice. PMID:25250173

  10. Bioequivalence of two formulations of montelukast sodium 4 mg oral granules in healthy adults

    PubMed Central

    2014-01-01

    Montelukast is an effective and well-tolerated treatment for the prophylaxis and chronic treatment of asthma, acute prevention of exercise-induced bronchoconstriction and symptomatic relief of seasonal allergic rhinitis and perennial allergic rhinitis. The aim of the study was to compare bioavailability, and characterise the pharmacokinetic profile and safety of Sandoz generic montelukast 4 mg oral granules relative to Singulair® mini (Merck, Sharp & Dohme). An open-label, randomised, single-dose, two-treatment, two-period, two-sequence, two-way crossover bioequivalence study was conducted in healthy male volunteers aged 18–55 years, under fasting conditions. The duration of the clinical part of the trial was ≈ 11 days. Montelukast levels in plasma were quantified using a validated liquid chromatography tandem mass spectrometry method, and pharmacokinetic parameters calculated from the drug concentration–time profile using a non-compartmental model. A total of 40 subjects completed both study periods. The ratio test/reference of geometric least squares means was calculated for both formulations of montelukast for the In-transformed pharmacokinetic parameters; the 90% confidence intervals (CIs) were within the pre-defined limits of 80.00–125.00%: 92.2% (90% CI: 87.42–97.30%) for Cmax, 98.1% (90% CI: 94.49–101.81%) for AUC0–t and 97.6% (90% CI: 94.14–101.27%) for AUC0–∞. Two study subjects each reported one mild adverse event: dyspepsia (possibly related to study medication) and throat pain (not considered related to study medication). Sandoz montelukast 4 mg oral granules are bioequivalent to Singulair® 4 mg mini oral granules, with a similar safety profile. This suggests that these two preparations can be considered interchangeable in clinical practice. PMID:25250173

  11. Which is the best primary medication for long-term smoking cessation--nicotine replacement therapy, bupropion or varenicline?

    PubMed

    Doggrell, Sheila A

    2007-12-01

    Nicotine chewing gum has been available since 1982, when it was shown to increase smoking cessation rates by approximately 1.5- to 2-fold after 12 months. Despite the introduction of many other preparations of nicotine (sublingual, lozenge, transdermal, nasal spray and inhaler) and numerous other clinical trials, there has been no major improvement in effectiveness for smoking cessation, just an increase in the choice of how the nicotine replacement therapy (NRT) is administered. Smoking cessation rates with NRT are similar in subjects with serious chest and cardiovascular disorders. There is no evidence that intensive counselling improves the smoking cessation rates with NRT over standard counselling. The first major alternative to NRT introduced for smoking cessation was bupropion, an inhibitor of the neuronal uptake of noradrenaline and dopamine. Bupropion is effective for smoking cessation, and effectiveness is improved by a moderate level of counselling. A long-term direct comparison of bupropion with transdermal nicotine showed than bupropion was more effective than nicotine. Despite this, NRT remains the standard treatment for smoking cessation in many countries. An exciting new development for the treatment of smoking cessation is varenicline, a partial agonist at nicotinic alpha4beta2 receptors. A direct comparison of varenicline with bupropion has shown that varenicline is as least as good as and probably more effective than bupropion for smoking cessation. At present, the number of subjects who have used varenicline in clinical trial is relatively small, and probably does not allow assessment of any rare serious adverse effects. Thus, it may be premature to recommend varenicline for smoking cessation in preference to bupropion. PMID:18001252

  12. Bupivacaine Lozenge Compared with Lidocaine Spray as Topical Pharyngeal Anesthetic before Unsedated Upper Gastrointestinal Endoscopy: A Randomized, Controlled Trial.

    PubMed

    Salale, Nesrin; Treldal, Charlotte; Mogensen, Stine; Rasmussen, Mette; Petersen, Janne; Andersen, Ove; Jacobsen, Jette

    2014-01-01

    Unsedated upper gastrointestinal endoscopy (UGE) can induce patient discomfort, mainly due to a strong gag reflex. The aim was to assess the effect of a bupivacaine lozenge as topical pharyngeal anesthetic compared with standard treatment with a lidocaine spray before UGE. Ninety-nine adult outpatients undergoing unsedated diagnostic UGE were randomized to receive either a bupivacaine lozenge (L-group, n = 51) or lidocaine spray (S-group, n = 42). Primary objective was assessment of patient discomfort including acceptance of the gag reflex during UGE. The L-group assessed the discomfort significantly lower on a visual analog scale compared with the S-group (P = 0.02). There was also a significant difference in the four-point scale assessment of the gag reflex (P = 0.03). It was evaluated as acceptable by 49% in the L-group compared with 31% in the S-group. A bupivacaine lozenge compared with a lidocaine spray proved to be a superior option as topical pharyngeal anesthetic before an UGE. PMID:25374463

  13. BEHAVIORAL MECHANISMS UNDERLYING NICOTINE REINFORCEMENT

    PubMed Central

    Rupprecht, Laura E.; Smith, Tracy T.; Schassburger, Rachel L.; Buffalari, Deanne M.; Sved, Alan F.; Donny, Eric C.

    2015-01-01

    Cigarette smoking is the leading cause of preventable deaths worldwide and nicotine, the primary psychoactive constituent in tobacco, drives sustained use. The behavioral actions of nicotine are complex and extend well beyond the actions of the drug as a primary reinforcer. Stimuli that are consistently paired with nicotine can, through associative learning, take on reinforcing properties as conditioned stimuli. These conditioned stimuli can then impact the rate and probability of behavior and even function as conditioning reinforcers that maintain behavior in the absence of nicotine. Nicotine can also act as a conditioned stimulus, predicting the delivery of other reinforcers, which may allow nicotine to acquire value as a conditioned reinforcer. These associative effects, establishing non-nicotine stimuli as conditioned stimuli with discriminative stimulus and conditioned reinforcing properties as well as establishing nicotine as a conditioned stimulus, are predicted by basic conditioning principles. However, nicotine can also act non-associatively. Nicotine directly enhances the reinforcing efficacy of other reinforcing stimuli in the environment, an effect that does not require a temporal or predictive relationship between nicotine and either the stimulus or the behavior. Hence, the reinforcing actions of nicotine stem both from the primary reinforcing actions of the drug (and the subsequent associative learning effects) as well as the reinforcement enhancement action of nicotine which is non-associative in nature. Gaining a better understanding of how nicotine impacts behavior will allow for maximally effective tobacco control efforts aimed at reducing the harm associated with tobacco use by reducing and/or treating its addictiveness. PMID:25638333

  14. Waterpipe tobacco products: nicotine labelling versus nicotine delivery

    PubMed Central

    Vansickel, Andrea R; Shihadeh, Alan; Eissenberg, Thomas

    2013-01-01

    Background Waterpipe tobacco package labelling typically indicates “0.0% tar” and “0.05% or 0.5% nicotine”. Objective To determine the extent to which nicotine labeling is related to nicotine delivery. Methods 110 waterpipe smokers engaged in a 45-minute waterpipe smoking session. Puff topography and plasma nicotine were measured. Three waterpipe tobacco brands were used: Nakhla (0.5% nicotine), Starbuzz (0.05% nicotine), and Al Fakher (0.05% nicotine). Data were analyzed by one-way ANOVA. Results Topography did not differ across brands. Peak plasma nicotine varied significantly across brands. Al Fakher had the highest nicotine delivery (11.4 ng/ml) followed by Nakhla (9.8 ng/ml) and Starbuzz (5.8 ng/ml). Conclusions Nicotine labelling on waterpipe tobacco products does not reflect delivery; smoking a brand with a “0.05% nicotine” label led to greater plasma nicotine levels than smoking a brand with a “0.5% nicotine” label. Waterpipe tobacco products should be labelled in a manner that does not mislead consumers. PMID:21636612

  15. Nicotinic Receptors in Neurodegeneration

    PubMed Central

    Posadas, Inmaculada; López-Hernández, Beatriz; Ceña, Valentín

    2013-01-01

    Many studies have focused on expanding our knowledge of the structure and diversity of peripheral and central nicotinic receptors. Nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily of pentameric ligand-gated ion channels, which include GABA (A and C), serotonin, and glycine receptors. Currently, 9 alpha (α2-α10) and 3 beta (β2-β4) subunits have been identified in the central nervous system (CNS), and these subunits assemble to form a variety of functional nAChRs. The pentameric combination of several alpha and beta subunits leads to a great number of nicotinic receptors that vary in their properties, including their sensitivity to nicotine, permeability to calcium and propensity to desensitize. In the CNS, nAChRs play crucial roles in modulating presynaptic, postsynaptic, and extrasynaptic signaling, and have been found to be involved in a complex range of CNS disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), schizophrenia, Tourette´s syndrome, anxiety, depression and epilepsy. Therefore, there is growing interest in the development of drugs that modulate nAChR functions with optimal benefits and minimal adverse effects. The present review describes the main characteristics of nAChRs in the CNS and focuses on the various compounds that have been tested and are currently in phase I and phase II trials for the treatment of neurodegenerative diseases including PD, AD and age-associated memory and mild cognitive impairment. PMID:24179465

  16. Adolescent exposure to nicotine and/or the cannabinoid agonist CP 55,940 induces gender-dependent long-lasting memory impairments and changes in brain nicotinic and CB(1) cannabinoid receptors.

    PubMed

    Mateos, B; Borcel, E; Loriga, R; Luesu, W; Bini, V; Llorente, R; Castelli, M P; Viveros, M-P

    2011-12-01

    We have analysed the long-term effects of adolescent (postnatal day 28-43) exposure of male and female rats to nicotine (NIC, 1.4 mg/kg/day) and/or the cannabinoid agonist CP 55,940 (CP, 0.4 mg/kg/day) on the following parameters measured in the adulthood: (1) the memory ability evaluated in the object location task (OL) and in the novel object test (NOT); (2) the anxiety-like behaviour in the elevated plus maze; and (3) nicotinic and CB(1) cannabinoid receptors in cingulated cortex and hippocampus. In the OL, all pharmacological treatments induced significant decreases in the DI of females, whereas no significant effects were found among males. In the NOT, NIC-treated females showed a significantly reduced DI, whereas the effect of the cannabinoid agonist (a decrease in the DI) was only significant in males. The anxiety-related behaviour was not changed by any drug. Both, nicotine and cannabinoid treatments induced a long-lasting increase in CB(1) receptor activity (CP-stimulated GTPγS binding) in male rats, and the nicotine treatment also induced a decrease in nicotinic receptor density in the prefrontal cortex of females. The results show gender-dependent harmful effects of both drugs and long-lasting changes in CB(1) and nicotinic receptors.

  17. Vaccines against nicotine.

    PubMed

    Cerny, Erich H; Cerny, Thomas

    2009-04-01

    Medications against any dependence-inducing drug face a dilemma: if they are efficient, they will induce withdrawal symptoms and the patient is likely to stop taking his medication. Anti drug vaccines are irreversible, provide protection over years and need booster injections far beyond the critical phase of acute withdrawal symptoms. Interacting rather with the drug in the blood than with a receptor in the brain, the vaccines are, in addition, free of side effects due to central interaction. For drugs like nicotine interacting with different types of receptors in many organs, this is a further advantage. There are three reasons that anti drug vaccines have first been developed against nicotine. Firstly, in most parts of the world 20 to 50% of the adult population smoke and any smoking cessation treatment will have an important impact on public health and be commercially a very attractive product. The second reason are the smokers themselves, who would like to quit in significant numbers and who have shown good compliance for any form of treatment. Thirdly, the quantities of cocaine or heroine taken by dependant persons are higher than the quantity of nicotine per cigarette, which makes an anti nicotine vaccine the easier vaccine project. Three anti nicotine vaccines are today in an advanced stage of clinical evaluation. We report here how those vaccines work, on the progress of the trials and future developments to expect. Results show that the efficiency of the vaccines is directly related to the antibody levels of the probates, a fact which will help to optimize further the vaccine effect. We expect the vaccines to appear on the market during a time window between 2009 and 2011. PMID:19276649

  18. Nicotinic receptors and attention.

    PubMed

    Hahn, Britta

    2015-01-01

    Facilitation of different attentional functions by nicotinic acetylcholine receptor (nAChR) agonists may be of therapeutic potential in disease conditions such as Alzheimer's disease or schizophrenia. For this reason, the neuronal mechanisms underlying these effects have been the focus of research in humans and in preclinical models. Attention-enhancing effects of the nonselective nAChR agonist nicotine can be observed in human nonsmokers and in laboratory animals, suggesting that benefits go beyond a reversal of withdrawal deficits in smokers. The ultimate aim is to develop compounds acting with greater selectivity than nicotine at a subset of nAChRs, with an effects profile narrowly matching the targeted cognitive deficits and minimizing unwanted effects. To date, compounds tested clinically target the nAChR subtypes most abundant in the brain. To help pinpoint more selectively expressed subtypes critical for attention, studies have aimed at identifying the secondary neurotransmitter systems whose stimulation mediates the attention-enhancing properties of nicotine. Evidence indicates that noradrenaline and glutamate, but not dopamine release, are critical mediators. Thus, attention-enhancing nAChR agents could spare the system central to nicotine dependence. Neuroimaging studies suggest that nAChR agonists act on a variety of brain systems by enhancing activation, reducing activation, and enhancing deactivation by attention tasks. This supports the notion that effects on different attentional functions may be mediated by distinct central mechanisms, consistent with the fact that nAChRs interact with a multitude of brain sites and neurotransmitter systems. The challenge will be to achieve the optimal tone at the right subset of nAChR subtypes to modulate specific attentional functions, employing not just direct agonist properties, but also positive allosteric modulation and low-dose antagonism.

  19. Nicotine dependence and psychiatric disorders.

    PubMed

    Salín-Pascual, Rafael J; Alcocer-Castillejos, Natasha V; Alejo-Galarza, Gabriel

    2003-01-01

    Nicotine addiction is the single largest preventable cause of morbidity and mortality in the Western World. Smoking is not any more just a bad habit, but a substance addiction problem. The pharmacological aspects of nicotine show that this substance has a broad distribution in the different body compartnents, due mainly to its lipophilic characteristic. There are nicotinic receptors as members of cholinergic receptors' family. They are located in neuromuscular junction and in the central nervous system (CNS). Although they are similar, pentameric structure with an ionic channel to sodium, there are some differences in the protein chains characteristics. Repeated administration of nicotine in rats, results in the sensitization phenomenon, which produces increase in the behavioral locomotor activity response. It has been found that most psychostimulants-induced behavioral sensitization through a nicotine receptor activation. Nicotine receptors in CNS are located mainly in presynaptic membrane and in that way they regulated the release of several neurotransmitters, among them acetylcholine, dopamine, serotonin, and norepinephrine. In some activities like sleep-wake cycle, nicotine receptors have a functional significance. Nicotine receptor stimulation promotes wake time, reduces both, total sleep time and rapid eye movement sleep (REMS). About nicotine dependence, this substance full fills all the criteria for dependence and withdrawal syndrome. There are some people that have more vulnerability for to become nicotine dependent, those are psychiatric patients. Among them schizophrenia, major depression, anxiety disorders and attention deficit disorder, represent the best example in this area. Nicotine may have some beneficial effects, among them are some neuroprotective effects in disorders like Parkinson's disease, and Gilles de la Tourette' syndrome. Also there are several evidences that support the role of nicotine in cognitive improvement functions like attention

  20. A novel Lozenge gene in silkworm, Bombyx mori regulates the melanization response of hemolymph.

    PubMed

    Xu, Man; Wang, Xue; Tan, Juan; Zhang, Kui; Guan, Xi; Patterson, Laurence H; Ding, Hanfei; Cui, Hongjuan

    2015-11-01

    Runt-related (RUNX) transcription factors are evolutionarily conserved either in vertebrate or invertebrate. Lozenge (Lz), a members of RUNX family as well as homologue of AML-1, functions as an important transcription factor regulating the hemocytes differentiation. In this paper, we identified and characterized RUNX family especially Lz in silkworm, which is a lepidopteran model insect. The gene expression analysis illustrated that BmLz was highly expressed in hemocytes throughout the whole development period, and reached a peak in glutonous stage. Over-expression of BmLz in silkworm accelerated the melanization process of hemolymph, and led to instantaneously up-regulation of prophenoloxidases (PPOs), which were key enzymes in the melanization process. Further down-regulation of BmLz expression by RNA interference resulted in the significant delay of melanization reaction of hemolymph. These findings suggested that BmLz regulated the melanization process of hemolymph by inducing PPOs expression, and played a critical role in innate immunity defense in silkworm.

  1. A novel Lozenge gene in silkworm, Bombyx mori regulates the melanization response of hemolymph.

    PubMed

    Xu, Man; Wang, Xue; Tan, Juan; Zhang, Kui; Guan, Xi; Patterson, Laurence H; Ding, Hanfei; Cui, Hongjuan

    2015-11-01

    Runt-related (RUNX) transcription factors are evolutionarily conserved either in vertebrate or invertebrate. Lozenge (Lz), a members of RUNX family as well as homologue of AML-1, functions as an important transcription factor regulating the hemocytes differentiation. In this paper, we identified and characterized RUNX family especially Lz in silkworm, which is a lepidopteran model insect. The gene expression analysis illustrated that BmLz was highly expressed in hemocytes throughout the whole development period, and reached a peak in glutonous stage. Over-expression of BmLz in silkworm accelerated the melanization process of hemolymph, and led to instantaneously up-regulation of prophenoloxidases (PPOs), which were key enzymes in the melanization process. Further down-regulation of BmLz expression by RNA interference resulted in the significant delay of melanization reaction of hemolymph. These findings suggested that BmLz regulated the melanization process of hemolymph by inducing PPOs expression, and played a critical role in innate immunity defense in silkworm. PMID:26164197

  2. Notch cooperates with Lozenge/Runx to lock haemocytes into a differentiation programme.

    PubMed

    Terriente-Felix, Ana; Li, Jinghua; Collins, Stephanie; Mulligan, Amy; Reekie, Ian; Bernard, Fred; Krejci, Alena; Bray, Sarah

    2013-02-01

    The diverse functions of Notch signalling imply that it must elicit context-specific programmes of gene expression. With the aim of investigating how Notch drives cells to differentiate, we have used a genome-wide approach to identify direct Notch targets in Drosophila haemocytes (blood cells), where Notch promotes crystal cell differentiation. Many of the identified Notch-regulated enhancers contain Runx and GATA motifs, and we demonstrate that binding of the Runx protein Lozenge (Lz) is required for enhancers to be competent to respond to Notch. Functional studies of targets, such as klumpfuss (ERG/WT1 family) and pebbled/hindsight (RREB1 homologue), show that Notch acts both to prevent the cells adopting alternate cell fates and to promote morphological characteristics associated with crystal cell differentiation. Inappropriate activity of Klumpfuss perturbs the differentiation programme, resulting in melanotic tumours. Thus, by acting as a master regulator, Lz directs Notch to activate selectively a combination of target genes that correctly locks cells into the differentiation programme. PMID:23325760

  3. Presenting your structures: the CCP4mg molecular-graphics software.

    PubMed

    McNicholas, S; Potterton, E; Wilson, K S; Noble, M E M

    2011-04-01

    CCP4mg is a molecular-graphics program that is designed to give rapid access to both straightforward and complex static and dynamic representations of macromolecular structures. It has recently been updated with a new interface that provides more sophisticated atom-selection options and a wizard to facilitate the generation of complex scenes. These scenes may contain a mixture of coordinate-derived and abstract graphical objects, including text objects, arbitrary vectors, geometric objects and imported images, which can enhance a picture and eliminate the need for subsequent editing. Scene descriptions can be saved to file and transferred to other molecules. Here, the substantially enhanced version 2 of the program, with a new underlying GUI toolkit, is described. A built-in rendering module produces publication-quality images. PMID:21460457

  4. Effects of acute nicotine on prepulse inhibition of auditory change-related cortical responses.

    PubMed

    Kodaira, Minori; Tsuruhara, Aki; Motomura, Eishi; Tanii, Hisashi; Inui, Koji; Kakigi, Ryusuke

    2013-11-01

    Prepulse inhibition (PPI) of startle is a measure of inhibitory function in which a weak leading stimulus suppresses the startle response to an intense stimulus. Usually, startle blink reflexes to an intense sound are used for measuring PPI. A recent magnetoencephalographic study showed that a similar phenomenon is observed for auditory change-related cortical response (Change-N1m) to an abrupt change in sound features. It has been well established that nicotine enhances PPI of startle. Therefore, in the present magnetoencephalographic study, the effects of acute nicotine on PPI of the Change-N1m were studied in 12 healthy subjects (two females and 10 males) under a repeated measures and placebo-controlled design. Nicotine (4 mg) was given as nicotine gum. The test Change-N1m response was elicited with an abrupt increase in sound pressure by 6 dB in a continuous background sound of 65 dB. PPI was produced by an insertion of a prepulse with a 3-dB-louder or 6-dB-weaker sound pressure than the background 75 ms before the test stimulus. Results show that nicotine tended to enhance the test Change-N1m response and significantly enhanced PPI for both prepulses. Therefore, nicotine's enhancing effect on PPI of the Change-N1m was similar to that on PPI of the startle. The present results suggest that the two measures share at least some mechanisms.

  5. Nicotinic receptors and schizophrenia.

    PubMed

    Ripoll, Nadège; Bronnec, Marie; Bourin, Michel

    2004-07-01

    The incidence of smoking is very high in non-schizophrenic subjects presenting various psychiatric disorders (35 to 54%). However, the incidence of smoking is extremely high in schizophrenic patients: 80% to 90%, versus 25% to 30% of the general population. Various studies have demonstrated that the use of tobacco transiently restores the schizophrenic patient's cognitive and sensory deficits. Smoking cessation also appears to exacerbate the symptoms of the disease. Post-mortem binding studies have revealed a disturbance of nicotinic receptor expression, affecting the alpha(7) and alpha(4)beta(2) subunits, in various cerebral areas. Genetic linkage studies have also shown that the alpha(7) subunit is involved in schizophrenia. This review assesses the involvement of the nicotinic system in schizophrenia and suggests ways in which this system may participate in the pathophysiology of this disease.

  6. Nicotine and periodontal tissues

    PubMed Central

    Malhotra, Ranjan; Kapoor, Anoop; Grover, Vishakha; Kaushal, Sumit

    2010-01-01

    Tobacco use has been recognized to be a significant risk factor for the development and progression of periodontal disease. Its use is associated with increased pocket depths, loss of periodontal attachment, alveolar bone and a higher rate of tooth loss. Nicotine, a major component and most pharmacologically active agent in tobacco is likely to be a significant contributing factor for the exacerbation of periodontal diseases. Available literature suggests that nicotine affects gingival blood flow, cytokine production, neutrophil and other immune cell function; connective tissue turnover, which can be the possible mechanisms responsible for overall effects of tobacco on periodontal tissues. Inclusion of tobacco cessation as a part of periodontal therapy encourages dental professionals to become more active in tobacco cessation counseling. This will have far reaching positive effects on our patients’ oral and general health. PMID:20922084

  7. The ternary system K2SO4MgSO4CaSO4

    USGS Publications Warehouse

    Rowe, J.J.; Morey, G.W.; Silber, C.C.

    1967-01-01

    Melting and subsolidus relations in the system K2SO4MgSO4CaSO4 were studied using heating-cooling curves, differential thermal analysis, optics, X-ray diffraction at room and high temperatures and by quenching techniques. Previous investigators were unable to study the binary MgSO4CaSO4 system and the adjacent area in the ternary system because of the decomposition of MgSO4 and CaSO4 at high temperatures. This problem was partly overcome by a novel sealed-tube quenching method, by hydrothermal synthesis, and by long-time heating in the solidus. As a result of this study, we found: (1) a new compound, CaSO4??3MgSO4 (m.p. 1201??C) with a field extending into the ternary system; (2) a high temperature form of MgSO4 with a sluggishly reversible inversion. An X-ray diffraction pattern for this polymorphic form is given; (3) the inversion of ??-CaSO4 (anhydrite) to ??-CaSO4 at 1195??C, in agreement with grahmann; (1) (4) the melting point of MgSO4 is 1136??C and that of CaSO4 is 1462??C (using sealed tube methods to prevent decomposition of the sulphates); (5) calcium langbeinite (K2SO4??2CaSO4) is the only compound in the K2SO4CaSO4 binary system. This resolved discrepancies in the results of previous investigators; (6) a continuous solid solution series between congruently melting K2SOP4??2MgSO4 (langbeinite) and incongruently melting K2SO4??2CaSO4 (calcium langbeinite); (7) the liquidus in the ternary system consists of primary phase fields of K2SO4, MgSO4, CaSO4, langbeinite-calcium langbeinite solid solution, and CaSO4??3MgSO4. The CaSO4 field extends over a large portion of the system. Previously reported fields for the compounds (K2SO4??MgSO4??nCaSO4), K2SO4??3CaSO4 and K2SO4??CaSO4 were not found; (8) a minimum in the ternary system at: 740??C, 25% MgSO4, 6% CaSO4, 69% K2SO4; and ternary eutectics at 882??C, 49% MgSO4, 19% CaSO4, 32% K2SO4; and 880??, 67??5% MgSO4, 5% CaSO4, 27??5% K2SO4. ?? 1967.

  8. Genetics of nicotinic acetylcholine receptors: relevance to nicotine addiction

    PubMed Central

    Mineur, Yann S.; Picciotto, Marina R.

    2008-01-01

    Human twin studies have suggested that there is a substantial genetic component underlying nicotine dependence, ongoing smoking and ability to quit. Similarly, animal studies have identified a number of genes and gene products that are critical for behaviors related to nicotine addiction. Classical genetic approaches, gene association studies and genetic engineering techniques have been used to identify the gene products involved in nicotine dependence. One class of genes involved in nicotine-related behavior is the family of nicotinic acetylcholine receptors (nAChRs). These receptors are the primary targets for nicotine in the brain. Genetic engineering studies in mice have identified a number of subunits that are critical for the ability of nicotine to activate the reward system in the brain, consisting of the dopaminergic cell bodies in the ventral tegmental area and their terminals in the nucleus accumbens and other portions of the mesolimbic system. In this review we will discuss the various lines of evidence suggesting that nAChRs may be involved in smoking behavior, and will review the human and animal studies that have been performed to date examining the genetic basis for nicotine dependence and smoking. PMID:17632086

  9. Exposure to nicotine during periadolescence or early adulthood alters aversive and physiological effects induced by ethanol.

    PubMed

    Rinker, Jennifer A; Hutchison, Mary Anne; Chen, Scott A; Thorsell, Annika; Heilig, Markus; Riley, Anthony L

    2011-07-01

    The majority of smokers begin their habit during adolescence, which often precedes experimentation with alcohol. Interestingly, very little preclinical work has been done examining how exposure to nicotine during periadolescence impacts the affective properties of alcohol in adulthood. Understanding how periadolescent nicotine exposure influences the aversive effects of alcohol might help to explain why it becomes more acceptable to this preexposed population. Thus, Experiment 1 exposed male Sprague Dawley rats to either saline or nicotine (0.4mg/kg, IP) from postnatal days 34 to 43 (periadolescence) and then examined changes in the aversive effects of alcohol (0, 0.56, 1.0 and 1.8g/kg, IP) in adulthood using the conditioned taste aversion (CTA) design. Changes in blood alcohol concentration (BAC) as well as alcohol-induced hypothermia and locomotor suppression were also assessed. To determine if changes seen were specific to nicotine exposure during periadolescence, the procedures were replicated in adults (Experiment 2). Preexposure to nicotine during periadolescence attenuated the acquisition of the alcohol-induced CTAs (at 1.0g/kg) and the hypothermic effects of alcohol (1.0g/kg). Adult nicotine preexposure produced similar attenuation in alcohol's aversive (at 1.8g/kg) and hypothermic (1.8g/kg) effects. Neither adolescent nor adult nicotine preexposure altered BACs or alcohol-induced locomotor suppression. These results suggest that nicotine may alter the aversive and physiological effects of alcohol, regardless of the age at which exposure occurs, possibly increasing its overall reinforcing value and making it more likely to be consumed.

  10. Nicotine cue: lack of effect of the alpha 7 nicotinic receptor antagonist methyllycaconitine.

    PubMed

    Brioni, J D; Kim, D J; O'Neill, A B

    1996-04-22

    To assess the role of the alpha 7 neuronal nicotinic acetylcholine receptor in the discriminative stimulus properties of (-)-nicotine, this study investigated the ability of the alpha 7 receptor antagonist methyllycaconitine to modulate the nicotine cue. In rats trained to discriminate (-)-nicotine from saline, intraperitoneal injections of methyllycaconitine neither induced nor blocked the nicotine cue. Intracerebroventricular administration of methyllycaconitine, neither potentiated nor blocked the effect of (-)-nicotine. On the other hand, intracerebroventricular injections of mecamylamine blocked the nicotine cue. The available evidence indicate that the nicotinic acetylcholine receptors in the brain blocked by methyllycaconitine, those presumably containing alpha 7 subunits, do not participate in the expression of the discriminative stimulus properties of (-)-nicotine.

  11. Melatonin 4 mg as prophylactic therapy for primary headaches: a pilot study

    PubMed Central

    Bougea, Anastasia; Spantideas, Nikolaos; Lyras, Vasilis; Avramidis, Theodoros; Thomaidis, Thomas

    2016-01-01

    Summary There is growing evidence that headaches are connected to melatonin secretion. Our aim was to assess the potential effectiveness of melatonin for primary headache prevention. Forty-nine patients (37 with migraine and 12 with chronic tension-type headache, TTH) were prescribed oral melatonin, 4 mg, 30 minutes before bedtime for six months. Forty-one (83.6%) of the 49 patients completed the study, while eight dropped out for personal reasons. A statistically significant reduction in headache frequency was found between baseline and final follow-up after six months of treatment (p=0.033 for TTH patients and p<0.001 for migraineurs). The Headache Impact Test score was significantly reduced in both groups of headache patients (p=0.002 and p<0.001, respectively). At baseline, melatonin levels, measured both during a headache attack and a pain-free period, did not differ between patients with TTH and migraineurs (p=0.539 and p=0.693, respectively), and no statistically significant differences in Hamilton Depression Rating Scale scores were found between the two groups. This pilot study shows promising results, in terms of headache frequency reduction and daily quality of life improvement, in both groups. PMID:27027892

  12. Solid-State Hydriding Mechanism in the LiBH4 + MgH2 System

    SciTech Connect

    Shaw, Leon L.; Wan, Xuefei; Hu, Jian Z.; Kwak, Ja Hun; Yang, Zhenguo

    2010-05-06

    The LiBH4+MgH2 system has great potential in reversible hydrogen storage for fuel cell vehicles. However, it has always been dehydrogenated and re-hydrogenated in the liquid state until recently. The solid-state hydriding and dehydriding are necessary in order to achieve hydrogen uptake and release near the ambient temperature. In this study, the solid-state hydriding mechanism of 2LiH+MgB2 mixtures has been investigated for the first time. It is found that the solid-state hydriding proceeds in two elementary steps. The first step is the ion exchange between the Mg2+ and Li+ ions in the MgB2 crystal to form an intermediate compound (Mg1-xLi2x)B2. The second step is the continuous ion exchange and simultaneous hydrogenation of (Mg1-xLi2x)B2 to form LiBH4 and MgH2. This finding is consistent with the observed diffusion-controlled hydriding kinetics.*

  13. Nicotine gum or patch treatment for smoking cessation and smoking reduction: a multi-centre study in Chinese physicians.

    PubMed

    Xiao, Dan; Zhong, Nanshan; Bai, Chunxue; Xiu, Qingyu; Xie, Canmao; Hu, Dayi; Mao, Yun; Perfekt, Roland; Kruse, Elisabeth; Li, Qing; Liu, John Jiangnan; Wang, Chen

    2014-03-01

    In China, around 23% of physicians (41% male, 3% female) currently smoke. Pharmacotherapy for tobacco dependence is available, but is not widely used in China. The purpose of this study was to estimate the effectiveness and the safety on smoking cessation of nicotine gum and nicotine patch in Chinese healthcare professionals. Three hundred regular smokers motivated to quit were recruited from six hospitals in China. All subjects were accepted nicotine replacement therapy, and they could choose nicotine gum (2 mg or 4 mg, depending on baseline smoking level) or nicotine patch (15 mg/16 h) for 12 weeks, with a 12-week follow-up. Limited behavioural support was provided. At Week 24, the 2-24 weeks continuous abstinence rate (verified by expired carbon monoxide) was 17%, the point prevalence abstinence rate (no smoking since the previous visit) was 35%, and 38% of subjects had continuously reduced their daily cigarette consumption by at least 50% versus baseline. Compliance with treatment was good, particularly with patch. No serious adverse event was reported, and most adverse events were mild or moderate. The most common treatment-related adverse events were gastrointestinal (both gum and patch) and local irritation symptoms. Nicotine patch and gum were well tolerated in Chinese smokers. Abstinence rates were comparable to those previously reported with nicotine replacement therapy, and many smokers who did not quit substantially reduced their cigarette consumption.

  14. Toward a comprehensive long term nicotine policy

    PubMed Central

    Gray, N; Henningfield, J; Benowitz, N; Connolly, G; Dresler, C; Fagerstrom, K; Jarvis, M; Boyle, P

    2005-01-01

    Global tobacco deaths are high and rising. Tobacco use is primarily driven by nicotine addiction. Overall tobacco control policy is relatively well agreed upon but a long term nicotine policy has been less well considered and requires further debate. Reaching consensus is important because a nicotine policy is integral to the target of reducing tobacco caused disease, and the contentious issues need to be resolved before the necessary political changes can be sought. A long term and comprehensive nicotine policy is proposed here. It envisages both reducing the attractiveness and addictiveness of existing tobacco based nicotine delivery systems as well as providing alternative sources of acceptable clean nicotine as competition for tobacco. Clean nicotine is defined as nicotine free enough of tobacco toxicants to pass regulatory approval. A three phase policy is proposed. The initial phase requires regulatory capture of cigarette and smoke constituents liberalising the market for clean nicotine; regulating all nicotine sources from the same agency; and research into nicotine absorption and the role of tobacco additives in this process. The second phase anticipates clean nicotine overtaking tobacco as the primary source of the drug (facilitated by use of regulatory and taxation measures); simplification of tobacco products by limitation of additives which make tobacco attractive and easier to smoke (but tobacco would still be able to provide a satisfying dose of nicotine). The third phase includes a progressive reduction in the nicotine content of cigarettes, with clean nicotine freely available to take the place of tobacco as society's main nicotine source. PMID:15923465

  15. Toward a comprehensive long term nicotine policy.

    PubMed

    Gray, N; Henningfield, J E; Benowitz, N L; Connolly, G N; Dresler, C; Fagerstrom, K; Jarvis, M J; Boyle, P

    2005-06-01

    Global tobacco deaths are high and rising. Tobacco use is primarily driven by nicotine addiction. Overall tobacco control policy is relatively well agreed upon but a long term nicotine policy has been less well considered and requires further debate. Reaching consensus is important because a nicotine policy is integral to the target of reducing tobacco caused disease, and the contentious issues need to be resolved before the necessary political changes can be sought. A long term and comprehensive nicotine policy is proposed here. It envisages both reducing the attractiveness and addictiveness of existing tobacco based nicotine delivery systems as well as providing alternative sources of acceptable clean nicotine as competition for tobacco. Clean nicotine is defined as nicotine free enough of tobacco toxicants to pass regulatory approval. A three phase policy is proposed. The initial phase requires regulatory capture of cigarette and smoke constituents liberalising the market for clean nicotine; regulating all nicotine sources from the same agency; and research into nicotine absorption and the role of tobacco additives in this process. The second phase anticipates clean nicotine overtaking tobacco as the primary source of the drug (facilitated by use of regulatory and taxation measures); simplification of tobacco products by limitation of additives which make tobacco attractive and easier to smoke (but tobacco would still be able to provide a satisfying dose of nicotine). The third phase includes a progressive reduction in the nicotine content of cigarettes, with clean nicotine freely available to take the place of tobacco as society's main nicotine source. PMID:15923465

  16. Genetic instability of the lozenge locus in Drosophila melanogaster: Characterization of the lz{sup 75V} allele

    SciTech Connect

    Voloshina, M.A.; Golubovskii, M.D.

    1995-12-01

    Genetic properties of lz{sup 75V}, an unstable allele of the lozenge locus, are described. The lz{sup 75V} allele appeared in progeny of a male from a Far East natural population of Drosophila melanogaster. Mutation of this allele produces a broad spectrum of mutant derivatives with phenotypes varying from normal to extreme. The arising alleles can be stable or unstable. Some lz{sup 75V} derivatives continuously preserve their spontaneous mutability in laboratory conditions, whereas other alleles of the same family show progressive stabilization at the intralocus or intrachromosome level. Instability of the lz{sup 75V}-bearing X chromosome is locus-specific: only the lozenge gene mutates with high frequency, while visible mutations at other loci rarely occur. As shown previously, the lz{sup 75V} allele appears to be caused by a P-element insertion. The appearance of spontaneous instability is discussed with regard to the general problem of transposition regulation in mobile elements. Different systems of hybrid dysgenesis, and, in particular, P elements are assumed to play an important role in induction of unstable mutations in nature. 24 refs., 5 tabs.

  17. Zinc(II) in saliva: determination of concentrations produced by different formulations of zinc gluconate lozenges containing common excipients.

    PubMed

    Zarembo, J E; Godfrey, J C; Godfrey, N J

    1992-02-01

    A study of the pH of saliva produced by humans sucking hard candy lozenges containing zinc gluconate and citric acid demonstrated the probability that the formulation delivered an insignificant amount of the contained zinc as Zn2+. This could account for the negative results of several clinical studies of this lozenge and similar formulations as treatment for the common cold. Direct measurement of unbound Zn2+ in saliva from this and other zinc gluconate formulations was required to substantiate the inference from the pH study. A specific-ion-electrode assay method was developed. Using this method, it was found that saliva completely suppresses the ionization of zinc to free Zn2+ in the presence of citric acid or a 30-fold molar excess of mannitol plus sorbitol. Under the same conditions, however, the presence of an excess of glycine does not interfere with ionization to produce Zn2+. This finding supports the hypothesis that the positive clinical results of three studies were due to the use of formulations which release ionic zinc.

  18. Nicotine and the adolescent brain

    PubMed Central

    Yuan, Menglu; Cross, Sarah J; Loughlin, Sandra E; Leslie, Frances M

    2015-01-01

    Adolescence encompasses a sensitive developmental period of enhanced clinical vulnerability to nicotine, tobacco, and e-cigarettes. While there are sociocultural influences, data at preclinical and clinical levels indicate that this adolescent sensitivity has strong neurobiological underpinnings. Although definitions of adolescence vary, the hallmark of this period is a profound reorganization of brain regions necessary for mature cognitive and executive function, working memory, reward processing, emotional regulation, and motivated behavior. Regulating critical facets of brain maturation are nicotinic acetylcholine receptors (nAChRs). However, perturbations of cholinergic systems during this time with nicotine, via tobacco or e-cigarettes, have unique consequences on adolescent development. In this review, we highlight recent clinical and preclinical data examining the adolescent brain's distinct neurobiology and unique sensitivity to nicotine. First, we discuss what defines adolescence before reviewing normative structural and neurochemical alterations that persist until early adulthood, with an emphasis on dopaminergic systems. We review how acute exposure to nicotine impacts brain development and how drug responses differ from those seen in adults. Finally, we discuss the persistent alterations in neuronal signaling and cognitive function that result from chronic nicotine exposure, while highlighting a low dose, semi-chronic exposure paradigm that may better model adolescent tobacco use. We argue that nicotine exposure, increasingly occurring as a result of e-cigarette use, may induce epigenetic changes that sensitize the brain to other drugs and prime it for future substance abuse. PMID:26018031

  19. Nicotine and the adolescent brain.

    PubMed

    Yuan, Menglu; Cross, Sarah J; Loughlin, Sandra E; Leslie, Frances M

    2015-08-15

    Adolescence encompasses a sensitive developmental period of enhanced clinical vulnerability to nicotine, tobacco, and e-cigarettes. While there are sociocultural influences, data at preclinical and clinical levels indicate that this adolescent sensitivity has strong neurobiological underpinnings. Although definitions of adolescence vary, the hallmark of this period is a profound reorganization of brain regions necessary for mature cognitive and executive function, working memory, reward processing, emotional regulation, and motivated behavior. Regulating critical facets of brain maturation are nicotinic acetylcholine receptors (nAChRs). However, perturbations of cholinergic systems during this time with nicotine, via tobacco or e-cigarettes, have unique consequences on adolescent development. In this review, we highlight recent clinical and preclinical data examining the adolescent brain's distinct neurobiology and unique sensitivity to nicotine. First, we discuss what defines adolescence before reviewing normative structural and neurochemical alterations that persist until early adulthood, with an emphasis on dopaminergic systems. We review how acute exposure to nicotine impacts brain development and how drug responses differ from those seen in adults. Finally, we discuss the persistent alterations in neuronal signaling and cognitive function that result from chronic nicotine exposure, while highlighting a low dose, semi-chronic exposure paradigm that may better model adolescent tobacco use. We argue that nicotine exposure, increasingly occurring as a result of e-cigarette use, may induce epigenetic changes that sensitize the brain to other drugs and prime it for future substance abuse. PMID:26018031

  20. Chronic nicotine administration does not alter cognitive or mood associated behavioural parameters.

    PubMed

    Ijomone, Omamuyovwi Meashack; Olaibi, Olayemi Kafilat; Mba, Christian; Biose, Ifechukwude Joachim; Tete, Samuel Anthony; Nwoha, Polycarp Umunna

    2015-03-01

    Nicotine, the major specific alkaloid in tobacco smoke, exhibits widespread pharmacological effects and may contribute to deterioration in behaviour. The present study thus examined the effects of its chronic administration on some cognitive and mood associated behaviours. Adult rats weighing between 150 and 200g were randomly divided into 4 groups each of 5 females and 5 males. Three groups were administered graded doses of nicotine at 0.25, 2 and 4mg/kg body weight via subcutaneous injections. One group served as control and received normal saline (vehicle for nicotine). Behavioural tests were performed using the Y-maze, elevated-plus maze (EPM) and tail suspension tests (TST) at various time points. Nicotine produced no significant effect in spontaneous alternation on Y-maze, nor on six parameters scored on EPM (open arm entries, time spent in open arms, time per open arm entries, open/closed arm quotient, closed arm entries, and total arm entries), and also no significant effect on immobility time in TST. This lack of effects was observed to be independent of sex and dose administered. The study shows that nicotine does not produce long-term changes in some cognitive and mood associated behaviours, thus suggesting it could be well tolerated even following chronic administration. PMID:25601213

  1. Multidose flurbiprofen 8.75 mg lozenges in the treatment of sore throat: a randomised, double-blind, placebo-controlled study in UK general practice centres.

    PubMed

    Blagden, M; Christian, J; Miller, K; Charlesworth, A

    2002-03-01

    The flurbiprofen 8.75 mg lozenge is a novel formulation that combines a demulcent effect with the analgesic activity of a non-steroidal anti-inflammatory drug. Previous controlled clinical studies have demonstrated the single- and multi-dose efficacy of these lozenges over placebo. The current study reflected the treatment of sore throat in general practice, investigating multiple dose efficacy where patients also had access to concomitant antibiotics and rescue medication. The efficacy of flurbiprofen 8.75 mg lozenge over placebo was confirmed: there was a significant difference in pain relief obtained from flurbiprofen 8.75 mg versus placebo, along with a significant reduction of difficulty in swallowing from the time of first assessment and significantly greater reductions in throat soreness and difficulty in swallowing throughout the study period. Additionally, significant benefit over placebo was demonstrated where concomitant antibiotic use was introduced, indicating that flurbiprofen 8.75 mg lozenges can be co-administered when antibiotic therapy is appropriate. No significant safety issues were identified. PMID:11926713

  2. Multidose flurbiprofen 8.75 mg lozenges in the treatment of sore throat: a randomised, double-blind, placebo-controlled study in UK general practice centres.

    PubMed

    Blagden, M; Christian, J; Miller, K; Charlesworth, A

    2002-03-01

    The flurbiprofen 8.75 mg lozenge is a novel formulation that combines a demulcent effect with the analgesic activity of a non-steroidal anti-inflammatory drug. Previous controlled clinical studies have demonstrated the single- and multi-dose efficacy of these lozenges over placebo. The current study reflected the treatment of sore throat in general practice, investigating multiple dose efficacy where patients also had access to concomitant antibiotics and rescue medication. The efficacy of flurbiprofen 8.75 mg lozenge over placebo was confirmed: there was a significant difference in pain relief obtained from flurbiprofen 8.75 mg versus placebo, along with a significant reduction of difficulty in swallowing from the time of first assessment and significantly greater reductions in throat soreness and difficulty in swallowing throughout the study period. Additionally, significant benefit over placebo was demonstrated where concomitant antibiotic use was introduced, indicating that flurbiprofen 8.75 mg lozenges can be co-administered when antibiotic therapy is appropriate. No significant safety issues were identified.

  3. Addressing the evidence for FDA nicotine replacement therapy label changes: a policy statement of the Association for the Treatment of Tobacco use and Dependence and the Society for Research on Nicotine and Tobacco.

    PubMed

    Fucito, Lisa M; Bars, Matthew P; Forray, Ariadna; Rojewski, Alana M; Shiffman, Saul; Selby, Peter; West, Robert; Foulds, Jonathan; Toll, Benjamin A

    2014-07-01

    Cigarette smoking creates a substantial public health burden. Identifying new, effective smoking cessation interventions that optimize existing interventions and promoting effective use of approved medications is a priority. When used as directed, nicotine replacement therapy (NRT) aids smoking cessation, but there is opportunity for improving its effectiveness. Until recently, NRT use guidelines advised smokers to begin using NRT on their quit date, only to use 1 NRT formulation at a time, to refrain from using NRT while smoking, and to stop NRT within 3 months regardless of progress. The Food and Drug Administration (FDA) issued a recent announcement allowing for NRT labeling changes with applications from pharmaceutical companies for such changes, and we applaud this decision. Nevertheless, additional revisions are warranted by current research. There is robust evidence that combining a longer-acting form (e.g., patch) with a shorter-acting form (e.g., lozenge) is more effective than NRT monotherapy and is safe. Moreover, extant evidence suggests that NRT use prior to a quit attempt or for smoking reduction as part of a quit attempt is safe and as effective as starting NRT on quit date. Specifically, prequit nicotine patch increases quit rates and may engage additional recalcitrant smokers. Last, NRT use longer than 3 months is safe and may be beneficial for relapse prevention in some smokers. This report summarizes the FDA announcement, reviews the evidence for further revisions to current FDA NRT guidelines, and makes recommendations for over-the-counter (OTC) NRT labeling to allow for (1) combined use of faster-acting NRT medications with nicotine patch, (2) nicotine patch use prior to quit date or NRT for smoking reduction as part of a quit attempt, and (3) prolonged NRT for up to 6 months without healthcare provider consultation. PMID:24919399

  4. Interoceptive conditioning with a nicotine stimulus is susceptible to reinforcer devaluation.

    PubMed

    Pittenger, Steven T; Bevins, Rick A

    2013-06-01

    Pavlovian conditioning processes contribute to the etiology of nicotine dependence. Conditioning involving interoceptive stimuli is increasingly recognized as playing a role in many diseases and psychopathologies, including drug addiction. Previous animal research on diminishing the influence of interoceptive conditioning has been limited to antagonism and nonreinforced exposures to the drug stimulus. The goal of the present research was to determine whether interoceptive conditioning with a nicotine stimulus could be diminished through an unconditioned stimulus (US) devaluation procedure. In two separate experiments, male Sprague-Dawley rats received nicotine injections (0.4 mg base/kg) followed by intermittent sucrose (26%) access in a conditioning chamber. On intermixed saline sessions, sucrose was withheld. Conditioning was demonstrated by a reliable increase in head entries in the dipper receptacle on nicotine versus saline sessions. After conditioning, rats in a devaluation condition were given access to sucrose in their home cages immediately followed by a lithium chloride (LiCl) injection on 3 consecutive days. On subsequent test days, nicotine-evoked conditioned responding was significantly attenuated. Within-subject (Experiment 1) and between-subjects (Experiment 2) controls revealed that the diminished responding was not attributable to mere exposure to the sucrose US in the devaluation phase. Experiment 2 included a LiCl-alone control group. Repeated illness induced by LiCl did not reduce later nicotine-evoked responding. These findings suggest that there is a direct association between the interoceptive stimulus effects of nicotine and the appetitive sucrose US (i.e., stimulus-stimulus) rather than a stimulus-response association.

  5. Continuous nicotine infusion reduces nicotine self-administration in rats with 23-h/day access to nicotine.

    PubMed

    LeSage, Mark G; Keyler, Dan E; Shoeman, Don; Raphael, Donna; Collins, Gregory; Pentel, Paul R

    2002-05-01

    The effects of continuous nicotine infusion on nicotine self-administration (NSA) were studied in rats as a model of nicotine replacement therapy (NRT) in humans. A NSA model in which rats had 23-h/day access to nicotine was used to approximate nicotine access conditions in cigarette smokers. In order to estimate serum nicotine concentrations associated with NSA, arterial and venous serum nicotine concentrations were measured during a simulation of NSA. Nicotine was noncontingently administered as 30 doses/12 h of 0.03 mg/kg/i.n.f. or 60 doses/12 h of 0.01 mg/kg/i.n.f. daily. Venous serum nicotine concentrations were measured after the first nicotine dose of the day, and arterial and venous concentrations were measured after doses in the middle of the day. The range of mean concentrations measured was similar to those reported in cigarette smokers (venous concentrations 6-59 ng/ml, arterial concentrations 42-96 ng/ml). The effects of continuous nicotine infusion on NSA were studied by noncontingently administering nicotine at various rates via osmotic pump to animals self-administering nicotine (0.01 or 0.03 mg/kg/i.n.f.) during 23-h/day sessions. Continuous nicotine infusion at all infusion rates substantially suppressed NSA, but suppression was rate-related only for the 0.01-mg/kg/inf NSA unit dose. Nicotine infusion rates producing venous serum nicotine concentrations equaling or exceeding the peak venous levels associated with simulated NSA were more effective than lower infusion rates only at the lower NSA unit dose. The highest nicotine infusion rate had no sustained effect on food-maintained responding, demonstrating its specificity for suppression of NSA. These data provide a model for studying NRT in the rat.

  6. Smoking cessation or reduction with nicotine replacement therapy: a placebo-controlled double blind trial with nicotine gum and inhaler

    PubMed Central

    2009-01-01

    Background Even with effective smoking cessation medications, many smokers are unable to abruptly stop using tobacco. This finding has increased interest in smoking reduction as an interim step towards complete cessation. Methods This multi-center, double-blind placebo-controlled study evaluated the efficacy and safety of nicotine 4 mg gum or nicotine 10 mg inhaler in helping smokers (N = 314) to reduce or quit smoking. It included smokers willing to control their smoking, and participants could set individual goals, to reduce or quit. The study was placebo-controlled, randomized in a ratio of 2:1 (Active:Placebo), and subjects could choose inhaler or gum after randomization. Outcome was short-term (from Week 6 to Month 4) and long-term (from Month 6 to Month 12) abstinence or reduction. Abstinence was defined as not a single cigarette smoked and expired CO readings of <10 ppm. Smoking reduction was defined as a reduction in number of cigarettes per day by 50% or more versus baseline, verified by a lower-than-baseline CO reading at each visit during the same periods. Results Significantly more smokers managed to quit in the Active group than in the Placebo group. Sustained abstinence rates at 4 months were 42/209 (20.1%) subjects in the Active group and 9/105 (8.6%) subjects in the Placebo group (p = 0.009). Sustained abstinence rates at 12 months were 39/209 (18.7%) and 9/105 (8.6%), respectively (p = 0.019). Smoking reduction did not differ between the groups, either at short-term or long-term. Twelve-month reduction results were 17.2% vs. 18.1%, respectively. No serious adverse events were reported. Conclusion In conclusion, treatment with 10 mg nicotine inhaler or 4 mg nicotine chewing gum resulted in a significantly higher abstinence rate than placebo. In addition a large number of smokers managed to reduce their cigarette consumption by more than 50% compared to baseline. PMID:19943947

  7. Evaluation of preoperative Strepsils lozenges on incidence of postextubation cough and sore throat in smokers undergoing anesthesia with endotracheal intubation

    PubMed Central

    Gupta, Divya; Agrawal, Sanjay; Sharma, Jagdish P.

    2014-01-01

    Post-operative sore throat (POST) is an undesirable side effect of endotracheal intubation. Pharmacological and non-pharmacological measures have been utilized for minimizing the morbidity caused by POST. We have tested use of Strepsils lozenges in providing efficacy for decreasing POST in smokers presenting for surgery under general anesthesia with endotracheal intubation. Materials and Methods: 100 patients, 20-65 years, American Society of Anesthesiologists (ASA) physical status I and II, either sex, history of smoking, posted for elective surgical procedure of more than 1 hour, requiring general anesthesia with endotracheal intubation were included and randomly divided into groups (n = 50) to receive Strepsils (Group A) and sugar candy (Group B). The patients were assessed for cough, sore throat, and hoarseness of voice after extubation, 30 min, 12 hrs, and 24 hrs after extubation. Results: At extubation no cough was seen in 39 (78%) patients (group A) compared to 23 (46%) patients (Group B), and mild cough in 22% (Group A) and 52% (Group B). Incidence of sore throat at extubation was lower in group A compared to Group B (P = 0.04). At other times of observations (30 min,12 hrs and 24 hrs) there was a significant decrease in incidence of sore throat in Group A compared to Group B (P = 0.000). Hoarseness of voice was not observed in any patient in either group. Conclusions: Use of preoperative Strepsils lozenges decreases incidence of POST and maybe utilized as a simple and cost-effective measure for decreasing the symptoms of POST and increasing the satisfaction of patients. PMID:24843341

  8. Nicotine vaccines to treat tobacco dependence.

    PubMed

    Goniewicz, Maciej L; Delijewski, Marcin

    2013-01-01

    Tobacco smoking is globally far more widespread than use of any other substance of abuse. Nicotine is an important tobacco constituent that is responsible for addictive properties of smoking. The currently available medications for the treatment of nicotine addiction have limited efficacy. A challenging novel therapeutic concept is vaccination against nicotine. An efficient vaccine would generate antibodies that sequester nicotine in the blood and prevent its access to the brain. The vaccine would have great potential for treating nicotine addiction and for relapse prevention. We reviewed the current status of vaccines against nicotine addiction that are undergoing clinical trials or are in preclinical development. We discuss problems associated with the development of nicotine vaccines, their efficacy in addiction treatment, challenges and ethical concerns. Existing evidence indicates that nicotine vaccination is well tolerated and capable of inducing an immune response but its effectiveness in increasing smoking abstinence has not been shown so far.

  9. 21 CFR 172.310 - Aluminum nicotinate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Aluminum nicotinate. 172.310 Section 172.310 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR... Special Dietary and Nutritional Additives § 172.310 Aluminum nicotinate. Aluminum nicotinate may be...

  10. 21 CFR 172.310 - Aluminum nicotinate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Aluminum nicotinate. 172.310 Section 172.310 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR... Special Dietary and Nutritional Additives § 172.310 Aluminum nicotinate. Aluminum nicotinate may be...

  11. 21 CFR 172.310 - Aluminum nicotinate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Aluminum nicotinate. 172.310 Section 172.310 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD... Additives § 172.310 Aluminum nicotinate. Aluminum nicotinate may be safely used as a source of niacin...

  12. 21 CFR 172.310 - Aluminum nicotinate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Aluminum nicotinate. 172.310 Section 172.310 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR... Special Dietary and Nutritional Additives § 172.310 Aluminum nicotinate. Aluminum nicotinate may be...

  13. 21 CFR 172.310 - Aluminum nicotinate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Aluminum nicotinate. 172.310 Section 172.310 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR... Special Dietary and Nutritional Additives § 172.310 Aluminum nicotinate. Aluminum nicotinate may be...

  14. Worms clear the smoke surrounding nicotine addiction.

    PubMed

    Kelley, Ann E

    2006-11-01

    In this issue of Cell, Feng et al. report a worm model of nicotine dependence that shows behavioral adaptations surprisingly similar to those in humans. These authors show a critical link between nicotinic receptors and TRP channels, which may represent a new therapeutic target for treating nicotine addiction.

  15. Solid Solution Effects on the MgAl2O4-MgGa2O4 System

    SciTech Connect

    O'Hara, Kelley; Smith, Jeffrey D; Hemrick, James Gordon

    2009-01-01

    Phase relations between two spinel compounds (MgAl2O4 and MgGa2O4) were studied. Stoichiometric MgAl2O4 was formed in the laboratory through a coprecipitation method. Complete solid solution formation int eh MgAl2O4-MgGa2O4 systems was confirmed through X-ray diffraction analysis. Solid solution between MgAl2O4-MgGa2O4 decreases thermal conductivity at all temperatures up to 900oC. At 200oC with 10 mol% additoin of MgGa2O4 thermal conductivity decreases approximately 25%, and at 900oC there was still an 8% decrease. Additionally, preliminary studies show that porosity between 5% and 10% does not have an appreciable effect on the thermal conductivity in this study.

  16. Phase Equilibria, Crystal Structure and Hydriding/Dehydriding Mechanism of Nd4Mg80Ni8 Compound

    NASA Astrophysics Data System (ADS)

    Luo, Qun; Gu, Qin-Fen; Zhang, Jie-Yu; Chen, Shuang-Lin; Chou, Kuo-Chih; Li, Qian

    2015-10-01

    In order to find out the optimal composition of novel Nd-Mg-Ni alloys for hydrogen storage, the isothermal section of Nd-Mg-Ni system at 400 °C is established by examining the equilibrated alloys. A new ternary compound Nd4Mg80Ni8 is discovered in the Mg-rich corner. It has the crystal structure of space group I41/amd with lattice parameters of a = b = 11.2743(1) Å and c = 15.9170(2) Å, characterized by the synchrotron powder X-ray diffraction (SR-PXRD). High-resolution transmission electron microscopy (HR-TEM) is used to investigate the microstructure of Nd4Mg80Ni8 and its hydrogen-induced microstructure evolution. The hydrogenation leads to Nd4Mg80Ni8 decomposing into NdH2.61-MgH2-Mg2NiH0.3 nanocomposites, where the high density phase boundaries provide a great deal of hydrogen atoms diffusion channels and nucleation sites of hydrides, which greatly enhances the hydriding/dehydriding (H/D) properties. The Nd4Mg80Ni8 exhibits a good cycle ability. The kinetic mechanisms of H/D reactions are studied by Real Physical Picture (RPP) model. The rate controlling steps are diffusion for hydriding reaction in the temperature range of 100 ~ 350 °C and surface penetration for dehydriding reaction at 291 ~ 347 °C. In-situ SR-PXRD results reveal the phase transformations of Mg to MgH2 and Mg2Ni to Mg2NiH4 as functions of hydrogen pressure and hydriding time.

  17. Strain localization parameters of AlCu4MgSi processed by high-energy electron beams

    SciTech Connect

    Lunev, A. G. Nadezhkin, M. V.; Konovalov, S. V.; Teresov, A. D.

    2015-10-27

    The influence of the electron beam surface treatment of AlCu4MgSi on the strain localization parameters and on the critical strain value of the Portevin–Le Chatelier effect has been considered. The strain localization parameters were measured using speckle imaging of the specimens subjected to the constant strain rate uniaxial tension at a room temperature. Impact of the surface treatment on the Portevin–Le Chatelier effect has been investigated.

  18. Phase Equilibria, Crystal Structure and Hydriding/Dehydriding Mechanism of Nd4Mg80Ni8 Compound

    PubMed Central

    Luo, Qun; Gu, Qin-Fen; Zhang, Jie-Yu; Chen, Shuang-Lin; Chou, Kuo-Chih; Li, Qian

    2015-01-01

    In order to find out the optimal composition of novel Nd-Mg-Ni alloys for hydrogen storage, the isothermal section of Nd-Mg-Ni system at 400 °C is established by examining the equilibrated alloys. A new ternary compound Nd4Mg80Ni8 is discovered in the Mg-rich corner. It has the crystal structure of space group I41/amd with lattice parameters of a = b = 11.2743(1) Å and c = 15.9170(2) Å, characterized by the synchrotron powder X-ray diffraction (SR-PXRD). High-resolution transmission electron microscopy (HR-TEM) is used to investigate the microstructure of Nd4Mg80Ni8 and its hydrogen-induced microstructure evolution. The hydrogenation leads to Nd4Mg80Ni8 decomposing into NdH2.61-MgH2-Mg2NiH0.3 nanocomposites, where the high density phase boundaries provide a great deal of hydrogen atoms diffusion channels and nucleation sites of hydrides, which greatly enhances the hydriding/dehydriding (H/D) properties. The Nd4Mg80Ni8 exhibits a good cycle ability. The kinetic mechanisms of H/D reactions are studied by Real Physical Picture (RPP) model. The rate controlling steps are diffusion for hydriding reaction in the temperature range of 100 ~ 350 °C and surface penetration for dehydriding reaction at 291 ~ 347 °C. In-situ SR-PXRD results reveal the phase transformations of Mg to MgH2 and Mg2Ni to Mg2NiH4 as functions of hydrogen pressure and hydriding time. PMID:26471964

  19. Examining the reinforcement-enhancement effects of phencyclidine and its interactions with nicotine on lever-pressing for a visual stimulus.

    PubMed

    Swalve, Natashia; Barrett, Scott T; Bevins, Rick A; Li, Ming

    2015-09-15

    Nicotine is a widely-abused drug, yet its primary reinforcing effect does not seem potent as other stimulants such as cocaine. Recent research on the contributing factors toward chronic use of nicotine-containing products has implicated the role of reinforcement-enhancing effects of nicotine. The present study investigates whether phencyclidine (PCP) may also possess a reinforcement-enhancement effect and how this may interact with the reinforcement-enhancement effect of nicotine. PCP was tested for two reasons: (1) it produces discrepant results on overall reward, similar to that seen with nicotine and (2) it may elucidate how other compounds may interact with the reinforcement-enhancement of nicotine. Adult male Sprague-Dawley rats were trained to lever press for brief visual stimulus presentations under fixed-ratio (FR) schedules of reinforcement and then were tested with nicotine (0.2 or 0.4 mg/kg) and/or PCP (2.0mg/kg) over six increasing FR values. A selective increase in active lever-pressing for the visual stimulus with drug treatment was considered evidence of a reinforcement-enhancement effect. PCP and nicotine separately increased active lever pressing for a visual stimulus in a dose-dependent manner and across the different FR schedules. The addition of PCP to nicotine did not increase lever-pressing for the visual stimulus, possibly due to a ceiling effect. The effect of PCP may be driven largely by its locomotor stimulant effects, whereas the effect of nicotine was independent of locomotor stimulation. This dissociation emphasizes that distinct pharmacological properties contribute to the reinforcement-enhancement effects of substances.

  20. PI3K/Akt-independent NOS/HO activation accounts for the facilitatory effect of nicotine on acetylcholine renal vasodilations: modulation by ovarian hormones.

    PubMed

    Gohar, Eman Y; El-gowilly, Sahar M; El-Gowelli, Hanan M; El-Demellawy, Maha A; El-Mas, Mahmoud M

    2014-01-01

    We investigated the effect of chronic nicotine on cholinergically-mediated renal vasodilations in female rats and its modulation by the nitric oxide synthase (NOS)/heme oxygenase (HO) pathways. Dose-vasodilatory response curves of acetylcholine (0.01-2.43 nmol) were established in isolated phenylephrine-preconstricted perfused kidneys obtained from rats treated with or without nicotine (0.5-4.0 mg/kg/day, 2 weeks). Acetylcholine vasodilations were potentiated by low nicotine doses (0.5 and 1 mg/kg/day) in contrast to no effect for higher doses (2 and 4 mg/kg/day). The facilitatory effect of nicotine was acetylcholine specific because it was not observed with other vasodilators such as 5'-N-ethylcarboxamidoadenosine (NECA, adenosine receptor agonist) or papaverine. Increases in NOS and HO-1 activities appear to mediate the nicotine-evoked enhancement of acetylcholine vasodilation because the latter was compromised after pharmacologic inhibition of NOS (L-NAME) or HO-1 (zinc protoporphyrin, ZnPP). The renal protein expression of phosphorylated Akt was not affected by nicotine. We also show that the presence of the two ovarian hormones is necessary for the nicotine augmentation of acetylcholine vasodilations to manifest because nicotine facilitation was lost in kidneys of ovariectomized (OVX) and restored after combined, but not individual, supplementation with medroxyprogesterone acetate (MPA) and estrogen (E2). Together, the data suggests that chronic nicotine potentiates acetylcholine renal vasodilation in female rats via, at least partly, Akt-independent HO-1 upregulation. The facilitatory effect of nicotine is dose dependent and requires the presence of the two ovarian hormones.

  1. Escalating doses of transdermal nicotine in heavy smokers: effects on smoking behavior and craving.

    PubMed

    Selby, Peter; Andriash, Katherine; Zawertailo, Laurie; Persad, Desmond; Zack, Martin; Busto, Usoa E

    2013-10-01

    Fixed-dose nicotine replacement therapy (NRT) is efficacious for smoking cessation in the general population of smokers. However, it is less effective in populations with psychiatric comorbidities and/or severe tobacco dependence where the percent nicotine replacement is suboptimal. The objective of this pilot study was to determine the effectiveness of nicotine patch dose titration in response to continued smoking in heavily dependent smokers with psychiatric comorbidity. In a single-arm, open-label study adult smokers (mean cigarettes per day, 25.4 ± 13.4; range, 14-43; n = 12) willing to quit were treated with escalating doses of transdermal nicotine and brief counseling intervention if they continued to smoke over a 9-week treatment period. Plasma nicotine and cotinine, along with expired carbon monoxide levels, and the subjective effects of smoking, urge to smoke, demand elasticity, and mood symptoms were also assessed. The mean NRT dose was 32.7 (SD, 16.4) mg/d (range, 7-56 mg/d). Smokers reported significant reductions in both cigarettes per day (mean decrease, 18.4 ± 11.5) confirmed by expired carbon monoxide (mean decrease, 13.5 ± 13.0) with no significant changes in plasma nicotine concentrations during the course of NRT dose titration. There were significant effects on the subjective effects of smoking and measures of smoking behavior. Most commonly reported adverse events were respiratory infections, skin irritation at patch site, nausea, and sleep disturbances, which were generally mild and transient. Titrating doses of NRT to effect with brief intervention hold promise as an effective clinical strategy to assist heavily dependent psychiatrically ill smokers to change their smoking behavior.

  2. Superconductivity in new iron pnictide oxide Fe2As2Sr4(Mg,Ti)2O6

    NASA Astrophysics Data System (ADS)

    Sato, Shinya; Ogino, Hiraku; Kishio, Kohji; Shimoyama, Jun-Ichi

    2010-03-01

    A new iron arsenide oxide Fe2As2Sr4MgTiO6, which is isostructural with the iron-based superconductor Fe2Pn2Sr4M2O6^[1,2], has been successfully synthesized by the solid-state reaction in quartz ampoules. Fe2As2Sr4MgTiO6 has antifluorite-type iron arsenide layer and K2NiF4-type oxide layer, while the M-site is composed of a combination of divalent (Mg^2+) and tetravalent (Ti^4+) cations as in the case of a double perovskite La(Mg,Ti)O3. This fact indicates chemical flexibility of the perovskite-related layer in this system. This compound showed bulk superconductivity with Tc of ˜20 K by partial substitution of Co for Fe. Moreover, high Tc above 35 K was recorded by samples starting from Co-free and Ti-rich compositions, Fe2As2Sr4(Mg1-xTix)2O6 (x =0.7˜0.8). [1] H. Ogino et al., Supercond. Sci. Technol. 22 (2009) 075008. [2] X. Zhu et al., Phys. Rev. B 79 (2009) 220512(R).

  3. Nicotinic acetylcholine receptors and cancer

    PubMed Central

    DANG, NINGNING; MENG, XIANGUANG; SONG, HAIYAN

    2016-01-01

    Nicotine, the primary addictive constituent of cigarettes, is believed to contribute to cancer promotion and progression through the activation of nicotinic acetylcholine receptors (nAChRs), which are membrane ligand-gated cation channels. nAChRs activation can be triggered by the neurotransmitter Ach, or certain other biological compounds, such as nicotine. In recent years, genome-wide association studies have indicated that allelic variation in the α5-α3-β4 nAChR cluster on chromosome 15q24-15q25.1 is associated with lung cancer risk. The role of nAChRs in other types of cancer has also been reported. The present review highlights the role of nAChRs in types of human cancer. PMID:27123240

  4. Nicotine levels in indoor athletic centres.

    PubMed

    Michael, C M; Demetriou, E; Kosmas, V; Krashia, A; Akkelidou, D

    1996-12-01

    The levels of nicotine during athletic events were measured at six indoor athletic centres in Cyprus. Samples of air were pumped through a tube containing XAD-4 resin. Quantitation of nicotine was carried out by GC with a method detection limit of 0.03 microgram of nicotine, recovery ranged between 99.5 and 100.5%. Confirmation of the nicotine presence was carried out by GC/MS. The concentrations of nicotine measured were between 3.6 and 39.0 micrograms/Nm3 with a geometric mean range 6.5-28.3 micrograms/Nm3.

  5. Reinstatement of nicotine self-administration in rats by presentation of nicotine-paired stimuli, but not nicotine priming.

    PubMed

    LeSage, Mark G; Burroughs, Danielle; Dufek, Matthew; Keyler, Daniel E; Pentel, Paul R

    2004-11-01

    The objective of the present study was to determine the relative efficacy of nicotine priming and nicotine-paired stimuli in reinstating extinguished NSA in rats. The relative efficacy of different stimulus conditions in reinstating NSA was also determined. Rats were trained to self-administer nicotine (0.03 mg/kg/inf) under an FR 5 schedule. Onset of a light above the active lever was correlated with nicotine availability, while offset of the light was paired with each nicotine infusion. In Experiment 1, saline extinction was arranged in the presence of these light stimuli. After extinction criteria were met, the effects of priming doses of nicotine (0.01, 0.03. and 0.06 mg/kg/inf, i.v.) on active lever pressing were determined. In Experiment 2, extinction of NSA was arranged in the absence of the light stimuli. After extinction criteria were met, reinstatement sessions were arranged involving either (1) a priming infusion of nicotine (0.03 mg/kg), (2) presentation of the same light stimuli as during NSA training, (3) constant illumination of the cue light, or (4) a combination of a nicotine priming infusion with one of the stimulus-light conditions. In Experiment 1, nicotine generally failed to reinstate NSA at any priming dose. In Experiment 2, both stimulus conditions reinstated NSA, with the stimulus condition identical to training producing a greater effect. Nicotine priming alone failed to significantly reinstate NSA. Nicotine priming combined with either stimulus condition was no more effective than each stimulus condition alone in reinstating NSA. These findings suggest that nicotine-paired cues are more effective than nicotine alone in reinstating extinguished NSA and are consistent with other studies showing that nicotine-paired stimuli play an important role in the reacquisition of NSA.

  6. Nicotine alters lung branching morphogenesis through the alpha7 nicotinic acetylcholine receptor.

    PubMed

    Wongtrakool, Cherry; Roser-Page, Susanne; Rivera, Hilda N; Roman, Jesse

    2007-09-01

    There is abundant epidemiological data linking prenatal environmental tobacco smoke with childhood asthma and wheezing, but the underlying molecular and physiological mechanisms that occur in utero to explain this link remain unelucidated. Several studies suggest that nicotine, which traverses the placenta, is a causative agent. Therefore, we studied the effects of nicotine on lung branching morphogenesis using embryonic murine lung explants. We found that the expression of alpha(7) nicotinic acetylcholine receptors, which mediate many of the biological effects of nicotine, is highest in pseudoglandular stage lungs compared with lungs at later stages. We then studied the effects of nicotine in the explant model and found that nicotine stimulated lung branching in a dose-dependent fashion. alpha-Bungarotoxin, an antagonist of alpha(7) nicotinic acetylcholine receptors, blocked the stimulatory effect of nicotine, whereas GTS-21, a specific agonist, stimulated branching, thereby mimicking the effects of nicotine. Explants deficient in alpha(7) nicotinic acetylcholine receptors did not respond to nicotine. Nicotine also stimulated the growth of the explant. Altogether, these studies suggest that nicotine stimulates lung branching morphogenesis through alpha(7) nicotinic acetylcholine receptors and may contribute to dysanaptic lung growth, which in turn may predispose the host to airway disease in the postnatal period.

  7. Discriminative and reinforcing stimulus effects of nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys.

    PubMed

    Mello, Nancy K; Newman, Jennifer L

    2011-06-01

    Concurrent cigarette smoking and cocaine use is well documented. However, the behavioral pharmacology of cocaine and nicotine combinations is poorly understood, and there is a need for animal models to examine this form of polydrug abuse. The purpose of this study was twofold: first to assess the effects of nicotine on the discriminative stimulus effects of cocaine, and second, to study self-administration of nicotine/cocaine combinations in a novel polydrug abuse model. In drug discrimination experiments, nicotine increased the discriminative stimulus effects of low cocaine doses in two of three monkeys, but nicotine did not substitute for cocaine in any monkey. Self-administration of cocaine and nicotine alone, and cocaine + nicotine combinations was studied under a second-order fixed ratio 2, variable ratio 16 (FR2[VR16:S]) schedule of reinforcement. Cocaine and nicotine alone were self-administered in a dose-dependent manner. The combination of marginally reinforcing doses of cocaine and nicotine increased drug self-administration behavior above levels observed with the same dose of either cocaine or nicotine alone. These findings indicate that nicotine may increase cocaine's discriminative stimulus and reinforcing effects in rhesus monkeys, and illustrate the feasibility of combining cocaine and nicotine in a preclinical model of polydrug abuse. Further studies of the behavioral effects of nicotine + cocaine combinations will contribute to our understanding the pharmacology of dual nicotine and cocaine dependence, and will be useful for evaluation of new treatment medications. PMID:21480727

  8. [Recent progress in vaccines against nicotine addiction].

    PubMed

    Wang, Gui-Bin; Zhu, Chuan-Jiang

    2013-08-01

    Tobacco smoking is a global healthcare problem that poses a substantial and costly health burden. Nicotine is the major constituent responsible for the addiction to tobacco. Current strategies helping tobacco smokers have limited utility in increasing rates of smoking cessation, consequently indicating the need for alternative therapies. A novel therapeutic method is vaccination against nicotine. Nicotine vaccine can generate specific antibodies that can sequester nicotine from cigarette smoke in the blood, and prevent its access to the brain and minimize positive reinforcing effects, which may help smokers to stop smoking. The vaccine will have great potential for the treatment of nicotine addiction and for relapse prevention. Here we will review the current status of vaccines against nicotine addiction and discuss the problems associated with the development of nicotine vaccines.

  9. Effect of gaseous ammonia on nicotine sorption

    SciTech Connect

    Webb, A.M.; Singer, B.C.; Nazaroff, W.W.

    2002-06-01

    Nicotine is a major constituent of environmental tobacco smoke. Sorptive interactions of nicotine with indoor surfaces can substantially alter indoor concentrations. The phenomenon is poorly understood, including whether sorption is fully reversible or partially irreversible. They hypothesize that acid-base chemistry on indoor surfaces might contribute to the apparent irreversibility of nicotine sorption under some circumstances. Specifically, they suggest that nicotine may become protonated on surfaces, markedly reducing its vapor pressure. If so, subsequent exposure of the surface to gaseous ammonia, a common base, could raise the surface pH, causing deprotonation and desorption of nicotine from surfaces. A series of experiments was conducted to explore the effect of ammonia on nicotine sorption to and reemission from surfaces. The results indicate that, under some conditions, exposure to gaseous ammonia can substantially increase the rate of desorption of previously sorbed nicotine from common indoor surface materials.

  10. Genetics of Nicotine Dependence and Pharmacotherapy

    PubMed Central

    Lessov-Schlaggar, Christina N.; Pergadia, Michele L.; Khroyan, Taline V.; Swan, Gary E.

    2008-01-01

    Nicotine dependence is substantially heritable. Several regions across the genome have been implicated in containing genes that confer liability to nicotine dependence and variation in individual genes has been associated with nicotine dependence. Smoking cessation measures are also heritable, and measured genetic variation is associated with nicotine dependence treatment efficacy. Despite significant strides in the understanding of the relative contribution of genetic and environmental factors to nicotine dependence and treatment, emergent challenges necessitate interdisciplinary coordinated effort for effective problem solving. These challenges include refinement of the nicotine dependence phenotype, better understanding of the dynamic interplay between genes and environment in nicotine dependence etiology, application and development of molecular and statistical methodology that can adequately address vast amounts of data, and continuous translational cross-talk. PMID:17888884

  11. Vaccination against nicotine alters the distribution of nicotine delivered via cigarette smoke inhalation to rats

    PubMed Central

    Pravetoni, M; Keyler, DE; Raleigh, MD; Harris, AC; LeSage, MG; Mattson, CK; Pettersson, S; Pentel, PR

    2011-01-01

    Preclinical models of nicotine vaccine pharmacology have relied on i.v. or s.c. administration of nicotine. Models using cigarette smoke inhalation might more accurately simulate nicotine exposure in smokers. Nicotine vaccine effects were examined in rats using two cigarette smoke exposure models: a 10 minute nose-only exposure (NSE) producing serum nicotine levels equivalent to the nicotine boost from 1 cigarette in a smoker, and a two hour whole-body exposure (WBE) producing serum nicotine levels similar to those associated with regular midday smoking. Vaccination prior to 10 min smoke NSE reduced nicotine distribution to brain by 90%, comparable to its effect on nicotine administered i.v. Vaccination prior to 2 hr smoke WBE reduced nicotine distribution to brain by 35%. The nicotine concentration in broncheoalveolar lavage (BAL) fluid obtained after 2 hr WBE was increased by 230% in vaccinated rats but was also increased in rats passively immunized with a nicotine-specific monoclonal antibody, and so was likely due to transfer of antibody from serum rather than local production at the pulmonary mucosa. Nicotine-specific IgA was not detectable in BAL fluid, but titers in serum were appreciable at 21–25% of the IgG titer and could contribute to vaccine efficacy. Both vaccination and passive immunization are effective in reducing nicotine distribution to brain in rats when nicotine is delivered via inhaled cigarette smoke. These data validate results previously obtained in rodents for nicotine vaccines using i.v. or s.c. nicotine dosing and provide a quantitative method for studying aspects of nicotine exposure which are unique to cigarette smoke inhalation. PMID:21333633

  12. Racial differences in the relationship between rate of nicotine metabolism and nicotine intake from cigarette smoking.

    PubMed

    Ross, Kathryn C; Gubner, Noah R; Tyndale, Rachel F; Hawk, Larry W; Lerman, Caryn; George, Tony P; Cinciripini, Paul; Schnoll, Robert A; Benowitz, Neal L

    2016-09-01

    Rate of nicotine metabolism has been identified as an important factor influencing nicotine intake and can be estimated using the nicotine metabolite ratio (NMR), a validated biomarker of CYP2A6 enzyme activity. Individuals who metabolize nicotine faster (higher NMR) may alter their smoking behavior to titrate their nicotine intake in order to maintain similar levels of nicotine in the body compared to slower nicotine metabolizers. There are known racial differences in the rate of nicotine metabolism with African Americans on average having a slower rate of nicotine metabolism compared to Whites. The goal of this study was to determine if there are racial differences in the relationship between rate of nicotine metabolism and measures of nicotine intake assessed using multiple biomarkers of nicotine and tobacco smoke exposure. Using secondary analyses of the screening data collected in a recently completed clinical trial, treatment-seeking African American and White daily smokers (10 or more cigarettes per day) were grouped into NMR quartiles so that the races could be compared at the same NMR, even though the distribution of NMR within race differed. The results indicated that rate of nicotine metabolism was a more important factor influencing nicotine intake in White smokers. Specifically, Whites were more likely to titrate their nicotine intake based on the rate at which they metabolize nicotine. However, this relationship was not found in African Americans. Overall there was a greater step-down, linear type relationship between NMR groups and cotinine or cotinine/cigarette in African Americans, which is consistent with the idea that differences in blood cotinine levels between the African American NMR groups were primarily due to differences in CYP2A6 enzyme activity without titration of nicotine intake among faster nicotine metabolizers. PMID:27180107

  13. Drug-dependent behaviors and nicotinic acetylcholine receptor expressions in Caenorhabditis elegans following chronic nicotine exposure.

    PubMed

    Polli, Joseph R; Dobbins, Dorothy L; Kobet, Robert A; Farwell, Mary A; Zhang, Baohong; Lee, Myon-Hee; Pan, Xiaoping

    2015-03-01

    Nicotine, the major psychoactive compound in tobacco, targets nicotinic acetylcholine receptors (nAChRs) and results in drug dependence. The nematode Caenorhabditis elegans' (C. elegans) genome encodes conserved and extensive nicotinic receptor subunits, representing a useful system to investigate nicotine-induced nAChR expressions in the context of drug dependence. However, the in vivo expression pattern of nAChR genes under chronic nicotine exposure has not been fully investigated. To define the role of nAChR genes involved in nicotine-induced locomotion changes and the development of tolerance to these effects, we characterized the locomotion behavior combining the use of two systems: the Worm Tracker hardware and the WormLab software. Our results indicate that the combined system is an advantageous alternative to define drug-dependent locomotion behavior in C. elegans. Chronic (24-h dosing) nicotine exposure at 6.17 and 61.7μM induced nicotine-dependent behaviors, including drug stimulation, tolerance/adaption, and withdrawal responses. Specifically, the movement speed of naïve worms on nicotine-containing environments was significantly higher than on nicotine-free environments, suggesting locomotion stimulation by nicotine. In contrast, the 24-h 6.17μM nicotine-treated worms exhibited significantly higher speeds on nicotine-free plates than on nicotine-containing plates. Furthermore significantly increased locomotion behavior during nicotine cessation was observed in worms treated with a higher nicotine concentration of 61.7μM. The relatively low locomotion speed of nicotine-treated worms on nicotine-containing environments also indicates adaption/tolerance of worms to nicotine following chronic nicotine exposure. In addition, this study provides useful information regarding the comprehensive in vivo expression profile of the 28 "core" nAChRs following different dosages of chronic nicotine treatments. Eleven genes (lev-1, acr-6, acr-7, acr-11, lev-8, acr

  14. Nicotine and the Developing Human

    PubMed Central

    England, Lucinda J.; Bunnell, Rebecca E.; Pechacek, Terry F.; Tong, Van T.; McAfee, Tim A.

    2015-01-01

    The elimination of cigarettes and other combusted tobacco products in the U.S. would prevent tens of millions of tobacco-related deaths. It has been suggested that the introduction of less harmful nicotine delivery devices, such as electronic cigarettes or other electronic nicotine delivery systems, will accelerate progress toward ending combustible cigarette use. However, careful consideration of the potential adverse health effects from nicotine itself is often absent from public health debates. Human and animal data support that nicotine exposure during periods of developmental vulnerability (fetal through adolescent stages) has multiple adverse health consequences, including impaired fetal brain and lung development, and altered development of cerebral cortex and hippocampus in adolescents. Measures to protect the health of pregnant women and children are needed and could include (1) strong prohibitions on marketing that increase youth uptake; (2) youth access laws similar to those in effect for other tobacco products; (3) appropriate health warnings for vulnerable populations; (4) packaging to prevent accidental poisonings; (5) protection of non-users from exposure to secondhand electronic cigarette aerosol; (6) pricing that helps minimize youth initiation and use; (7) regulations to reduce product addiction potential and appeal for youth; and (8) the age of legal sale. PMID:25794473

  15. Evaluation of an initiation protocol of 4 mg of warfarin for atrial fibrillation in the outpatient setting

    PubMed Central

    Sridhar, Vikas Srinivasan; Leung, Philemon; Seymour, Nicole; Nagge, Jeff

    2014-01-01

    Abstract Objective To describe the efficacy and safety of an initiation algorithm for 4 mg of warfarin in ambulatory patients with atrial fibrillation. Design Prospectively planned retrospective chart review. Setting Centre for Family Medicine Family Health Team in Kitchener, Ont. Participants Ambulatory patients requiring anticoagulation for atrial fibrillation. Interventions Patients were prescribed 4 mg of warfarin to be taken once daily for 3 days. An international normalized ratio (INR) measured on the morning of the fourth day was used to predict the maintenance dose of warfarin. Subsequent INR measurements were obtained biweekly until patients reached their actual maintenance dose. Main outcome measures Number of INR values greater than or equal to 4.0 before the warfarin maintenance dose was achieved. Secondary outcome measures included thromboembolic and bleeding events, number of days required to reach therapeutic INR, and correlation between predicted and actual warfarin maintenance dose. Results Twenty-five patients were included in the study. The average age was 76.0 years (range 56.0 to 89.0), and 17 patients were women. The average CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, and stroke or transient ischemic attack) score was 2.0. Only 1 patient had an INR greater than 4.0 during the study period. The mean time to achieve a therapeutic INR was 11.0 days. The day 4 INR was moderately predictive of the maintenance dose (r2 = 0.47). There were no adverse events that required medical attention during the study period. Conclusion In this pilot study, an initiation algorithm for 4 mg of warfarin was safe and achieved a therapeutic INR within a reasonable time frame in outpatients with atrial fibrillation. PMID:25551135

  16. Effects of alpha-7 nicotinic acetylcholine receptor positive allosteric modulator on lipopolysaccharide-induced neuroinflammatory pain in mice.

    PubMed

    Abbas, Muzaffar; Rahman, Shafiqur

    2016-07-15

    Evidence indicates that microglial activation contributes to the pathophysiology and maintenance of neuroinflammatory pain involving central nervous system alpha-7 nicotinic acetylcholine receptors. The objective of the present study was to determine the effects of 3a,4,5,9b-Tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS), an alpha-7 nicotinic acetylcholine receptor positive allosteric modulator (PAM), on tactile allodynia and thermal hyperalgesia following lipopolysaccharide (LPS)-induced microglial activation in hippocampus, a neuroinflammatory pain model in mice. In addition, we examined the effects of TQS on microglial activation marker, an ionized calcium-binding adapter molecule 1 (Iba-1), in the hippocampus may be associated with neuroinflammatory pain. Pretreatment of TQS (4mg/kg) significantly reduced LPS (1mg/kg)-induced tactile allodynia and thermal hyperalgesia. Moreover, pretreatment of methyllycaconitine (3mg/kg) significantly reversed TQS-induced antiallodynic and antihyperalgesic responses indicating the involvement of alpha-7 nicotinic acetylcholine receptor. Pretreatment of TQS significantly decreased LPS-induced increased in hippocampal Iba-1 expression. Overall, these results suggest that TQS reduces LPS-induced neuroinflammatory pain like symptoms via modulating microglial activation likely in the hippocampus and/or other brain region by targeting alpha-7 nicotinic acetylcholine receptor. Therefore, alpha-7 nicotinic acetylcholine receptor PAM such as TQS could be a potential drug candidate for the treatment of neuroinflammatory pain.

  17. Lidocaine 8 mg sore throat lozenges in the treatment of acute pharyngitis. A new therapeutic option investigated in comparison to placebo treatment.

    PubMed

    Wonnemann, Meinolf; Helm, Ilka; Stauss-Grabo, Manuela; Röttger-Luer, Patricia; Tran, Cam-Tuan; Canenbley, Rainer; Donath, Frank; Nowak, Horst; Schug, Barbara S; Blume, Henning H

    2007-01-01

    An acute pharyngitis is characterised by mild to severe sore throat mostly accompanied by inflammation, throat pain, pain on swallowing, and burning. This randomised, double-blind, placebo-controlled phase III study was conducted for comparison of the efficacy and safety of a newly developed lidocaine (2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide, CAS 137-58-6) 8 mg lozenge formulation (Trachisan Halsschmerztabletten) for the treatment of acute sore throat not necessarily to be treated with antibiotics. 240 patients of both genders were enrolled. The study was performed in a single centre setting and consisted of two parts. A 2-h stationary phase (single dose treatment) was directly followed by a 46-h ambulatory phase, where patients were allowed to take up to a maximum of 11 further lozenges (multiple dose treatment). Pain intensity was assessed via Visual Analogue Scale during the course of the study. Moreover, the global efficacy and tolerability of the treatments were assessed. Lidocaine 8 mg sore throat lozenges were found to be superior to placebo for all efficacy parameters investigated. For the primary efficacy parameter, area under the curve of pain intensity from baseline over 2 h (AUC(0-2h)), i.e. after single-dose treatment, a significant treatment difference with a p-value of p < 0.001 in favour of the verum treatment could be demonstrated. Significant superiority could also be demonstrated for the descriptive AUC(0-48h) values, reflecting the treatment effect during the ambulatory multiple dose phase. Pain relief, minimum pain intensity, meaningful pain relief and the time of onset of meaningful pain relief as well as the assessments of global efficacy underlined the superiority of the treatment with lidocaine 8 mg sore throat lozenges. Global tolerability of the verum treatment was rated as "good" or "very good" in the majority of cases, the number of study drug related adverse events was low and evenly distributed to both treatment groups

  18. Lidocaine 8 mg sore throat lozenges in the treatment of acute pharyngitis. A new therapeutic option investigated in comparison to placebo treatment.

    PubMed

    Wonnemann, Meinolf; Helm, Ilka; Stauss-Grabo, Manuela; Röttger-Luer, Patricia; Tran, Cam-Tuan; Canenbley, Rainer; Donath, Frank; Nowak, Horst; Schug, Barbara S; Blume, Henning H

    2007-01-01

    An acute pharyngitis is characterised by mild to severe sore throat mostly accompanied by inflammation, throat pain, pain on swallowing, and burning. This randomised, double-blind, placebo-controlled phase III study was conducted for comparison of the efficacy and safety of a newly developed lidocaine (2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide, CAS 137-58-6) 8 mg lozenge formulation (Trachisan Halsschmerztabletten) for the treatment of acute sore throat not necessarily to be treated with antibiotics. 240 patients of both genders were enrolled. The study was performed in a single centre setting and consisted of two parts. A 2-h stationary phase (single dose treatment) was directly followed by a 46-h ambulatory phase, where patients were allowed to take up to a maximum of 11 further lozenges (multiple dose treatment). Pain intensity was assessed via Visual Analogue Scale during the course of the study. Moreover, the global efficacy and tolerability of the treatments were assessed. Lidocaine 8 mg sore throat lozenges were found to be superior to placebo for all efficacy parameters investigated. For the primary efficacy parameter, area under the curve of pain intensity from baseline over 2 h (AUC(0-2h)), i.e. after single-dose treatment, a significant treatment difference with a p-value of p < 0.001 in favour of the verum treatment could be demonstrated. Significant superiority could also be demonstrated for the descriptive AUC(0-48h) values, reflecting the treatment effect during the ambulatory multiple dose phase. Pain relief, minimum pain intensity, meaningful pain relief and the time of onset of meaningful pain relief as well as the assessments of global efficacy underlined the superiority of the treatment with lidocaine 8 mg sore throat lozenges. Global tolerability of the verum treatment was rated as "good" or "very good" in the majority of cases, the number of study drug related adverse events was low and evenly distributed to both treatment groups

  19. The Role of Nicotine in Schizophrenia.

    PubMed

    Featherstone, Robert E; Siegel, Steven J

    2015-01-01

    Schizophrenia is associated with by severe disruptions in thought, cognition, emotion, and behavior. Patients show a marked increase in rates of smoking and nicotine dependence relative to nonaffected individuals, a finding commonly ascribed to the potential ameliorative effects of nicotine on symptom severity and cognitive impairment. Indeed, many studies have demonstrated improvement in patients following the administration of nicotine. Such findings have led to an increased emphasis on the development of therapeutic agents to target the nicotinic system as well as increasing the impetus to understand the genetic basis for nicotinic dysfunction in schizophrenia. The goal of this review article is to provide a critical summary of evidence for the role of the nicotinic system in schizophrenia. The first part will review the role of nicotine in normalization of primary dysfunctions and endophenotypical changes found in schizophrenia. The second part will provide a summary of genetic evidence linking polymorphisms in nicotinic receptor genes to smoking and schizophrenia. The third part will summarize attempts to treat schizophrenia using agents specifically targeting nicotinic and nicotinic receptor subtypes. Although currently available antipsychotic treatments are generally able to manage some aspects of schizophrenia (e.g., positive symptoms) they fail to address several other critically effected aspects of the disease. As such, the search for novel mechanisms to treat this disease is necessary. PMID:26472525

  20. Psychophysiological interactions between caffeine and nicotine.

    PubMed

    Rose, J E; Behm, F M

    1991-02-01

    The interactive effects of caffeine and nicotine were studied in twelve subjects. Mood and physiologic responses to the pharmacologic components nicotine and caffeine were measured, while controlling for the sensory/behavioral aspects of smoking and coffee drinking. Two experimental sessions presented a caffeine x nicotine design, with caffeinated or decaffeinated coffee followed at thirty-minute intervals by controlled inhalations of nicotine and nonnicotine smoke. Results showed that there was a significant interactive effect of caffeine and nicotine on subjective arousal such that nicotine decreased arousal only in the presence of caffeine. These findings extend previous work showing interactive effects of caffeine and self-titrated doses of cigarette smoke in affecting subjective arousal. The effects of nicotine on subjective arousal may, therefore, depend not only on nicotine dose, but also on the presence of caffeine. Heart rate was increased by nicotine and both systolic and diastolic blood pressures were elevated by caffeine. Caffeine also potentiated the increase in diastolic blood pressure resulting from smoke inhalations, but this occurred irrespective of nicotine dose. PMID:2057503

  1. The Role of Nicotine in Schizophrenia.

    PubMed

    Featherstone, Robert E; Siegel, Steven J

    2015-01-01

    Schizophrenia is associated with by severe disruptions in thought, cognition, emotion, and behavior. Patients show a marked increase in rates of smoking and nicotine dependence relative to nonaffected individuals, a finding commonly ascribed to the potential ameliorative effects of nicotine on symptom severity and cognitive impairment. Indeed, many studies have demonstrated improvement in patients following the administration of nicotine. Such findings have led to an increased emphasis on the development of therapeutic agents to target the nicotinic system as well as increasing the impetus to understand the genetic basis for nicotinic dysfunction in schizophrenia. The goal of this review article is to provide a critical summary of evidence for the role of the nicotinic system in schizophrenia. The first part will review the role of nicotine in normalization of primary dysfunctions and endophenotypical changes found in schizophrenia. The second part will provide a summary of genetic evidence linking polymorphisms in nicotinic receptor genes to smoking and schizophrenia. The third part will summarize attempts to treat schizophrenia using agents specifically targeting nicotinic and nicotinic receptor subtypes. Although currently available antipsychotic treatments are generally able to manage some aspects of schizophrenia (e.g., positive symptoms) they fail to address several other critically effected aspects of the disease. As such, the search for novel mechanisms to treat this disease is necessary.

  2. Subjective effects of transdermal nicotine among nonsmokers.

    PubMed

    Ashare, Rebecca L; Baschnagel, Joseph S; Hawk, Larry W

    2010-04-01

    The subjective experience of nicotine, which may be influenced by personality traits as well as environmental factors, may be important for understanding the factors associated with the initiation and maintenance of nicotine dependence. The present study examined the effects of 7 mg transdermal nicotine among a relatively large sample (n = 91; 44 women) of college-aged nonsmokers. Using a placebo controlled, double-blind, within-subjects design, nicotine's effects were examined at rest and again after participants completed a sustained attention task. Sex and personality factors (Behavioral Inhibition and Behavioral Approach; BIS/BAS Scales; Carver & White, 1994) were examined as potential moderators. Overall, the effects of nicotine were generally modest and unpleasant. In the context of the cognitive task, nicotine increased nausea and negative affect but reduced fatigue, relative to placebo. In contrast, effects of nicotine during the initial 4 hr of patch administration, in which participants were in their natural environments, were moderated by individual differences in behavioral approach. Neither behavioral inhibition nor gender reliably moderated any subjective effects of nicotine. The present work suggests transdermal nicotine exerts only modest, mostly negative effects among nonsmokers. Future work should examine both contextual and personality moderators in large samples of participants who are exposed to nicotine through multiple routes of administration. PMID:20384428

  3. An open-label, single-center, phase IV clinical study of the effectiveness of zinc gluconate glycine lozenges (Cold-Eeze) in reducing the duration and symptoms of the common cold in school-aged subjects.

    PubMed

    McElroy, Betty Howell; Miller, Shelley Porter

    2003-01-01

    Each year, more than 62 million cases of the common cold in the United States require medical attention and more than 80% affect school-aged children. The objective of this prospective, intent-to-treat, phase IV study was to determine the therapeutic and prophylactic effectiveness of zinc gluconate glycine lozenges (Cold-Eeze) for the common cold. Zinc lozenges were administered once daily during the cold season for prophylaxis. For therapeutic purposes, lozenges were given 4 times per day. The primary objective of the study was the treatment effect on cold duration, and the secondary objective was the effect on the number of common colds. A putative control from our previous study was used for comparison. A total of 178 children, ages 12 to 18 years, was enrolled, of which 134 met criteria for efficacy analysis. The average cold duration with therapeutic lozenge use was 6.9 +/- 3.1 days, significantly shorter than the 9.0 +/- 3.5 days found in the control group (P < 0.001). The mean number of colds was 1.28 +/- 1.03 with zinc lozenge prophylaxis versus 1.7 +/- 1.91 without prophylaxis (P < 0.05), a 25% reduction. With prophylaxis, 25% of the subjects did not experience a cold and two-thirds never had a cold or only had 1 cold. There was no antibiotic use for any cold, and there were no adverse events reported. Results of this study are consistent with those from our previous retrospective study showing significantly shorter cold duration and fewer colds with the use of zinc gluconate glycine lozenges. The zinc gluconate glycine lozenges are well tolerated and are an easy-to-administer therapy that has the potential to substantially reduce cold-related school absences and antibiotic use and misuse as well as to provide a cost saving. PMID:12975716

  4. Tobacco smoking, nicotine, and nicotine and non-nicotine replacement therapies.

    PubMed

    Frishman, W H; Ky, T; Ismail, A

    2001-01-01

    Tobacco smoking is associated with an increased risk for the development of coronary and pulmonary vascular diseases and smoking cessation will greatly reduce this risk. Nicotine replacement and nonnicotine modalities have been used alone and in combination to help in smoking cessation. These treatment modalities appear to be safe in patients with known stable coronary artery disease. PMID:11975821

  5. Prenatal exposure of rats to nicotine causes persistent alterations of nicotinic cholinergic receptors

    PubMed Central

    Gold, Allison B.; Keller, Ashleigh B.; Perry, David C.

    2010-01-01

    We examined for immediate and persistent changes in nAChRs in cerebral cortex, thalamus and striatum of male rats caused by prenatal exposure to nicotine from gestational day 3 to postnatal day 10 (PN10), and how such exposure affected the responses of adolescents to subsequent nicotine challenge. Receptor numbers were assessed by [3H]epibatidine binding and receptor function was measured by acetylcholine-stimulated 86Rb efflux (cerebral cortex and thalamus) and nicotine-stimulated dopamine release (striatum). Immediate effects of prenatal nicotine, assessed in PN10 animals, were not detected for any parameter. A subsequent 14 day nicotine exposure in adolescence revealed persistent changes caused by prenatal nicotine exposure. Nicotine exposure in adolescents caused up-regulation of binding in all three regions; however, this up-regulation was lost in thalamus from animals prenatally exposed to nicotine. Nicotine exposure in adolescents caused decreased nicotine-stimulated dopamine release in striatum; this effect was also lost in animals prenatally exposed to nicotine. Comparison of parameters in PN10 and PN42 rats revealed developmental changes in the CNS cholinergic system. In thalamus, binding increased with age, as did the proportion of 86Rb efflux with high sensitivity to acetylcholine. In cortex, binding also increased with age, but there was no change in total 86Rb efflux, and the proportion of high to low sensitivity efflux declined with age. Nicotine-stimulated striatal dopamine release (both total and α-conotoxin MII-resistant release) increased with age in naïve animals, but not in those prenatally exposed to nicotine. These findings demonstrate that prenatal exposure to nicotine causes alterations in the regulation of nAChRs by nicotine that persist into adolescence. These changes may play a role in the increased risk for nicotine addiction observed in adolescent offspring of smoking mothers. PMID:19028470

  6. Effect of nicotine and cocaine on neurofilaments and receptors in whole brain tissue and synaptoneurosome preparations.

    PubMed

    Kovacs, K; Lajtha, A; Sershen, H

    2010-04-29

    The present study examined the effect of repeated nicotine and cocaine administration on the expression of neurofilament proteins (NF-L, -M, and -H), actin, and on alpha-7 nicotinic, dopamine D1 and NMDA NR1 receptors in brain. Whole tissue homogenate and synaptoneurosomal preparations from hippocampus, striatum and cortex were assayed. C57BL/6By mice were treated for 2 weeks with a daily injection of nicotine (0.4 mg/kg) or cocaine (25mg/kg). The mice were killed 60 min after the last injection and tissue prepared for Western blot analysis of expression of NFs and receptor expression. Actin protein was affected by cocaine and nicotine treatment, decreasing in homogenate fraction (striatum and cortex) and showing an increase in the synaptoneurosome preparation (hippocampus and cortex). NF expression was affected; with regional and response differences dependent on tissue preparation. NF-M increased in all three brain regions; NF-L increased in the cortex and NF-H increased in the striatum in the synaptoneurosomal preparations. Change in nicotinic and dopamine receptor expression was dependent on region and tissue preparation. NMDA NR1 expression increased in the three brain regions in the synaptoneurosomal preparation. The results suggest that specific brain protein levels are affected by repeated drug administration. Drug effects on cytoskeletal elements are selective, regionally heterogeneous, and change with time after drug administration. Changes in cytoskeletal proteins maybe part of the mechanism in drug-induced neurotransmitter changes. We have found previously that drug-induced changes in neurotransmitters are regionally heterogeneous and are drug specific. We now found similar regional heterogeneity and drug specificity in drug-induced changes in cytoskeletal and receptor proteins.

  7. Nicotinic Cholinergic Synaptic Mechanisms in the Ventral Tegmental Area Contribute to Nicotine Addiction

    ERIC Educational Resources Information Center

    Pidoplichko, Volodymyr I.; Noguchi, Jun; Areola, Oluwasanmi O.; Liang, Yong; Peterson, Jayms; Zhang, Tianxiang; Dani, John A.

    2004-01-01

    Tobacco use is a major health problem that is estimated to cause 4 million deaths a year worldwide. Nicotine is the main addictive component of tobacco. It acts as an agonist to activate and desensitize nicotinic acetylcholine receptors (nAChRs). A component of nicotine's addictive power is attributable to actions on the mesolimbic dopaminergic…

  8. Preparation and clinical evaluation of a novel lozenge containing polaprezinc, a zinc-L-carnosine, for prevention of oral mucositis in patients with hematological cancer who received high-dose chemotherapy.

    PubMed

    Hayashi, Hiroko; Kobayashi, Ryo; Suzuki, Akio; Yamada, Yuto; Ishida, Masayuki; Shakui, Toshinobu; Kitagawa, Junichi; Hayashi, Hideki; Sugiyama, Tadashi; Takeuchi, Hirofumi; Tsurumi, Hisashi; Itoh, Yoshinori

    2016-08-01

    We previously reported that oral ingestion of polaprezinc, a zinc-L-carnosine, suspended in sodium alginate solution prevents oral mucositis in patients receiving radiotherapy or high-dose chemotherapy. In the present study, we developed a novel preparation of polaprezinc and evaluated clinical effect of the lozenge preparation in patients receiving high-dose chemotherapy for hematopoietic stem cell transplantation. The preparation contained 18.75 mg polaprezinc in a tablet and showed an excellent uniformity and stability up to 24 weeks after storage under room temperature. The incidence rate of grade ≥ 2 oral mucositis was 74 % in patients without premedication, whereas the rate was remarkably reduced in patients receiving the suspension (23 %) or lozenge (13 %) of polaprezinc (P < 0.01). The use of non-opioid analgesic drugs such as anti-inflammatory agents and local anesthetics for oral pain was also greatly reduced by polaprezinc suspension or its lozenge (16 % for suspension and 13 % for lozenge compared with 89 % with no premedication, P < 0.01). These findings suggest that polaprezinc lozenge is simple to apply and highly effective for prevention of oral mucositis associated with high-dose chemotherapy for hematopoietic stem cell transplantation. PMID:27418192

  9. Nicotinic modulation of cortical circuits

    PubMed Central

    Arroyo, Sergio; Bennett, Corbett; Hestrin, Shaul

    2014-01-01

    The ascending cholinergic neuromodulatory system sends projections throughout cortex and has been shown to play an important role in a number of cognitive functions including arousal, working memory, and attention. However, despite a wealth of behavioral and anatomical data, understanding how cholinergic synapses modulate cortical function has been limited by the inability to selectively activate cholinergic axons. Now, with the development of optogenetic tools and cell-type specific Cre-driver mouse lines, it has become possible to stimulate cholinergic axons from the basal forebrain (BF) and probe cholinergic synapses in the cortex for the first time. Here we review recent work studying the cell-type specificity of nicotinic signaling in the cortex, synaptic mechanisms mediating cholinergic transmission, and the potential functional role of nicotinic modulation. PMID:24734005

  10. New mechanisms and perspectives in nicotine withdrawal

    PubMed Central

    Jackson, K.J.; Muldoon, P.P.; De Biasi, M.; Damaj, M.I.

    2014-01-01

    Diseases associated with tobacco use constitute a major health problem worldwide. Upon cessation of tobacco use, an unpleasant withdrawal syndrome occurs in dependent individuals. Avoidance of the negative state produced by nicotine withdrawal represents a motivational component that promotes continued tobacco use and relapse after smoking cessation. With the modest success rate of currently available smoking cessation therapies, understanding mechanisms involved in the nicotine withdrawal syndrome are crucial for developing successful treatments. Animal models provide a useful tool for examining neuroadaptative mechanisms and factors influencing nicotine withdrawal, including sex, age, and genetic factors. Such research has also identified an important role for nicotinic receptor subtypes in different aspects of the nicotine withdrawal syndrome (e.g., physical vs. affective signs). In addition to nicotinic receptors, the opioid and endocannabinoid systems, various signal transduction pathways, neurotransmitters, and neuropeptides have been implicated in the nicotine withdrawal syndrome. Animal studies have informed human studies of genetic variants and potential targets for smoking cessation therapies. Overall, the available literature indicates that the nicotine withdrawal syndrome is complex, and involves a range of neurobiological mechanisms. As research in nicotine withdrawal progresses, new pharmacological options for smokers attempting to quit can be identified, and treatments with fewer side effects that are better tailored to the unique characteristics of patients may become available. PMID:25433149

  11. Cigarette smoking, nicotine dependence, and treatment.

    PubMed Central

    Sees, K L

    1990-01-01

    Since the 1988 Surgeon General's report on nicotine addiction, more attention is being given to nicotine dependence as a substantial contributing factor in cigarette smokers' inability to quit. Many new medications are being investigated for treating nicotine withdrawal and for assisting in long-term smoking abstinence. Medications alone probably will not be helpful; they should be used as adjuncts in comprehensive smoking abstinence programs that address not only the physical dependence on nicotine but also the psychological dependence on cigarette smoking. PMID:2190425

  12. Hydrogen occupancy in the RNi{sub 4}Mg (R=Y, La, Ce, and Nd) intermetallic compounds and hydrides

    SciTech Connect

    Hahn-Herrera, Otto; Orgaz, Emilio; Aburto, Andrea

    2009-10-15

    We have investigated the effect of hydrogen on the electronic strtucture of the RNi{sub 4}Mg (R=Y, La, Ce, Pr, and Nd) intermetallics. By means of a two-step approach, the projected plane-wave and linearized plane-waves methods, we studied the hydrogen-insertion energetics on the intermetallic matrix and the H-vacancy formation in the hydride compound. We found that particular interstitial sites in the intermetallics are suitable to allocate hydrogen and form a solid solution. The effect of these interstitials on the electronic structure is discussed. In the other hand, the hydrogen-occupied sites in the hydride are found to be energetically equivalent.

  13. Effects of nicotine, methamphetamine and cocaine on extracellular levels of acetylcholine in the interpeduncular nucleus of rats.

    PubMed

    Hussain, Rifat J; Taraschenko, Olga D; Glick, Stanley D

    2008-08-01

    There is increasing evidence that the cholinergic habenulo-interpeduncular pathway and the dopaminergic mesolimbic pathway may jointly mediate the reinforcing properties of addictive drugs. However, the effects of addictive drug on the functioning of the habenulo-interpeduncular pathway have not been well-characterized. Thus, several drugs of abuse (i.e., nicotine, cocaine, amphetamine) have been shown to alter the morphology of the habenulo-interpeduncular pathway, causing selective degeneration of the cholinergic neurons in this area. On the other hand, morphine was shown to alter the neurochemistry of the habenulo-interpeduncular pathway, inducing biphasic changes in acetylcholine release in the interpeduncular nucleus. In order to determine the effects of cocaine, amphetamine and nicotine on cholinergic neurotransmission in the habenulo-interpeduncular pathway, levels of acetylcholine were assessed during microdialysis in freely moving rats. Nicotine (0.1 and 0.4 mg/kg s.c.) produced a dose-dependent decrease in extracellular levels of acetylcholine, while methamphetamine (1 and 4 mg/kg i.p.) produced an increase in acetylcholine release in the interpeduncular nucleus. Cocaine (5 and 20 mg/kg i.p.) produced a biphasic effect on extracellular acetylcholine release, i.e., a low dose enhanced the release of acetylcholine and a high dose decreased its release. These results suggest that the habenulo-intepeduncular pathway may be a common target for drugs of abuse and, by modulating the mesolimbic pathway, may mediate unique aspects of the rewarding effects of different drugs.

  14. Developmental cholinotoxicants: nicotine and chlorpyrifos.

    PubMed

    Slotkin, T A

    1999-02-01

    The stimulation of cholinergic receptors in target cells during a critical developmental period provides signals that influence cell replication and differentiation. Accordingly, environmental agents that promote cholinergic activity evoke neurodevelopmental damage because of the inappropriate timing or intensity of stimulation. Nicotine evokes mitotic arrest in brain cells possessing high concentrations of nicotinic cholinergic receptors. In addition, the cholinergic overstimulation programs the expression of genes that evoke apoptosis and delayed cell loss. Effects of cholinesterase inhibitors exhibit many similarities to those of nicotine. Chlorpyrifos administered to developing rats in doses that do not evoke signs of overt toxicity decreased DNA synthesis and caused shortfalls in cell numbers in brain regions enriched in cholinergic innervation. In embryo cultures, chlorpyrifos also evoked apoptosis during neurulation. However, chlorpyrifos also evokes noncholinergic disruption of cell development by interfering with cell signaling via adenylyl cyclase, leading to widespread disruption that is not limited to cholinergic systems. We have tested this hypothesis in vitro with PC12 cells, which lack the enzymes necessary to produce chlorpyrifos oxon, the metabolite that inhibits cholinesterase. Chlorpyrifos inhibited DNA synthesis in undifferentiated PC12 cells, which have relatively few cholinergic receptors. Furthermore, chlorpyrifos was more effective than nicotine and its effects were not blocked by cholinergic antagonists. When cells were allowed to differentiate in the presence of chlorpyrifos, cell replication was inhibited even more profoundly and cell acquisition was arrested. At higher concentrations, chlorpyrifos also inhibited neuritic outgrowth. Thus, chlorpyrifos elicits damage by both noncholinergic and cholinergic mechanisms extending from early stages of neural cell replication through late stages of axonogenesis and terminal differentiation

  15. Developmental cholinotoxicants: nicotine and chlorpyrifos.

    PubMed Central

    Slotkin, T A

    1999-01-01

    The stimulation of cholinergic receptors in target cells during a critical developmental period provides signals that influence cell replication and differentiation. Accordingly, environmental agents that promote cholinergic activity evoke neurodevelopmental damage because of the inappropriate timing or intensity of stimulation. Nicotine evokes mitotic arrest in brain cells possessing high concentrations of nicotinic cholinergic receptors. In addition, the cholinergic overstimulation programs the expression of genes that evoke apoptosis and delayed cell loss. Effects of cholinesterase inhibitors exhibit many similarities to those of nicotine. Chlorpyrifos administered to developing rats in doses that do not evoke signs of overt toxicity decreased DNA synthesis and caused shortfalls in cell numbers in brain regions enriched in cholinergic innervation. In embryo cultures, chlorpyrifos also evoked apoptosis during neurulation. However, chlorpyrifos also evokes noncholinergic disruption of cell development by interfering with cell signaling via adenylyl cyclase, leading to widespread disruption that is not limited to cholinergic systems. We have tested this hypothesis in vitro with PC12 cells, which lack the enzymes necessary to produce chlorpyrifos oxon, the metabolite that inhibits cholinesterase. Chlorpyrifos inhibited DNA synthesis in undifferentiated PC12 cells, which have relatively few cholinergic receptors. Furthermore, chlorpyrifos was more effective than nicotine and its effects were not blocked by cholinergic antagonists. When cells were allowed to differentiate in the presence of chlorpyrifos, cell replication was inhibited even more profoundly and cell acquisition was arrested. At higher concentrations, chlorpyrifos also inhibited neuritic outgrowth. Thus, chlorpyrifos elicits damage by both noncholinergic and cholinergic mechanisms extending from early stages of neural cell replication through late stages of axonogenesis and terminal differentiation

  16. Predictors of the nicotine reinforcement threshold, compensation, and elasticity of demand in a rodent model of nicotine reduction policy*

    PubMed Central

    Grebenstein, Patricia E.; Burroughs, Danielle; Roiko, Samuel A.; Pentel, Paul R.; LeSage, Mark G.

    2015-01-01

    Background The FDA is considering reducing the nicotine content in tobacco products as a population-based strategy to reduce tobacco addiction. Research is needed to determine the threshold level of nicotine needed to maintain smoking and the extent of compensatory smoking that could occur during nicotine reduction. Sources of variability in these measures across sub-populations also need to be identified so that policies can take into account the risks and benefits of nicotine reduction in vulnerable populations. Methods The present study examined these issues in a rodent nicotine self- administration model of nicotine reduction policy to characterize individual differences in nicotine reinforcement thresholds, degree of compensation, and elasticity of demand during progressive reduction of the unit nicotine dose. The ability of individual differences in baseline nicotine intake and nicotine pharmacokinetics to predict responses to dose reduction was also examined. Results Considerable variability in the reinforcement threshold, compensation, and elasticity of demand was evident. High baseline nicotine intake was not correlated with the reinforcement threshold, but predicted less compensation and less elastic demand. Higher nicotine clearance predicted low reinforcement thresholds, greater compensation, and less elastic demand. Less elastic demand also predicted lower reinforcement thresholds. Conclusions These findings suggest that baseline nicotine intake, nicotine clearance, and the essential value of nicotine (i.e. elasticity of demand) moderate the effects of progressive nicotine reduction in rats and warrant further study in humans. They also suggest that smokers with fast nicotine metabolism may be more vulnerable to the risks of nicotine reduction. PMID:25891231

  17. Characterization of SPECTRUM Variable Nicotine Research Cigarettes

    PubMed Central

    Richter, Patricia; Steven, Pappas R.; Bravo, Roberto; Lisko, Joseph G.; Damian, Maria; Gonzalez-Jimenez, Nathalie; Gray, Naudia; Keong, Lisa M.; Kimbrell, Jacob B.; Kuklenyik, Peter; Lawler, Tameka S.; Lee, Grace E.; Mendez, Magaly; Perez, Jose; Smith, Shakia; Tran, Hang; Tyx, Robert; Watson, Clifford H.

    2016-01-01

    Objective To provide researchers an extensive characterization of the SPECTRUM variable nicotine research cigarettes. Methods Data on cigarette physical properties, nicotine content, harmful and potentially harmful constituents in the tobacco filler was compiled. Results Data on physical properties, concentrations of menthol, nicotine and minor alkaloids, tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, ammonia, and toxic metals in the filler tobacco for all available varieties of Spectrum research cigarettes are provided. The similarity in the chemistry and physical properties of SPECTRUM cigarettes to commercial cigarettes renders them acceptable for use in behavioral studies. Baseline information on harmful and potentially harmful constituents in research tobacco products, particularly constituent levels such as minor alkaloids that fall outside typical ranges reported for commercial, provide researchers with the opportunity to monitor smoking behavior and to identify biomarkers that will inform efforts to understand the role of nicotine in creating and sustaining addiction. Conclusions Well characterized research cigarettes suitable for human consumption are an important tool in clinical studies for investigating the physiological impacts of cigarettes delivering various levels of nicotine, the impact of reduced nicotine cigarettes on nicotine addiction, and the relationship between nicotine dose and smoking behavior. PMID:26779559

  18. Nicotinic alteration of decision-making.

    PubMed

    Naudé, Jérémie; Dongelmans, Malou; Faure, Philippe

    2015-09-01

    Addiction to nicotine is characterized by impulses, urges and lack of self-control towards cigarettes. A key element in the process of addiction is the development of habits oriented towards nicotine consumption that surpass flexible systems as a consequence of a gradual adaptation to chronic drug exposure. However, the long-term effects of nicotine on brain circuits also induce wide changes in decision-making processes, affecting behaviors unrelated to cigarettes. This review aims at providing an update on the implications of nicotine on general decision-making processes, with an emphasis on impulsivity and risk-taking. As impulsivity is a rather ambiguous behavioral trait, we build on economic and normative theories to better characterize these nicotine-induced alterations in decision-making. Nonetheless, experimental data are sparse and often contradictory. We will discuss how the latest findings on the neurobiological basis of choice behavior may help disentangling these issues. We focus on the role of nicotine acetylcholine receptors and their different subunits, and on the spatio-temporal dynamics (i.e. diversity of the neural circuits, short- and long-term effects) of both endogenous acetylcholine and nicotine action. Finally, we try to link these neurobiological results with neuro-computational models of attention, valuation and action, and of the role of acetylcholine in these decision processes. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID:25498234

  19. Nicotinic alteration of decision-making.

    PubMed

    Naudé, Jérémie; Dongelmans, Malou; Faure, Philippe

    2015-09-01

    Addiction to nicotine is characterized by impulses, urges and lack of self-control towards cigarettes. A key element in the process of addiction is the development of habits oriented towards nicotine consumption that surpass flexible systems as a consequence of a gradual adaptation to chronic drug exposure. However, the long-term effects of nicotine on brain circuits also induce wide changes in decision-making processes, affecting behaviors unrelated to cigarettes. This review aims at providing an update on the implications of nicotine on general decision-making processes, with an emphasis on impulsivity and risk-taking. As impulsivity is a rather ambiguous behavioral trait, we build on economic and normative theories to better characterize these nicotine-induced alterations in decision-making. Nonetheless, experimental data are sparse and often contradictory. We will discuss how the latest findings on the neurobiological basis of choice behavior may help disentangling these issues. We focus on the role of nicotine acetylcholine receptors and their different subunits, and on the spatio-temporal dynamics (i.e. diversity of the neural circuits, short- and long-term effects) of both endogenous acetylcholine and nicotine action. Finally, we try to link these neurobiological results with neuro-computational models of attention, valuation and action, and of the role of acetylcholine in these decision processes. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

  20. Cholinergic nicotinic receptors in the vestibular epithelia.

    PubMed

    Thornhill, R A

    1991-10-01

    Receptor binding studies specific for nicotinic cholinergic receptors have been carried out on isolated vestibular epithelia of the frogs Rana catesbiana and Rana temporaria. Evidence is presented for the presence of nicotinic-like cholinergic receptors specifically associated with the sensory areas. PMID:1797345

  1. Measurement of nicotine in household dust

    SciTech Connect

    Kim, Sungroul Aung, Ther; Berkeley, Emily; Diette, Gregory B.; Breysse, Patrick N.

    2008-11-15

    An analytical method of measuring nicotine in house dust was optimized and associations among three secondhand smoking exposure markers were evaluated, i.e., nicotine concentrations of both house dust and indoor air, and the self-reported number of cigarettes smoked daily in a household. We obtained seven house dust samples from self-reported nonsmoking homes and 30 samples from smoking homes along with the information on indoor air nicotine concentrations and the number of cigarettes smoked daily from an asthma cohort study conducted by the Johns Hopkins Center for Childhood Asthma in the Urban Environment. House dust nicotine was analyzed by isotope dilution gas chromatography-mass spectrometry (GC/MS). Using our optimized method, the median concentration of nicotine in the dust of self-reported nonsmoking homes was 11.7 ng/mg while that of smoking homes was 43.4 ng/mg. We found a substantially positive association (r=0.67, P<0.0001) between house dust nicotine concentrations and the numbers of cigarettes smoked daily. Optimized analytical methods showed a feasibility to detect nicotine in house dust. Our results indicated that the measurement of nicotine in house dust can be used potentially as a marker of longer term SHS exposure.

  2. Nicotine Replacement: Effects on Postcessation Weight Gain.

    ERIC Educational Resources Information Center

    Gross, Janet; And Others

    1989-01-01

    Examined nicotine replacement effects on postcessation weight gain in smoking cessation volunteers. Randomly assigned abstinent subjects to active nicotine or placebo gum conditions for 10 weeks. Analyses revealed strong evidence for gum effect on weight gain, with active gum users gaining mean total of 3.8 pounds compared with 7.8 pounds for…

  3. Cognitive Effects of Nicotine: Genetic Moderators

    PubMed Central

    Herman, Aryeh I.; Sofuoglu, Mehmet

    2010-01-01

    Cigarette smoking is the main preventable cause of death in developed countries and the development of more effective treatments is necessary. Cumulating evidence suggests that cognitive enhancement may contribute to the addictive actions of nicotine. Several studies have demonstrated that nicotine enhances cognitive performance in both smokers and non-smokers. Genetic studies support the role of both dopamine (DA) and nicotinic acetylcholine receptors (nAChRs) associated with nicotine-induced cognitive-enhancement. Based on knock-out mice studies, β2 nAChRs are thought to be essential in mediating the cognitive effects of nicotine. α7 nAChRs are associated with attentional and sensory filtering response, especially in schizophrenic individuals. Genetic variation in D2 type DA receptors and the catechol-O-methyltransferase (COMT) enzyme appears to moderate cognitive deficits induced by smoking abstinence. Serotonin transporter (5-HTT) gene variation also moderates nicotine- induced improvement in spatial working memory. Less is known about the contribution of genetic variation in dopamine transporter (DAT) and D4 type DA receptor genetic variation on the cognitive effects of nicotine. Future research will provide a clearer understanding of the mechanism underlying the cognitive-enhancing actions of nicotine. PMID:20456288

  4. General mechanisms of nicotine-induced fibrogenesis

    PubMed Central

    Jensen, Kendal; Nizamutdinov, Damir; Guerrier, Micheleine; Afroze, Syeda; Dostal, David; Glaser, Shannon

    2012-01-01

    Cigarette smoking contributes to the development of cancer, and pathogenesis of other diseases. Many chemicals have been identified in cigarettes that have potent biological properties. Nicotine is especially known for its role in addiction and plays a role in other physiological effects of smoking and tobacco use. Recent studies have provided compelling evidence that, in addition to promoting cancer, nicotine also plays a pathogenic role in systems, such as the lung, kidney, heart, and liver. In many organ systems, nicotine modulates fibrosis by altering the functions of fibroblasts. Understanding the processes modulated by nicotine holds therapeutic potential and may guide future clinical and research decisions. This review discusses the role of nicotine in the general fibrogenic process that governs fibrosis and fibrosis-related diseases, focusing on the cellular mechanisms that have implications in multiple organ systems. Potential research directions for the management of nicotine-induced fibrosis, and potential clinical considerations with regard to nicotine-replacement therapy (NRT) are presented.—Jensen, K., Nizamutdinov, D., Guerrier, M., Afroze, S., Dostal, D., Glaser, S. General mechanisms of nicotine-induced fibrogenesis. PMID:22906950

  5. Role of muscarinic and nicotinic cholinergic receptors in an experimental model of epilepsy-induced analgesia.

    PubMed

    de Freitas, Renato Leonardo; de Oliveira, Rithiele Cristina; de Carvalho, Andressa Daiane; Felippotti, Tatiana Tocchini; Bassi, Gabriel Shimizu; Elias-Filho, Daoud Hibrahim; Coimbra, Norberto Cysne

    2004-10-01

    The blockade of GABA-mediated Cl(-) influx with pentylenetetrazol (PTZ) was used in the present work to induce seizures in animals. The neurotransmission in the postictal period has been the focus of many studies, and there is evidence suggesting antinociceptive mechanisms following tonic-clonic seizures in both animals and men. The aim of this work was to study the involvement of acetylcholine in the antinociception induced by convulsions elicited by peripheral administration of PTZ (64 mg/kg). Analgesia was measured by the tail-flick test in eight albino Wistar rats per group. Convulsions were followed by significant increases in tail-flick latencies (TFLs) at least for 120 min of the postictal period. Peripheral administration of atropine (0.25, 1 and 4 mg/kg) caused a significant dose-dependent decrease in the TFL in seizing animals, as compared to controls. These data were corroborated by peripheral administration of mecamylamine, a nicotinic cholinergic receptor blocker, at the same doses (0.25, 1 and 4 mg/kg) used for the muscarinic cholinergic receptor antagonist. The recruitment of the muscarinic receptor was made 10 min postconvulsions and in subsequent periods of postictal analgesia, whereas the involvement of the nicotinic cholinergic receptor was implicated only after 30 min postseizures. The cholinergic antagonists caused a minimal reduction in body temperature, but did not impair baseline TFL, spontaneous exploration or motor coordination in the rotarod test at the maximal dose of 4 mg/kg. These results indicate that acetylcholine may be involved as a neurotransmitter in postictal analgesia.

  6. Microstructure and dielectric tunable properties of Ba0.6Sr0.4TiO3-Mg2SiO4-MgO composite.

    PubMed

    He, Yanyan; Xu, Yebin; Liu, Ting; Zeng, Chunlian; Chen, Wanping

    2010-07-01

    Ba(0.6)Sr(0.4)TiO(3)-Mg(2)SiO(4)-MgO composite ceramics were prepared by a solid-state reaction method and their dielectric tunable characteristics were investigated for the potential application as microwave tunable materials. The addition of Mg(2)SiO(4)-MgO into Ba(0.6)Sr(0.4)TiO(3) forms ferroelectric (Ba(0.6)Sr(0.4)TiO(3))-dielectric (Mg(2)SiO(4)-MgO) composites and shifts the Curie temperature to a lower temperature. The dielectric constant and loss tangent of Ba(0.6)Sr(0.4)TiO(3)-Mg(2)Si(O4)- MgO composites have been decreased and the overall tunability is maintained at a sufficiently high level. The microwave dielectric properties of Ba(0.6)Sr(0.4)TiO(3)-Mg(2)Si(O4)-MgO composites were evaluated. Ba(0.6)Sr(0.4)TiO(3)-Mg(2)SiO(4)-MgO composites have tunability of 9.2 to 10.5% at 100 kHz under 2 kV/mm, indicating that it is a promising candidate material for tunable microwave applications requiring a low dielectric constant.

  7. Role of α5-containing nicotinic receptors in neuropathic pain and response to nicotine.

    PubMed

    Xanthos, Dimitris N; Beiersdorf, Johannes W; Thrun, Ariane; Ianosi, Bogdan; Orr-Urtreger, Avi; Huck, Sigismund; Scholze, Petra

    2015-08-01

    Nicotinic receptors in the central nervous system (nAChRs) are known to play important roles in pain processing and modulate behavioral responses to analgesic drugs, including nicotine. The presence of the α5-neuronal nicotinic accessory subunit in the nicotinic receptor complex is increasingly understood to modulate reward and aversive states, addiction, and possibly pathological pain. In the current study, using α5-knockout (KO) mice and subunit-specific antibodies, we assess the role of α5-containing neuronal nicotinic receptors in neuropathic pain and in the analgesic response to nicotine. After chronic constriction injury (CCI) or partial sciatic nerve ligation (PSNL), no differences in mechanical, heat, or cold hyperalgesia were found in wild-type (WT) versus α5-KO littermate mice. The number of α5-containing nAChRs was decreased (rather than increased) after CCI in the spinal cord and in the thalamus. Nevertheless, thermal analgesic response to nicotine was marginally reduced in CCI α5-KO mice at 4 days after CCI, but not at later timepoints or after PSNL. Interestingly, upon daily intermittent nicotine injections in unoperated mice, WT animals developed tolerance to nicotine-induced analgesia to a larger extent than α5-KO mice. Our results suggest that α5-containing nAChRs mediate analgesic tolerance to nicotine but do not play a major role in neuropathic pain.

  8. Effects of Nicotine and Nicotine Expectancy on Attentional Bias for Emotional Stimuli

    PubMed Central

    Adams, Sally; Attwood, Angela S.; Munafò, Marcus R.

    2016-01-01

    Introduction Nicotine’s effects on mood are thought to enhance its addictive potential. However, the mechanisms underlying the effects of nicotine on affect regulation have not been reliably demonstrated in human laboratory studies. We investigated the effects of abstinence (experiment one), and nicotine challenge and expectancy (experiment two) on attentional bias towards facial emotional stimuli differing in emotional valence. Methods In experiment one, 46 nicotine-deprived smokers were randomized to either continue to abstain from smoking or to smoke immediately before testing. In experiment two, 96 nicotine deprived smokers were randomized to smoke a nicotinized or denicotinized cigarette and to be told that the cigarette did or did not contain nicotine. In both experiments participants completed a visual probe task, where positively valenced (happy) and negatively valenced (sad) facial expressions were presented, together with neutral facial expressions. Results In experiment one, there was evidence of an interaction between probe location and abstinence on reaction time, indicating that abstinent smokers showed an attentional bias for neutral stimuli. In experiment two, there was evidence of an interaction between probe location, nicotine challenge and expectation on reaction time, indicating that smokers receiving nicotine, but told that they did not receive nicotine, showed an attentional bias for emotional stimuli. Conclusions Our data suggest that nicotine abstinence appears to disrupt attentional bias towards emotional facial stimuli. These data provide support for nicotine’s modulation of attentional bias as a central mechanism for maintaining affect regulation in cigarette smoking. PMID:25335948

  9. Dual effects of nicotine on dopamine neurons mediated by different nicotinic receptor subtypes.

    PubMed

    Schilström, Björn; Rawal, Nina; Mameli-Engvall, Monica; Nomikos, George G; Svensson, Torgny H

    2003-03-01

    Burst firing of dopaminergic neurons has been found to represent a particularly effective means of increasing dopamine release in terminal areas as well as activating immediate early genes in dopaminoceptive cells. Spontaneous burst firing is largely controlled by the level of activation of NMDA receptors in the ventral tegmental area (VTA) as a consequence of glutamate released from afferents arising mainly in the prefrontal cortex. Nicotine has been found to effectively increase burst firing of dopaminergic cells. This effect of nicotine may be due to an alpha 7 nicotinic receptor-mediated presynaptic facilitation of glutamate release in the VTA. By the use of in-vivo single-cell recordings and immunohistochemistry we here evaluated the role of alpha 7 nicotinic receptors in nicotine-induced burst firing of dopamine cells in the VTA and the subsequent activation of immediate early genes in dopaminoceptive target areas. Nicotine (0.5 mg/kg s.c.) was found to increase firing rate and burst firing of dopaminergic neurons. In the presence of methyllycaconitine (MLA, 6.0 mg/kg i.p.) nicotine only increased firing rate. Moreover, in the presence of dihydro-beta-erythroidine (DH beta E, 1.0 mg/kg i.p.), an antagonist at non-alpha 7 nicotinic receptors, nicotine produced an increase in burst firing without increasing the firing rate. Nicotine also increased Fos-like immunoreactivity in dopamine target areas, an effect that was antagonized with MLA but not with DH beta E. Our data suggest that nicotine's augmenting effect on burst firing is, indeed, due to stimulation of alpha 7 nicotinic receptors whereas other nicotinic receptors seem to induce an increase in firing frequency.

  10. REINFORCING EFFECTS OF NICOTINE AND NON-NICOTINE COMPONENTS OF CIGARETTE SMOKE

    PubMed Central

    Rose, Jed E.; Salley, Al; Behm, Frederique M.; Bates, James E.; Westman, Eric C.

    2014-01-01

    We assessed the reinforcing effects of nicotine and non-nicotine components of cigarette smoke, by presenting a concurrent choice paradigm in which participants had access to intravenous (IV) nicotine infusions vs. saline (placebo) infusions and puffs from denicotinized (“denic”) cigarettes vs. air (sham puffs). We also measured the effects on self-administration of prior satiation with each component. Sixteen smokers participated in 7 sessions, consisting of: 1) a baseline smoking assessment, which was used to tailor the nicotine dose per infusion to that of puffs from subjects’ preferred brands of cigarettes; 2) two sessions in which participants were trained to discriminate IV nicotine vs. saline infusions and denic smoke vs. sham (air) puffs; and 3) four sessions assessing choice behavior after different satiation conditions. Results showed that subjects self-administered more puffs of denic smoke than any other alternative, including IV nicotine. IV nicotine, however, was preferred over IV saline and sham puffs. Preference for denic smoke vs. IV nicotine was highly correlated with subjective ratings of “comfort” associated with the two alternatives. Satiation with smoke diminished the number of denic puffs taken during choice periods, while prior administration of nicotine did not affect the number of puffs taken. Smoking withdrawal symptoms were alleviated both by nicotine administration and by denic smoke. These results show that in established smokers, non-nicotine aspects of cigarette smoking have potent reinforcing effects. While current smoking cessation pharmacotherapies primarily address the nicotine component of cigarette addiction, future cessation strategies should also be designed to target non-nicotine factors. PMID:20358364

  11. Toxicological Analysis of Low-Nicotine and Nicotine-Free Cigarettes

    PubMed Central

    Chen, Jinguo; Higby, Richard; Tian, Defa; Tan, Duanjun; Johnson, Michael D.; Xiao, Yingxian; Kellar, Kenneth J; Feng, Shibao; Shields, Peter G.

    2008-01-01

    Low-nicotine and nicotine-free cigarettes are commercially available under the brand-name Quest®. Some consumers may believe that these are safer cigarettes, and they may smoke more cigarettes or inhale more smoke to compensate for low nicotine yields. Thus, we have studied the toxicological effects of these two cigarettes and compared them with the Kentucky reference cigarette 2R4F. Also, the availability of nicotine-free cigarettes allows for the assessing the role of nicotine in cigarette smoke. In addition to nicotine, some tobacco-specific nitrosamines, aldehydes, and volatile organic compounds were also reduced in the Quest® cigarettes compared to the 2R4F. However, aromatic amines were higher in the nicotine-free compared with low nicotine cigarettes. The Ames test revealed that cigarette smoke condensates from the nicotinefree (CSC-F), low nicotine (CSC-L) and 2R4F (CSC-R) cigarettes had a similar mutagenic potency. Exposure to any CSC caused a similar dose-dependent LDH leakage from normal human bronchial epithelial cells. However, CSC-F had more inhibitory effects on the cell growth than CSC-L and CSC-R. Adding nicotine to the CSC-F attenuated this inhibition. Both Quest® CSCs decreased gap junction intercellular communication and caused cell cycle arrest. CSC exposure increased cytoplasmic nucleosomes, sub-G1/G0 population and apoptotic comet tails. Proapoptotic protein Bax increased independent of p53 induction after exposure to CSC-F. In conclusion, these studies are not consistent with a perception that low-nicotine or nicotine-free cigarettes may have less toxicity in human cells. Nicotine, as it exists in CSC, attenuates cytotoxicity possibly in part through inhibition of apoptotic pathways. PMID:18599178

  12. Nicotine activates and up-regulates nicotinic acetylcholine receptors in bronchial epithelial cells.

    PubMed

    Fu, Xiao Wen; Lindstrom, Jon; Spindel, Eliot R

    2009-07-01

    Prenatal nicotine exposure impairs normal lung development and leads to diminished pulmonary function after birth. Previous work from our laboratory has demonstrated that nicotine alters lung development by affecting a nonneuronal cholinergic autocrine loop that is expressed in lung. Bronchial epithelial cells (BECs) express choline acetyltransferase, the choline high-affinity transporter and nicotinic acetylcholine (ACh) receptor (nAChR) subunits. We now demonstrate through a combination of morphological and electrophysiological techniques that nicotine affects this autocrine loop by up-regulating and activating cholinergic signaling. RT-PCR showed the expression of alpha 3, alpha 4, alpha 7, alpha 9, alpha 10, beta2, and beta 4 nAChR mRNAs in rhesus monkey lung and cultured BECs. The expression of alpha 7, alpha 4, and beta2 nAChR was confirmed by immunofluorescence in the cultured BECs and lung. The electrophysiological characteristics of nAChR in BECs were determined using whole-cell patch-clamp on cultured BECs. Both ACh and nicotine evoked an inward current, with a rapid desensitizing current. Nicotine induced inward currents in a concentration-dependent manner, with an EC(50) of 26.7 microM. Nicotine-induced currents were reversibly blocked by the nicotinic antagonists, mecamylamine, dihydro-beta-erythroidine, and methyllcaconitine. Incubation of BECs with 1 microM nicotine for 48 hours enhanced nicotine-induced currents by roughly 26%. The protein tyrosine phosphorylation inhibitor, genistein, increased nicotine-induced currents by 58% and enhanced methyllcaconitine-sensitive currents (alpha 7 nAChR activities) 2.3-fold, whereas the protein tyrosine phosphatase inhibitor, pervanadate, decreased the effects of nicotine. These results demonstrate that chronic nicotine exposure up-regulates nAChR activity in developing lung, and that nAChR activity can be further modified by tyrosine phosphorylation.

  13. Adolescent nicotine treatment changes the response of acetylcholine systems to subsequent nicotine administration in adulthood.

    PubMed

    Slotkin, Theodore A; Bodwell, Bethany E; Ryde, Ian T; Seidler, Frederic J

    2008-05-15

    Nicotine alters the developmental trajectory of acetylcholine (ACh) systems in the immature brain, with vulnerability extending from fetal stages through adolescence. We administered nicotine to adolescent rats (postnatal days PN30-47) and then examined the subsequent response to nicotine given in adulthood (PN90-107), simulating plasma levels in smokers, and performing evaluations during nicotine treatment (PN105) and withdrawal (PN110, PN120 and PN130), as well as assessing persistent changes at 6 months of age (PN180). We measured nicotinic acetylcholine receptor (nAChR) binding, choline acetyltransferase (ChAT) activity, a marker for ACh terminals, and hemicholinium-3 (HC3) binding to the choline transporter, an index of ACh presynaptic activity. By itself, adolescent nicotine exposure evoked sex-selective deficits in cerebrocortical HC3 binding while elevating ChAT in young adulthood in striatum and midbrain. Nicotine given in adulthood produced profound nAChR upregulation lasting 2 weeks after discontinuing treatment, and decrements in cerebrocortical and striatal HC3 binding emerged during withdrawal, indicative of reduced ACh synaptic activity. For all three parameters, adolescent nicotine altered the responses to nicotine given in adulthood, producing both sensitization and desensitization that depended on sex and brain region, effects that parallel the disparate behavioral outcomes reported for these treatments. The interaction seen here for the impact of adolescent nicotine exposure on adult nicotine responses was substantially greater than that found previously for the effects of prenatal nicotine exposure on adult responses. Our findings thus reinforce the importance of adolescence as a critical period in which the future responsiveness to nicotine is programmed.

  14. Adolescent nicotine treatment changes the response of acetylcholine systems to subsequent nicotine administration in adulthood.

    PubMed

    Slotkin, Theodore A; Bodwell, Bethany E; Ryde, Ian T; Seidler, Frederic J

    2008-05-15

    Nicotine alters the developmental trajectory of acetylcholine (ACh) systems in the immature brain, with vulnerability extending from fetal stages through adolescence. We administered nicotine to adolescent rats (postnatal days PN30-47) and then examined the subsequent response to nicotine given in adulthood (PN90-107), simulating plasma levels in smokers, and performing evaluations during nicotine treatment (PN105) and withdrawal (PN110, PN120 and PN130), as well as assessing persistent changes at 6 months of age (PN180). We measured nicotinic acetylcholine receptor (nAChR) binding, choline acetyltransferase (ChAT) activity, a marker for ACh terminals, and hemicholinium-3 (HC3) binding to the choline transporter, an index of ACh presynaptic activity. By itself, adolescent nicotine exposure evoked sex-selective deficits in cerebrocortical HC3 binding while elevating ChAT in young adulthood in striatum and midbrain. Nicotine given in adulthood produced profound nAChR upregulation lasting 2 weeks after discontinuing treatment, and decrements in cerebrocortical and striatal HC3 binding emerged during withdrawal, indicative of reduced ACh synaptic activity. For all three parameters, adolescent nicotine altered the responses to nicotine given in adulthood, producing both sensitization and desensitization that depended on sex and brain region, effects that parallel the disparate behavioral outcomes reported for these treatments. The interaction seen here for the impact of adolescent nicotine exposure on adult nicotine responses was substantially greater than that found previously for the effects of prenatal nicotine exposure on adult responses. Our findings thus reinforce the importance of adolescence as a critical period in which the future responsiveness to nicotine is programmed. PMID:18395624

  15. [Drugs used to treat nicotine addiction].

    PubMed

    Zieleń, Iwona; Sliwińska-Mossoń, Mariola; Milnerowicz, Halina

    2012-01-01

    Tobacco smoking in Poland is fairly widespread on a large scale. Research suggests that the early twenty-first century, the percentage of female daily smokers aged 20 and above was 26%, and men the same age 43%. In addition, epidemiological studies have shown that smoking was the cause of approximately sixty-nine thousand deaths in Poland (including fifty-seven thousand men and twelve thousand women). It is common ground that cigarette smoking has a negative effect on our body. It represents one of the main and most commonly defined risk factors for many diseases that can be eliminated. Smoking often leads to addiction, and nicotine is an addictive drug. Nicotine addiction is characterized by symptoms such as: "hunger" smoking, difficulty in controlling behavior on smoking or the number of cigarettes smoked, nicotine withdrawal, the occurrence of tolerance, neglect of interests, as well as devoting more time on activities related to smoking, follow-up smoking despite knowledge of its dangers. The most commonly used in Poland, a questionnaire to identify nicotine dependence is a test Fagerstöma. Currently assigned some importance, "the doctor a conversation the patient" and motivating him to stop smoking and maintain abstinence as long as possible. But beyond the "conversation" is also used as an aid to medical treatment for the patient to stop smoking, especially to alleviate withdrawal symptoms. The first attempts of pharmacological help in the effort to weaning from smoking began in the thirties. Were conducted fairly successful, although uncontrolled trials with lobeline, an alkaloid of action similar to nicotine. In Poland, the drugs of first choice in the treatment of nicotine dependence are nicotine replacement therapies (nicotine gum and patches that contain nicotine) and bupropion SR. Quite a popular drugs to help in the fight against addiction are also cytisine and varenicline. The choice of the drug is usually the result of medical experience in the use

  16. Influence of the oral dissolution time on the absorption rate of locally administered solid formulations for oromucosal use: the flurbiprofen lozenges paradigm.

    PubMed

    Imberti, Roberto; De Gregori, Simona; Lisi, Lucia; Navarra, Pierluigi

    2014-01-01

    Flurbiprofen is a nonsteroidal anti-inflammatory agent preferentially used for local oromucosal treatment of painful and/or inflammatory conditions of the oropharynx such as gingivitis, stomatitis, periodontitis, pharyngitis and laryngitis. In this study, we have investigated the bioavailability of a new generic formulation of flurbiprofen lozenges developed by Epifarma Srl, compared to the originator Benactiv Gola® taken as reference. Within the framework of a formal bioequivalence study, we investigated in particular the putative influence of oral dissolution time (i.e. the time spent suckling the lozenge from its intake to complete dissolution) on the absorption rate, and the contribution of this factor to the total variability of plasma flurbiprofen during absorption. We found that the amount of flurbiprofen absorbed into the systemic circulation is not significantly higher for the test drug compared to that of the reference product. We observed that the length of oral dissolution time is inversely correlated to 10-min flurbiprofen plasma levels in the test but not in the reference formulation. We estimated that oral dissolution time accounts for about 14% of overall variability in flurbiprofen plasma 10 min after test drug administration.

  17. Influence of the oral dissolution time on the absorption rate of locally administered solid formulations for oromucosal use: the flurbiprofen lozenges paradigm.

    PubMed

    Imberti, Roberto; De Gregori, Simona; Lisi, Lucia; Navarra, Pierluigi

    2014-01-01

    Flurbiprofen is a nonsteroidal anti-inflammatory agent preferentially used for local oromucosal treatment of painful and/or inflammatory conditions of the oropharynx such as gingivitis, stomatitis, periodontitis, pharyngitis and laryngitis. In this study, we have investigated the bioavailability of a new generic formulation of flurbiprofen lozenges developed by Epifarma Srl, compared to the originator Benactiv Gola® taken as reference. Within the framework of a formal bioequivalence study, we investigated in particular the putative influence of oral dissolution time (i.e. the time spent suckling the lozenge from its intake to complete dissolution) on the absorption rate, and the contribution of this factor to the total variability of plasma flurbiprofen during absorption. We found that the amount of flurbiprofen absorbed into the systemic circulation is not significantly higher for the test drug compared to that of the reference product. We observed that the length of oral dissolution time is inversely correlated to 10-min flurbiprofen plasma levels in the test but not in the reference formulation. We estimated that oral dissolution time accounts for about 14% of overall variability in flurbiprofen plasma 10 min after test drug administration. PMID:25277061

  18. The genetics of nicotine dependence.

    PubMed

    Li, Ming D

    2006-04-01

    Despite almost two decades of intensive tobacco-control efforts, approximately 23% of American adults continue to smoke, and 13% are nicotine-dependent. Cigarette smoking is the greatest preventable cause of cancer, accounting for at least 30% of all cancer deaths and 87% of lung cancer deaths. Smoking behavior is influenced by both genetic and environmental factors. Many years of twin and adoption studies have demonstrated that the heritability of liability for nicotine dependence (ND) is at least 50%. During the past several years, significant efforts have been made to identify susceptibility genes for ND using both genome-wide linkage and association analysis approaches. It is expected that identification of susceptibility genes for ND will allow the development and tailoring of both prevention strategies for individuals at risk and effective treatment programs and medicines for individuals who use tobacco products. This review summarizes the recent progress in genetic studies of ND. As genotyping technology is being improved and well-characterized clinical samples on smoking behavior become available, more and more genes and genetic variants responsible for ND will be identified in the near future. PMID:16539894

  19. Nicotinic receptors in addiction pathways.

    PubMed

    Leslie, Frances M; Mojica, Celina Y; Reynaga, Daisy D

    2013-04-01

    Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that consist of pentameric combinations of α and β subunits. These receptors are widely distributed throughout the brain and are highly expressed in addiction circuitry. The role of nAChRs in regulating neuronal activity and motivated behavior is complex and varies both in and among brain regions. The rich diversity of central nAChRs has hampered the characterization of their structure and function with use of classic pharmacological techniques. However, recent molecular approaches using null mutant mice with specific regional lentiviral re-expression, in combination with neuroanatomical and electrophysiological techniques, have allowed the elucidation of the influence of different nAChR types on neuronal circuit activity and behavior. This review will address the influence of nAChRs on limbic dopamine circuitry and the medial habenula-interpeduncular nucleus complex, which are critical mediators of reinforced behavior. Characterization of the mechanisms underlying regulation of addiction pathways by endogenous cholinergic transmission and by nicotine may lead to the identification of new therapeutic targets for treating tobacco dependence and other addictions. PMID:23247824

  20. Nicotine reduction revisited: science and future directions.

    PubMed

    Hatsukami, Dorothy K; Perkins, Kenneth A; Lesage, Mark G; Ashley, David L; Henningfield, Jack E; Benowitz, Neal L; Backinger, Cathy L; Zeller, Mitch

    2010-10-01

    Regulation of nicotine levels in cigarettes and other tobacco products is now possible with the passage of the Family Smoking Prevention and Tobacco Control Act (FSPTCA) in 2009, giving the US Food and Drug Administration (FDA) authority to regulate tobacco products, and with Articles 9-11 of the WHO Framework Convention on Tobacco Control. Both regulatory approaches allow establishing product standards for tobacco constituents, including nicotine. The FSPTCA does not allow nicotine levels to be decreased to zero, although the FDA has the authority to reduce nicotine yields to very low, presumably non-addicting levels. The proposal to reduce levels of nicotine to a level that is non-addicting was originally suggested in 1994. Reduction of nicotine in tobacco products could potentially have a profound impact on reducing tobacco-related morbidity and mortality. To examine this issue, two meetings were convened in the US with non-tobacco-industry scientists of varied disciplines, tobacco control policymakers and representatives of government agencies. This article provides an overview of the current science in the area of reduced nicotine content cigarettes and key conclusions and recommendations for research and policy that emerged from the deliberations of the meeting members.

  1. [Nicotine abusing in adult children of alcoholics].

    PubMed

    Suwała, Małgorzata

    2010-01-01

    Adult Children of Alcoholics (ACA) are people who were raised in families abusing alcohol where one of the parents (or both) was addicted to alcohol and where alcohol was the main problem affecting all areas of life. It is estimated that in Poland adult population consists of ACA in 35-40%. Those people represent higher risk of addiction to psychoactive substances, most of all alcohol, but also nicotine. Higher addiction propensity among ACA is a result of their personality's features consisting so called "ACA syndrome". The goal of the study was to determine nicotine addiction frequency and assessment of self-propensity to addiction in chosen ACA group, gathered in three abstinent clubs for alcoholics in Warsaw. Nicotine addiction frequency among the study group members was 58.4% and alcohol addiction frequency was 21.2%. Strong nicotine addiction represented 49.2% of smokers. Men more often than women were addicted to nicotine (0.67 vs. 0.52), on the other hand women were more often than men alcohol addicts (0.18 vs. 0.15). All smokers and nicotine addicts (assessment by HIS test) were aware of their addiction. In relation to initial addiction diagnosis by CAGE test regarded higher percentage of people than it resulted from study group self-assessment (21.2% vs. 16.8). Professional psychotherapy for ACA did not influence substantially the nicotine addiction frequency in the study group. PMID:21360917

  2. Structure and bonding in Yb4MgGe4: Yb2+/Yb3+ mixed-valency and charge separation.

    PubMed

    Tobash, Paul H; Bobev, Svilen

    2006-03-22

    Reported are the synthesis and the structural characterization of a new derivative of the RE5Tt4 family (RE = Rare-earth; Tt = Tetrel, = Si, Ge, i.e., group 14 element), Yb5-xMgxGe4 (x approximately 1). Crystal data for Yb4.04(1)Mg0.96(1)Ge4 at 23 degrees C: orthorhombic, space group Pnma (No. 62), Z = 4; a = 7.155(2) A, b = 14.769(5) A, c = 7.688(2) A; V = 812.5(4) A3. This phase is an example of a substitution of lanthanide metal (Yb) with a nonmagnetic element (Mg) within this structure type. Its structure can alternatively be described as an intergrowth of the hypothetical Yb2MgGe2, which features flat infinite [MgGe2]4- layers and the hypothetical YbGe with [Ge2]6- dimers. The flat [MgGe2]4- layers propagate in two dimensions (a and c), and they are offset by a distance of 1/4.a with respect to one another and are interspaced with layers of [Ge2]6- dimers and Yb cations filling the space between them. According to the structural and physical property data, Yb4MgGe4 is a heterogeneous mixed-valent compound, i.e. a system where one of the two symmetry-inequivalent Yb sites has atoms in closed-shell Yb2+ configuration, whereas the Yb3+ cations occupy a different crystallographic site.

  3. Role of α5 Nicotinic Acetylcholine Receptors in Pharmacological and Behavioral Effects of Nicotine in Mice

    PubMed Central

    Marks, M. J.; Vann, R. E.; Chen, X.; Gamage, T. F.; Warner, J. A.; Damaj, M. I.

    2010-01-01

    Incorporation of the α5 nicotinic acetylcholine receptor (nAChR) subunit can greatly influence nAChR function without altering receptor number. Although few animal studies have assessed the role of the α5 nAChR in nicotine-mediated behaviors, recent evidence suggests an association between polymorphisms in the α5 nAChR gene and nicotine dependence phenotypes in humans. Thus, additional studies are imperative to elucidate the role and function of the α5 nAChR subunit in nicotine dependence. Using α5(−/−) mice, the current study aimed to examine the role of α5 nAChRs in the initial pharmacological effects of nicotine, nicotine reward using the conditioned place preference model, and the discriminative effects of nicotine using a two-lever drug discrimination model. 86Rb+ efflux and 125I-epibatidine binding assays were conducted to examine the effect of α5 nAChR subunit deletion on expression and activity of functional nAChRs. Results show that α5(−/−) mice are less sensitive to the initial effects of nicotine in antinociception, locomotor activity, and hypothermia measures and that the α5 nAChR is involved in nicotine reward. Alternatively, α5(−/−) mice did not differ from wild-type littermates in sensitivity to the discriminative stimulus effects of nicotine. Furthermore, deletion of the α5 nAChR subunit resulted in a statistically significant decrease in function in the thalamus and hindbrain, but the decreases noted in spinal cord were not statistically significant. Receptor number was unaltered in all areas tested. Taken together, results of the study suggest that α5 nAChRs are involved in nicotine-mediated behaviors relevant to development of nicotine dependence. PMID:20400469

  4. New operant model of nicotine-seeking behaviour in mice.

    PubMed

    Martín-García, Elena; Barbano, Maria Flavia; Galeote, Lola; Maldonado, Rafael

    2009-04-01

    Nicotine addiction represents a major health problem in the world with dramatic socio-economic consequences. Recent studies using genetically modified mice have provided a better understanding of the neurobiological mechanisms involved in nicotine responses. However, the study of nicotine addiction requires sophisticated behavioural models that are still not fully developed in mice. Here, we report the validation of a new reliable operant model of nicotine-seeking behaviour in mice. C57BL/6 mice were trained to self-administer nicotine (0.03 mg/kg per infusion) under a fixed ratio 1 schedule of reinforcement for 10 d. A light cue was contingently associated with the nicotine infusion. After reaching the acquisition criteria of nicotine self-administration, mice were exposed to extinction sessions similar to the self-administration training except that nicotine was not available and the associated cues were not presented. Nicotine-seeking behaviour was then reinstated by exposure to nicotine-associated environment cues, a priming injection of nicotine or stress, the three main conditions leading to nicotine relapse in humans. The exposure to the cues associated with nicotine infusion was the most effective stimulus reinstating nicotine-seeking behaviour in 90% of mice. A priming injection of nicotine (0.18 mg/kg) produced nicotine reinstatement in 30% of the animals, whereas stress exposure (0.22 mA footshock) reinstated nicotine-seeking behaviour in 50% of mice. The validation of this new model of nicotine-seeking behaviour and reinstatement in mice provides an important tool to help clarify the genetic and neurochemical bases of nicotine addiction.

  5. Nicotine-containing versus de-nicotinized cigarettes: effects on craving and withdrawal.

    PubMed

    Gross, J; Lee, J; Stitzer, M L

    1997-01-01

    Nicotine exposure levels and subjective effects from smoking a de-nicotinized cigarette (Next) were examined under controlled conditions. Ten tobacco smokers smoked 20 puffs from their own brand (1.1 mg nicotine delivery, commercial cigarettes), a 0.7 mg nicotine "light" cigarette, or the Next de-nicotinized cigarette (< 0.1 mg nicotine) during independent experimental test sessions. The Next cigarette did not deliver and appreciable nicotine, did not elevate heart rate during smoking, and was rated as less satisfying than the smokers' own brand. Subjective ratings of cigarette carving and tobacco withdrawal symptoms increased during a 90 min post-smoking abstinence period. However, there were no measurable differences on these subjective ratings across the three cigarette test brands. It is concluded that nicotine can be removed from cigarettes without affecting the onset time course or intensity of cigarette cravings and other tobacco withdrawal symptoms in an acute abstinence model. Further studies to determine the subjective and physiological effects of nicotine-free cigarettes would contribute to a greater understanding of tobacco withdrawal and the processes involved in smoking maintenance.

  6. Electrical stimulation of the insular region attenuates nicotine-taking and nicotine-seeking behaviors.

    PubMed

    Pushparaj, Abhiram; Hamani, Clement; Yu, Wilson; Shin, Damian S; Kang, Bin; Nobrega, José N; Le Foll, Bernard

    2013-03-01

    Pharmacological inactivation of the granular insular cortex is able to block nicotine-taking and -seeking behaviors in rats. In this study, we explored the potential of modulating activity in the insular region using electrical stimulation. Animals were trained to self-administer nicotine (0.03 mg/kg per infusion) under a fixed ratio-5 (FR-5) schedule of reinforcement followed by a progressive ratio (PR) schedule. Evaluation of the effect of stimulation in the insular region was performed on nicotine self-administration under FR-5 and PR schedules, as well on reinstatement of nicotine-seeking behavior induced by nicotine-associated cues or nicotine-priming injections. The effect of stimulation was also examined in brain slices containing insular neurons. Stimulation significantly attenuated nicotine-taking, under both schedules of reinforcement, as well as nicotine-seeking behavior induced by cues and priming. These effects appear to be specific to nicotine-associated behaviors, as stimulation did not have any effect on food-taking behavior. They appear to be anatomically specific, as stimulation surrounding the insular region had no effect on behavior. Stimulation of brain slices containing the insular region was found to inactivate insular neurons. Our results suggest that deep brain stimulation to modulate insular activity should be further explored. PMID:23249816

  7. Nicotinic Mechanisms in the Treatment of Psychotic Disorders: A Focus on the α7 Nicotinic Receptor

    PubMed Central

    Freedman, Robert

    2013-01-01

    Nicotine is heavily abused by persons with schizophrenia. Nicotine better enables people with schizophrenia to filter out extraneous auditory stimuli. Nicotine also improves prepulse inhibition when compared to placebo. Nicotine similarly increases the amplitude of patients’ duration mismatch negativity. The 15q13-14 region of the genome coding for the α7 nicotinic receptor is linked to schizophrenia. Multiple single nucleotide polymorphisms have been identified in this 15q13-14 gene promoter region that are more frequently present in people with schizophrenia than in normal controls. Abnormalities in expression and regulation of central nicotinic cholinoceptors with decreased α7 binding in multiple brain regions are also present. Nicotine enhances cognition in schizophrenia. Alternative agents that activate the nicotinic receptor have been tested including 3-[2,4-dimethoxybenzylidene]anabaseine (DMXB-A). This compound improved attention, working memory, and negative symptoms in an add-on study in non-smoking patients with schizophrenia. There are multiple other nicotinic agents, including positive allosteric modulators, in the preclinical stages of development. Finally, the effects of varenicline and clozapine and their relation to smoking cessation are discussed. PMID:23027417

  8. Enhanced hydrogen storage properties of the 2LiBH4-MgH2 composite with BaTiO3 as an additive.

    PubMed

    Wang, Jiasheng; Han, Shumin; Wang, Zhibin; Ke, Dandan; Liu, Jingjing; Ma, Mingzhen

    2016-04-28

    The 2LiBH4-MgH2 + 20 wt% BaTiO3 composite was prepared by ball-milling LiBH4, MgH2 and BaTiO3, and the effect of BaTiO3 on the hydrogen storage properties of the composite was investigated. TG-DSC results show that the onset dehydrogenation temperature of the composite is 299 °C, which is 124 °C lower than that of 2LiBH4-MgH2, and the dehydrogenation amount of the composite increases from 6.86 wt% to 7.48 wt% at 500 °C. Kinetic tests show that the dehydrogenation amount of 2LiBH4-MgH2 + 20 wt% BaTiO3 reaches 1.5 wt% within 400 seconds, almost 10 times that of 2LiBH4-MgH2. BaTiO3 reacts with LiBH4 during the dehydrogenation of the composite and generates BaB6 and TiO2. BaB6 is beneficial to lower the stability of LiBH4, while TiO2 has a catalytic effect in improving the hydrogenation/dehydrogenation kinetics of the reaction between Mg and LiBH4.

  9. Relief of sore throat with the anti-inflammatory throat lozenge flurbiprofen 8.75 mg: a randomised, double-blind, placebo-controlled study of efficacy and safety.

    PubMed

    Watson, N; Nimmo, W S; Christian, J; Charlesworth, A; Speight, J; Miller, K

    2000-10-01

    In this double-blind study, 301 patients with subjective and objective signs of sore throat were randomly assigned to flurbiprofen 8.75 mg (n = 129), flurbiprofen 12.5 mg (n = 43) or placebo (demulcent lozenge without active drug [n = 129]). Efficacy was assessed by changes in subjective rating scales primarily after a single dose and also over a 4-day period. Flurbiprofen 8.75 mg was superior to placebo in a number of efficacy parameters, notably throat soreness. Throat soreness was significantly reduced after 15 minutes (p < 0.05), with effects sustained for at least 2 hours (p < 0.05). Multiple dosing with flurbiprofen 8.75 mg lozenges continued to provide effective symptomatic relief over the 4-day treatment period. The small sample size was considered contributory to the variable results obtained with flurbiprofen 12.5 mg lozenges, but overall these were not inconsistent with previous trials. Both treatments were tolerated well. Flurbiprofen 8.75 mg lozenges provide an effective and well tolerated treatment for sore throat.

  10. Relief of sore throat with the anti-inflammatory throat lozenge flurbiprofen 8.75 mg: a randomised, double-blind, placebo-controlled study of efficacy and safety.

    PubMed

    Watson, N; Nimmo, W S; Christian, J; Charlesworth, A; Speight, J; Miller, K

    2000-10-01

    In this double-blind study, 301 patients with subjective and objective signs of sore throat were randomly assigned to flurbiprofen 8.75 mg (n = 129), flurbiprofen 12.5 mg (n = 43) or placebo (demulcent lozenge without active drug [n = 129]). Efficacy was assessed by changes in subjective rating scales primarily after a single dose and also over a 4-day period. Flurbiprofen 8.75 mg was superior to placebo in a number of efficacy parameters, notably throat soreness. Throat soreness was significantly reduced after 15 minutes (p < 0.05), with effects sustained for at least 2 hours (p < 0.05). Multiple dosing with flurbiprofen 8.75 mg lozenges continued to provide effective symptomatic relief over the 4-day treatment period. The small sample size was considered contributory to the variable results obtained with flurbiprofen 12.5 mg lozenges, but overall these were not inconsistent with previous trials. Both treatments were tolerated well. Flurbiprofen 8.75 mg lozenges provide an effective and well tolerated treatment for sore throat. PMID:11198725

  11. Disrupting nicotine reinforcement: from cigarette to brain.

    PubMed

    Rose, Jed E

    2008-10-01

    Cigarette smoking is a tenacious addiction that is maintained to a significant extent by the reinforcing effects of nicotine. An emerging theme in smoking cessation treatment is the development of methods for interfering with these reinforcing effects. By attenuating nicotine reinforcement, treatments may enhance a smoker's chances of successfully remaining abstinent. Several treatment approaches will be described, including the use of denicotinized cigarettes, nicotine vaccines, nicotinic receptor agonists and antagonists, and modulators of brain reinforcement processes. These techniques highlight the numerous sites along the path between the cigarette and the brain that can be targeted for intervention. In addition to unimodal therapies, treatment combinations will be discussed that might more effectively block cigarette reward and thereby further enhance smoking abstinence. PMID:18991961

  12. Many Teens 'Vaping' for Flavor, Not Nicotine

    MedlinePlus

    ... a fifth of 12th graders who used an e-cigarette used a nicotine substance To use the sharing ... Why are American teens tempted to try an e-cigarette? A new study suggests most are interested in ...

  13. Cardiorespiratory effects of nicotine exposure during development.

    PubMed

    Hafström, Ola; Milerad, Joseph; Sandberg, Kenneth L; Sundell, Håkan W

    2005-11-15

    Exposure to tobacco smoke is a major risk factor for the sudden infant death syndrome. Nicotine is thought to be the ingredient in tobacco smoke that is responsible for a multitude of cardiorespiratory effects during development, and pre- rather than postnatal exposure is considered to be most detrimental. Nicotine interacts with endogenous acetylcholine receptors in the brain and lung, and developmental exposure produces structural changes as well as alterations in neuroregulation. Abnormalities have been described in sympathicovagal balance, arousal threshold and latency, breathing pattern at rest and apnea frequency, ventilatory response to hyperoxia or hypoxia, heart rate regulation and ability to autoresuscitate during severe hypoxia. This review discusses studies performed on infants of smoking mothers and nicotine-exposed animals yielding varying and sometimes inconsistent results that may be due to differences in experimental design, species and the dose of exposure. Taken together however, developmental nicotine exposure appears to induce vulnerability during hypoxia and a potential inability to survive severe asphyxia.

  14. Nicotinic receptors and Alzheimer's disease.

    PubMed

    Bourin, Michel; Ripoll, Nadège; Dailly, Eric

    2003-01-01

    Nicotinic receptors (NRs) belong to the group of polymeric receptors of the cell membrane and are key elements of cholinergic transmission. Numerous subtypes of NRs exist with the alpha 4 beta 2 and alpha 7 types being encountered most frequently. Deficiencies in NRs seem to play a role in Alzheimer's disease, which is characterised by accumulation of senile plaques, mainly composed of beta-amyloid peptide (beta A). Although the aetiology of this disease is unknown, different pathogenesis hypotheses implicating alpha 7 NRs have been proposed, with the receptors exerting a direct or indirect action on the mechanism of beta A toxicity. Allosteric modulators of NRs, such as the cholinesterase inhibitor galantamine, that facilitate the action of acetylcholine on these receptors may provide therapeutic benefits in the areas of cognition, attention and antineurodegenerative activity.

  15. The role of nicotinic receptor alpha 7 subunits in nicotine discrimination.

    PubMed

    Stolerman, I P; Chamberlain, S; Bizarro, L; Fernandes, C; Schalkwyk, L

    2004-03-01

    The subtypes of nicotinic receptors at which the behavioural effects of nicotine originate are not fully understood. The experiments described here use mice lacking the alpha7 subunit of nicotinic receptors to investigate the role of alpha7-containing receptors in nicotine discrimination. Wild-type and alpha7-knockout mice were trained in a two-lever nicotine discrimination procedure using a tandem schedule of food reinforcement. Mutant mice exhibited baseline rates of lever-pressing as low as 52.2% of rates in wild-type controls (n=21-24). Mutant and wild-type mice acquired discrimination of nicotine (0.4 or 0.8 mg/kg) at a similar rate (n=10-12) and reached similar final levels of accuracy (71.9 +/- 4.4% and 90.8 +/- 3.1% after 60 training sessions for 0.4 and 0.8 mg/kg training doses, respectively, in mutant mice, as compared with 75.0 +/- 6.5% and 87.6 +/- 4.8% for wild types). The genotypes exhibited similar steep dose-response curves for nicotine discrimination. In both genotypes, dose-response curves for mice trained with 0.8 mg/kg of nicotine were displaced three- to four-fold to the right as compared with those for the mice trained with the smaller dose. The predominant effect of nicotine on the overall rate of responding was a reduction at the largest doses tested and there was no difference between the genotypes. The results suggest that nicotinic receptors containing the alpha7 subunit do not contribute to the discriminative stimulus or response-rate-depressant effects of nicotine, although they may regulate baseline rates of operant responding.

  16. The role of nicotinic receptor alpha 7 subunits in nicotine discrimination.

    PubMed

    Stolerman, I P; Chamberlain, S; Bizarro, L; Fernandes, C; Schalkwyk, L

    2004-03-01

    The subtypes of nicotinic receptors at which the behavioural effects of nicotine originate are not fully understood. The experiments described here use mice lacking the alpha7 subunit of nicotinic receptors to investigate the role of alpha7-containing receptors in nicotine discrimination. Wild-type and alpha7-knockout mice were trained in a two-lever nicotine discrimination procedure using a tandem schedule of food reinforcement. Mutant mice exhibited baseline rates of lever-pressing as low as 52.2% of rates in wild-type controls (n=21-24). Mutant and wild-type mice acquired discrimination of nicotine (0.4 or 0.8 mg/kg) at a similar rate (n=10-12) and reached similar final levels of accuracy (71.9 +/- 4.4% and 90.8 +/- 3.1% after 60 training sessions for 0.4 and 0.8 mg/kg training doses, respectively, in mutant mice, as compared with 75.0 +/- 6.5% and 87.6 +/- 4.8% for wild types). The genotypes exhibited similar steep dose-response curves for nicotine discrimination. In both genotypes, dose-response curves for mice trained with 0.8 mg/kg of nicotine were displaced three- to four-fold to the right as compared with those for the mice trained with the smaller dose. The predominant effect of nicotine on the overall rate of responding was a reduction at the largest doses tested and there was no difference between the genotypes. The results suggest that nicotinic receptors containing the alpha7 subunit do not contribute to the discriminative stimulus or response-rate-depressant effects of nicotine, although they may regulate baseline rates of operant responding. PMID:14975691

  17. Prenatal nicotine exposure increases apnoea and reduces nicotinic potentiation of hypoglossal inspiratory output in mice

    PubMed Central

    Robinson, Dean M; Peebles, Karen C; Kwok, Henry; Adams, Brandon M; Clarke, Lan-Ling; Woollard, Gerald A; Funk, Gregory D

    2002-01-01

    We examined the effects of in utero nicotine exposure on postnatal development of breathing pattern and ventilatory responses to hypoxia (7.4 % O2) using whole-body plethysmography in mice at postnatal day 0 (P0), P3, P9, P19 and P42. Nicotine delayed early postnatal changes in breathing pattern. During normoxia, control and nicotine-exposed P0 mice exhibited a high frequency of apnoea (fA) which declined by P3 in control animals (from 6.7 ± 0.7 to 2.2 ± 0.7 min−1) but persisted in P3 nicotine-exposed animals (5.4 ± 1.3 min−1). Hypoxia induced a rapid and sustained reduction in fA except in P0 nicotine-exposed animals where it fell initially and then increased throughout the hypoxic period. During recovery, fA increased above control levels in both groups at P0. By P3 this increase was reduced in control but persisted in nicotine-exposed animals. To examine the origin of differences in respiratory behaviour, we compared the activity of hypoglossal (XII) nerves and motoneurons in medullary slice preparations. The frequency and variability of the respiratory rhythm and the envelope of inspiratory activity in XII nerves and motoneurons were indistinguishable between control and nicotine-exposed animals. Activation of postsynaptic nicotine receptors caused an inward current in XII motoneurons that potentiated XII nerve burst amplitude by 25 ± 5 % in control but only 14 ± 3 % in nicotine-exposed animals. Increased apnoea following nicotine exposure does not appear to reflect changes in basal activity of rhythm or pattern-generating networks, but may result, in part, from reduced nicotinic modulation of XII motoneurons. PMID:11826179

  18. Brain β2*-nicotinic acetylcholine receptor occupancy after use of a nicotine inhaler

    PubMed Central

    Esterlis, Irina; Mitsis, Effie M.; Batis, Jeffery C.; Bois, Frederic; Picciotto, Marina R.; Stiklus, Stephanie M.; Kloczynski, Tracy; Perry, Edward; Seibyl, John P.; McKee, Sherry; Staley, Julie K.; Cosgrove, Kelly P.

    2012-01-01

    The Nicotrol® (Pfizer, USA) nicotine inhaler reduces craving by mimicking the behavioural component of cigarettes and delivering controlled doses of nicotine, which binds to the beta-2 subunit-containing nicotinic acetylcholine receptors (β2*-nAChRs). Previous studies examined β2*-nAChR occupancy after administration of regular and low-nicotine cigarettes. Here, we measured occupancy of β2*-nAChRs after administration of nicotine via inhaler, and the relationship between occupancy and changes in craving for tobacco smoking and withdrawal symptoms. Tobacco smokers participated in [123I]5-IA-85380 SPECT studies with either a nicotine inhaler (n=9) or tobacco cigarette (n=4) challenge. [123I]5-IA was administered as a bolus plus constant infusion. After equilibrium was achieved, three 30-min baseline scans were collected, and subjects either used the nicotine inhaler or a regular cigarette, and up to six additional scans were obtained. Receptor occupancy was determined based on the Lassen plot method. Craving for tobacco smoking and withdrawal symptoms were evaluated pre- and post-challenge. Use of the nicotine inhaler produced an average 55.9±6.4% occupancy of β2*-nAChRs 2–5 h post-challenge, whereas use of a cigarette produced significantly higher receptor occupancy (F=10.6, p=0.009) with an average 67.6±14.1% occupancy 1.5–5 h post-challenge. There was a significant decrease in withdrawal symptoms post-nicotine inhaler use (F=6.13, p=0.04). These results demonstrate significant differences in occupancy of β2*-nAChRs by nicotine after use of the inhaler vs. a cigarette and confirm the ability of the nicotine inhaler to relieve withdrawal symptoms. PMID:21029513

  19. alpha4beta2 nicotinic acetylcholine receptors on dopaminergic neurons mediate nicotine reward and anxiety relief

    PubMed Central

    McGranahan, Tresa M.; Patzlaff, Natalie E.; Grady, Sharon R.; Heinemann, Stephen F.; Booker, T.K.

    2012-01-01

    Nicotine is the primary psychoactive substance in tobacco and it exerts its effects by interaction with various subtypes of nicotinic acetylcholine receptors (nAChRs) in the brain. One of the major subtypes expressed in brain, the alpha4beta2-nAChR, endogenously modulates neuronal excitability and thereby, modifies certain normal, as well as nicotine-induced, behaviors. Although alpha4-containing nAChRs are widely expressed across the brain, a major focus has been on their roles within midbrain dopaminergic regions involved in drug addition, mental illness and movement control in humans. We developed a unique model system to examine the role of alpha4-nAChRs within dopaminergic neurons by a targeted genetic deletion of the alpha4 subunit from dopaminergic neurons in mice. The loss alpha4 mRNA and alpha4beta2-nAChRs from dopaminergic neurons was confirmed, as well as selective loss of alpha4beta2-nAChR function from dopaminergic but not GABAergic neurons. Two behaviors central to nicotine dependence, reward and anxiety relief, were examined. Alpha4-nAChRs specifically on dopaminergic neurons were demonstrated to be necessary for nicotine reward as measured by nicotine place preference, but not for another drug of addiction, cocaine. Alpha4-nAChRs are necessary for the anxiolytic effects of nicotine in the elevated plus maze and elimination of alpha4-beta2-nAChRs specifically from dopaminergic neurons decreased sensitivity to the anxiolytic effects of nicotine. Deletion of alpha4-nAChRs specifically from dopaminergic neurons also increased sensitivity to nicotine-induced locomotor depression, however nicotine-induced hypothermia was unaffected. This is the first work to develop a dopaminergic specific deletion of a nAChR subunit and examine resulting changes in nicotine behaviors. PMID:21795541

  20. [Behavioral characteristics of nicotine seeking: a role of the nicotine-conditioned effects and other mechanisms].

    PubMed

    Itasaka, Michio; Hironaka, Naoyuki; Miyata, Hisatsugu

    2015-06-01

    Nicotine dependence and its neural mechanisms have been well documented by pharmacological, behavioral and neuroscience studies. In this review, we introduce recent new findings in this theme, particularly on the role of nicotine -associated stimuli as non-pharmacological factors affecting maintaining/reinstating nicotine seeking. By using the techniques of drug self-administration and conditioned place preference, nicotine's specific property of forming seeking/taking behavior is well characterized, and the mechanisms of seeking/taking could be partly explained by discrete and/or contextual conditioned stimuli (dCS and cCS). After having the repeated Pavlovian conditioning in the training/conditioning sessions, CSs begin to play a key role for eliciting nicotine seeking behavior, with the activation of mesolimbic dopaminergic systems. In our study, intracranial self- stimulation (ICSS) was used to assess the mesolimbic dopamine activity. The nicotine-associated cCS also activated this neural system, which resulted in decreasing the ICSS threshold approximately 20% in the testing session under the cCS presentation. This finding would support the evidence of CS-induced incentive motivation for nicotine. According to the incentive salience hypothesis, the mesolimbic dopamine reflects the motivation elicited by incentives (CSs), and induces the drug seeking behavior, which is activated through amygdala--nucleus accumbens--medial prefrontal cortex circuit. Additionally, human brain imaging studies have revealed that tobacco- associated stimuli activate not only these regions, but also right temporo-parietal junction of human cortex, which is relevant to the visual attention. In summary, the above evidence shows that nicotine-conditioned stimuli might have powerful incentive salience and regulate nicotine seeking/taking behavior in animals and humans, though stress and nicotine-withdrawal could also enhance nicotine taking in the same way as other dependence -producing

  1. [Behavioral characteristics of nicotine seeking: a role of the nicotine-conditioned effects and other mechanisms].

    PubMed

    Itasaka, Michio; Hironaka, Naoyuki; Miyata, Hisatsugu

    2015-06-01

    Nicotine dependence and its neural mechanisms have been well documented by pharmacological, behavioral and neuroscience studies. In this review, we introduce recent new findings in this theme, particularly on the role of nicotine -associated stimuli as non-pharmacological factors affecting maintaining/reinstating nicotine seeking. By using the techniques of drug self-administration and conditioned place preference, nicotine's specific property of forming seeking/taking behavior is well characterized, and the mechanisms of seeking/taking could be partly explained by discrete and/or contextual conditioned stimuli (dCS and cCS). After having the repeated Pavlovian conditioning in the training/conditioning sessions, CSs begin to play a key role for eliciting nicotine seeking behavior, with the activation of mesolimbic dopaminergic systems. In our study, intracranial self- stimulation (ICSS) was used to assess the mesolimbic dopamine activity. The nicotine-associated cCS also activated this neural system, which resulted in decreasing the ICSS threshold approximately 20% in the testing session under the cCS presentation. This finding would support the evidence of CS-induced incentive motivation for nicotine. According to the incentive salience hypothesis, the mesolimbic dopamine reflects the motivation elicited by incentives (CSs), and induces the drug seeking behavior, which is activated through amygdala--nucleus accumbens--medial prefrontal cortex circuit. Additionally, human brain imaging studies have revealed that tobacco- associated stimuli activate not only these regions, but also right temporo-parietal junction of human cortex, which is relevant to the visual attention. In summary, the above evidence shows that nicotine-conditioned stimuli might have powerful incentive salience and regulate nicotine seeking/taking behavior in animals and humans, though stress and nicotine-withdrawal could also enhance nicotine taking in the same way as other dependence -producing

  2. Effects of chronic buspirone treatment on nicotine and concurrent nicotine+cocaine self-administration.

    PubMed

    Mello, Nancy K; Fivel, Peter A; Kohut, Stephen J

    2013-06-01

    Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal pharmacotherapy would reduce both cigarette smoking and cocaine abuse. Buspirone (Buspar) is a clinically available, non-benzodiazepine anxiolytic medication that acts on serotonin and dopamine systems. In preclinical studies, it reduced cocaine self-administration following both acute and chronic treatment in rhesus monkeys. The present study evaluated the effectiveness of chronic buspirone treatment on self-administration of intravenous (IV) nicotine and IV nicotine+cocaine combinations. Five cocaine-experienced adult rhesus monkeys (Macaca mulatta) were trained to self-administer nicotine or nicotine+cocaine combinations, and food pellets (1 g) during four 1-h daily sessions under a second-order schedule of reinforcement (FR 2 (VR16:S)). Each nicotine+cocaine combination maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05-0.001). Buspirone (0.032-0.56 mg/kg/h) was administered IV through one lumen of a double-lumen catheter every 20 min for 23 h each day, for 7-10 consecutive days. Each 7-10-day sequence of buspirone treatment was followed by saline-control treatment for at least 3 days until food- and drug-maintained responding returned to baseline. Buspirone dose-dependently reduced responding maintained by nicotine alone (0.001-0.1 mg/kg/inj; P<0.01) and by nicotine (0.001 or 0.0032 mg/kg/inj)+cocaine combinations (0.0032 mg/kg/inj; P<0.05-0.001) with no significant effects on food-maintained responding. We conclude that buspirone selectively attenuates the reinforcing effects of nicotine alone and nicotine+cocaine polydrug combinations in a nonhuman primate model of drug self-administration. PMID:23337868

  3. Negative affective states and cognitive impairments in nicotine dependence.

    PubMed

    Hall, F Scott; Der-Avakian, Andre; Gould, Thomas J; Markou, Athina; Shoaib, Mohammed; Young, Jared W

    2015-11-01

    Smokers have substantial individual differences in quit success in response to current treatments for nicotine dependence. This observation may suggest that different underlying motivations for continued tobacco use across individuals and nicotine cessation may require different treatments in different individuals. Although most animal models of nicotine dependence emphasize the positive reinforcing effects of nicotine as the major motivational force behind nicotine use, smokers generally report that other consequences of nicotine use, including the ability of nicotine to alleviate negative affective states or cognitive impairments, as reasons for continued smoking. These states could result from nicotine withdrawal, but also may be associated with premorbid differences in affective and/or cognitive function. Effects of nicotine on cognition and affect may alleviate these impairments regardless of their premorbid or postmorbid origin (e.g., before or after the development of nicotine dependence). The ability of nicotine to alleviate these symptoms would thus negatively reinforce behavior, and thus maintain subsequent nicotine use, contributing to the initiation of smoking, the progression to dependence and relapse during quit attempts. The human and animal studies reviewed here support the idea that self-medication for pre-morbid and withdrawal-induced impairments may be more important factors in nicotine addiction and relapse than has been previously appreciated in preclinical research into nicotine dependence. Given the diverse beneficial effects of nicotine under these conditions, individuals might smoke for quite different reasons. This review suggests that inter-individual differences in the diverse effects of nicotine associated with self-medication and negative reinforcement are an important consideration in studies attempting to understand the causes of nicotine addiction, as well as in the development of effective, individualized nicotine cessation

  4. Negative affective states and cognitive impairments in nicotine dependence.

    PubMed

    Hall, F Scott; Der-Avakian, Andre; Gould, Thomas J; Markou, Athina; Shoaib, Mohammed; Young, Jared W

    2015-11-01

    Smokers have substantial individual differences in quit success in response to current treatments for nicotine dependence. This observation may suggest that different underlying motivations for continued tobacco use across individuals and nicotine cessation may require different treatments in different individuals. Although most animal models of nicotine dependence emphasize the positive reinforcing effects of nicotine as the major motivational force behind nicotine use, smokers generally report that other consequences of nicotine use, including the ability of nicotine to alleviate negative affective states or cognitive impairments, as reasons for continued smoking. These states could result from nicotine withdrawal, but also may be associated with premorbid differences in affective and/or cognitive function. Effects of nicotine on cognition and affect may alleviate these impairments regardless of their premorbid or postmorbid origin (e.g., before or after the development of nicotine dependence). The ability of nicotine to alleviate these symptoms would thus negatively reinforce behavior, and thus maintain subsequent nicotine use, contributing to the initiation of smoking, the progression to dependence and relapse during quit attempts. The human and animal studies reviewed here support the idea that self-medication for pre-morbid and withdrawal-induced impairments may be more important factors in nicotine addiction and relapse than has been previously appreciated in preclinical research into nicotine dependence. Given the diverse beneficial effects of nicotine under these conditions, individuals might smoke for quite different reasons. This review suggests that inter-individual differences in the diverse effects of nicotine associated with self-medication and negative reinforcement are an important consideration in studies attempting to understand the causes of nicotine addiction, as well as in the development of effective, individualized nicotine cessation

  5. Onset of action of a lozenge containing flurbiprofen 8.75 mg: a randomized, double-blind, placebo-controlled trial with a new method for measuring onset of analgesic activity.

    PubMed

    Schachtel, Bernard; Aspley, Sue; Shephard, Adrian; Shea, Timothy; Smith, Gary; Sanner, Kathleen; Savino, Laurie; Rezuke, Jeanne; Schachtel, Emily

    2014-02-01

    A new onset-of-action model was utilized to distinguish the pharmacologic activity of flurbiprofen 8.75mg delivered in a lozenge from the demulcent effect of the lozenge base. In a randomized, double-blind, placebo-controlled trial, patients with sore throat rated pain on a Sore Throat Pain Intensity Scale before taking one flurbiprofen or placebo lozenge and at frequent (2-minute) intervals over the first hour after treatment. Further ratings of the Sore Throat Pain Intensity Scale and other patient-reported outcomes (difficulty swallowing, swollen throat, pain relief) were obtained at varying intervals over 6 hours. Onset of pharmacologic activity was defined as the median time of first perceived pain reduction if a patient reported clinically meaningful (at least moderate) relief. The conventional method of comparing mean treatment responses at each time point was also implemented. Demulcent action was detected at the first 2-minute assessment. By the new method, 102 flurbiprofen-treated patients were identified as first perceiving pain relief at 12 minutes, compared with >120 minutes by 102 patients using placebo (P<0.001). By the conventional method, mean percentage pain reduction for flurbiprofen 8.75 mg was first significantly differentiated from placebo at 26 minutes (P<0.05). Efficacy of flurbiprofen lozenge was demonstrated for 3.5-4hours on the 4 patient-reported outcomes (all P<0.05 compared with placebo). There were no serious adverse events. This patient-centered onset-of-action model identifies the initiation of pain relief in patients who are definite drug responders, here demonstrating that a flurbiprofen 8.75-mg lozenge provides early relief of sore throat.

  6. Efficacy and tolerability of an ectoine mouth and throat spray compared with those of saline lozenges in the treatment of acute pharyngitis and/or laryngitis: a prospective, controlled, observational clinical trial.

    PubMed

    Müller, Dörte; Lindemann, Torben; Shah-Hosseini, Kija; Scherner, Olaf; Knop, Markus; Bilstein, Andreas; Mösges, Ralph

    2016-09-01

    The aim of this observational trial was to evaluate the efficacy and tolerability of a mouth and throat spray containing ectoine in the treatment of acute pharyngitis and/or laryngitis. The outcome was compared with control treatment using saline lozenges. This study was designed as a prospective, controlled, non-randomized, observational multicenter clinical trial and was conducted in Germany. The study population consisted of 95 patients. The decision for treatment with either spray or lozenges was based on the patients' preference for pharyngeal or oral application. Investigators assessed symptoms specific to acute pharyngitis/laryngitis and determined the pharyngitis symptom score. Both patients and investigators evaluated the tolerability and efficacy of the treatment applied. Treatment with the spray showed higher efficacy, 1.95 ± 0.81 versus 1.68 ± 0.67 (investigators) and 1.97 ± 0.88 versus 1.57 ± 0.69 (patients, p < 0.05). Treatment with the spray resulted in significantly greater reduction of cervical lymph node swelling (p < 0.05), ∆ spray = 0.44 ± 0.62, ∆ lozenges = 0.21 ± 0.62. The lozenges showed some advantage in relieving cough, ∆ lozenges = 0.62 ± 0.94 versus ∆ spray = 0.44 ± 0.85. Both patients and investigators rated the tolerability of both medical devices as "good" to "very good". Adverse events of mild to moderate severity were either possibly related or not related to the medical devices used. No serious adverse events occurred. Taken together, while the tolerability was consistent in both treatment groups, the ectoine-based spray showed superior efficacy in treating acute pharyngitis and/or laryngitis. PMID:27126336

  7. Efficacy and tolerability of an ectoine mouth and throat spray compared with those of saline lozenges in the treatment of acute pharyngitis and/or laryngitis: a prospective, controlled, observational clinical trial.

    PubMed

    Müller, Dörte; Lindemann, Torben; Shah-Hosseini, Kija; Scherner, Olaf; Knop, Markus; Bilstein, Andreas; Mösges, Ralph

    2016-09-01

    The aim of this observational trial was to evaluate the efficacy and tolerability of a mouth and throat spray containing ectoine in the treatment of acute pharyngitis and/or laryngitis. The outcome was compared with control treatment using saline lozenges. This study was designed as a prospective, controlled, non-randomized, observational multicenter clinical trial and was conducted in Germany. The study population consisted of 95 patients. The decision for treatment with either spray or lozenges was based on the patients' preference for pharyngeal or oral application. Investigators assessed symptoms specific to acute pharyngitis/laryngitis and determined the pharyngitis symptom score. Both patients and investigators evaluated the tolerability and efficacy of the treatment applied. Treatment with the spray showed higher efficacy, 1.95 ± 0.81 versus 1.68 ± 0.67 (investigators) and 1.97 ± 0.88 versus 1.57 ± 0.69 (patients, p < 0.05). Treatment with the spray resulted in significantly greater reduction of cervical lymph node swelling (p < 0.05), ∆ spray = 0.44 ± 0.62, ∆ lozenges = 0.21 ± 0.62. The lozenges showed some advantage in relieving cough, ∆ lozenges = 0.62 ± 0.94 versus ∆ spray = 0.44 ± 0.85. Both patients and investigators rated the tolerability of both medical devices as "good" to "very good". Adverse events of mild to moderate severity were either possibly related or not related to the medical devices used. No serious adverse events occurred. Taken together, while the tolerability was consistent in both treatment groups, the ectoine-based spray showed superior efficacy in treating acute pharyngitis and/or laryngitis.

  8. Onset of action of a lozenge containing flurbiprofen 8.75 mg: a randomized, double-blind, placebo-controlled trial with a new method for measuring onset of analgesic activity.

    PubMed

    Schachtel, Bernard; Aspley, Sue; Shephard, Adrian; Shea, Timothy; Smith, Gary; Sanner, Kathleen; Savino, Laurie; Rezuke, Jeanne; Schachtel, Emily

    2014-02-01

    A new onset-of-action model was utilized to distinguish the pharmacologic activity of flurbiprofen 8.75mg delivered in a lozenge from the demulcent effect of the lozenge base. In a randomized, double-blind, placebo-controlled trial, patients with sore throat rated pain on a Sore Throat Pain Intensity Scale before taking one flurbiprofen or placebo lozenge and at frequent (2-minute) intervals over the first hour after treatment. Further ratings of the Sore Throat Pain Intensity Scale and other patient-reported outcomes (difficulty swallowing, swollen throat, pain relief) were obtained at varying intervals over 6 hours. Onset of pharmacologic activity was defined as the median time of first perceived pain reduction if a patient reported clinically meaningful (at least moderate) relief. The conventional method of comparing mean treatment responses at each time point was also implemented. Demulcent action was detected at the first 2-minute assessment. By the new method, 102 flurbiprofen-treated patients were identified as first perceiving pain relief at 12 minutes, compared with >120 minutes by 102 patients using placebo (P<0.001). By the conventional method, mean percentage pain reduction for flurbiprofen 8.75 mg was first significantly differentiated from placebo at 26 minutes (P<0.05). Efficacy of flurbiprofen lozenge was demonstrated for 3.5-4hours on the 4 patient-reported outcomes (all P<0.05 compared with placebo). There were no serious adverse events. This patient-centered onset-of-action model identifies the initiation of pain relief in patients who are definite drug responders, here demonstrating that a flurbiprofen 8.75-mg lozenge provides early relief of sore throat. PMID:24231654

  9. Structural, Electronic and Elastic Properties of MgH2, CaH2 and Ca4Mg3H14 for Hydrogen Storage Materials

    NASA Astrophysics Data System (ADS)

    Djellab, Sihem; Bouhadda, Youcef; Bououdina, Mohamed; Fenineche, Noureddine; Boudouma, Youcef

    2016-08-01

    The structural, electronic and elastic properties of MgH2, CaH2 and Ca4Mg3H14 have been determined using first principles calculation based on density functional theory. The calculated lattice constants were in good agreement with the experimental values. The electronic density of states revealed that these hydrides are insulators. The calculated elastic constants of MgH2, CaH2 and Ca4Mg3H14 indicated that these hydrides are mechanically stable at zero pressure. The bulk modulus B, shear modulus G, Young's modulus E, and Poisson's ratio ν were derived, and the ductility was discussed.

  10. Need for validation of Fagerstrom Test for Nicotine Dependence in Indian Context: Implications for Nicotine Replacement Therapy

    PubMed Central

    Sharma, Manoj Kumar; Sharma, Priyamvada

    2016-01-01

    Background: Variety of smokeable and chewable tobacco products with diverse nicotine content are used in India. Nicotine quantity in tobacco products has a direct bearing on developing tobacco dependence. The present work used this information to derive scores on the Fagerstrom test for nicotine dependence (FTND). It was used to determine the dosing of nicotine replacement treatment (NRT). Materials and Methods: Nicotine score quantitation was taken from the previous study. This data was applied to FTND to determine the relationship of nicotine content to the potential degree of dependence. Results: Application of nicotine quantitation to FTND in a hypothetical experiment significantly altered the scores from medium to high depending on the brand the used. Conclusion: Application of qunatitation of nicotine content in FTND score has implications for the assessment of tobacco dependence and NRT dose. The study implies validation of FTND using nicotine quantity in the consumed tobacco product as a scorable parameter in the FTND. PMID:27114620

  11. Inside-out neuropharmacology of nicotinic drugs.

    PubMed

    Henderson, Brandon J; Lester, Henry A

    2015-09-01

    Upregulation of neuronal nicotinic acetylcholine receptors (AChRs) is a venerable result of chronic exposure to nicotine; but it is one of several consequences of pharmacological chaperoning by nicotine and by some other nicotinic ligands, especially agonists. Nicotinic ligands permeate through cell membranes, bind to immature AChR oligomers, elicit incompletely understood conformational reorganizations, increase the interaction between adjacent AChR subunits, and enhance the maturation process toward stable AChR pentamers. These changes and stabilizations in turn lead to increases in both anterograde and retrograde traffic within the early secretory pathway. In addition to the eventual upregulation of AChRs at the plasma membrane, other effects of pharmacological chaperoning include modifications to endoplasmic reticulum stress and to the unfolded protein response. Because these processes depend on pharmacological chaperoning within intracellular organelles, we group them as "inside-out pharmacology". This term contrasts with the better-known, acute, "outside-in" effects of activating and desensitizing plasma membrane AChRs. We review current knowledge concerning the mechanisms and consequences of inside-out pharmacology. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID:25660637

  12. Hormones, nicotine, and cocaine: clinical studies.

    PubMed

    Mello, Nancy K

    2010-06-01

    Nicotine and cocaine each stimulate hypothalamic-pituitary-adrenal and -gonadal axis hormones, and there is increasing evidence that the hormonal milieu may modulate the abuse-related effects of these drugs. This review summarizes some clinical studies of the acute effects of cigarette smoking or IV cocaine on plasma drug and hormone levels and subjective effects ratings. The temporal covariance between these dependent measures was assessed with a rapid (2 min) sampling procedure in nicotine-dependent volunteers or current cocaine users. Cigarette smoking and IV cocaine each stimulated a rapid increase in LH and ACTH, followed by gradual increases in cortisol and DHEA. Positive subjective effects ratings increased immediately after initiation of cigarette smoking or IV cocaine administration. However, in contrast to cocaine's sustained positive effects (<20 min), ratings of "high" and "rush" began to decrease within one or two puffs of a high-nicotine cigarette while nicotine levels were increasing. Peak nicotine levels increased progressively after each of three successive cigarettes smoked at 60 min intervals, but the magnitude of the subjective effects ratings and peak ACTH and cortisol levels diminished. Only DHEA increased consistently after successive cigarettes. The possible influence of neuroactive hormones on nicotine dependence and cocaine abuse and the implications for treatment of these addictive disorders are discussed.

  13. Nicotine Chemistry, Metabolism, Kinetics and Biomarkers

    PubMed Central

    Hukkanen, Janne; Jacob, Peyton

    2010-01-01

    Nicotine underlies tobacco addiction, influences tobacco use patterns, and is used as a pharmacological aid to smoking cessation. The absorption, distribution and disposition characteristics of nicotine from tobacco and medicinal products are reviewed. Nicotine is metabolized primarily by the liver enzymes CYP2A6, UDP-glucuronosyltransfease (UGT), and flavin-containing monooxygenase (FMO). In addition to genetic factors, nicotine metabolism is influenced by diet and meals, age, sex, use of estrogen-containing hormone preparations, pregnancy and kidney disease, other medications, and smoking itself. Substantial racial/ethnic differences are observed in nicotine metabolism, which are likely influenced by both genetic and environmental factors. The most widely used biomarker of nicotine intake is cotinine, which may be measured in blood, urine, saliva, hair, or nails. The current optimal plasma cotinine cut-point to distinguish smokers from non-smokers in the general US population is 3 ng ml−1. This cut-point is much lower than that established 20 years ago, reflecting less secondhand smoke exposure due to clear air policies and more light or occasional smoking. PMID:19184645

  14. The α3β4* nicotinic acetylcholine receptor subtype mediates nicotine reward and physical nicotine withdrawal signs independently of the α5 subunit in the mouse

    PubMed Central

    Jackson, Kia J.; Sanjakdar, Sarah S.; Muldoon, Pretal P.; McIntosh, J. Michael; Damaj, M. Imad

    2013-01-01

    The 15q25 gene cluster contains genes that code for the α5, α3, and β4 nicotinic acetylcholine receptor (nAChRs) subunits, and in human genetic studies, has shown the most robust association with smoking behavior and nicotine dependence to date. The limited available animal studies implicate a role for the α5 and β4 nAChR subunits in nicotine dependence and withdrawal; however studies focusing on the behavioral role of the α3β4* nAChR receptor subtype in nicotine dependence are lacking. Because of the apparent role of the α3β4* nAChR subtype in nicotine dependence, the goal of the current study was to better evaluate the involvement of this subtype in nicotine mediated behavioral responses. Using the selective α3β4* nAChR antagonist, α-conotoxin AuIB, we assessed the role of α3β4* nAChRs in acute nicotine, nicotine reward, and physical and affective nicotine withdrawal. Because α5 has also been implicated in nicotine dependence behaviors in mice and can form functional receptors with α3β4*, we also evaluated the role of the α3β4α5* nAChR subtype in nicotine reward and somatic nicotine withdrawal signs by blocking the α3β4* nAChR subtype in α5 nAChR knockout mice with AuIB. AuIB had no significant effect on acute nicotine behaviors, but dose-dependently attenuated nicotine reward and physical withdrawal signs, with no significant effect in affective withdrawal measures. Interestingly, AuIB also attenuated nicotine reward and somatic signs in α5 nAChR knockout mice. This study shows that α3β4* nAChRs mediate nicotine reward and physical nicotine withdrawal, but not acute nicotine behaviors or affective nicotine withdrawal signs in mice. The α5 subunit is not required in the receptor assembly to mediate these effects. Our findings suggest an important role for the α3β4* nAChR subtype in nicotine reward and physical aspects of the nicotine withdrawal syndrome. PMID:23416040

  15. The α3β4* nicotinic acetylcholine receptor subtype mediates nicotine reward and physical nicotine withdrawal signs independently of the α5 subunit in the mouse.

    PubMed

    Jackson, Kia J; Sanjakdar, Sarah S; Muldoon, Pretal P; McIntosh, J Michael; Damaj, M Imad

    2013-07-01

    The 15q25 gene cluster contains genes that code for the α5, α3, and β4 nicotinic acetylcholine receptor (nAChRs) subunits, and in human genetic studies, has shown the most robust association with smoking behavior and nicotine dependence to date. The limited available animal studies implicate a role for the α5 and β4 nAChR subunits in nicotine dependence and withdrawal; however studies focusing on the behavioral role of the α3β4* nAChR receptor subtype in nicotine dependence are lacking. Because of the apparent role of the α3β4* nAChR subtype in nicotine dependence, the goal of the current study was to better evaluate the involvement of this subtype in nicotine mediated behavioral responses. Using the selective α3β4* nAChR antagonist, α-conotoxin AuIB, we assessed the role of α3β4* nAChRs in acute nicotine, nicotine reward, and physical and affective nicotine withdrawal. Because α5 has also been implicated in nicotine dependence behaviors in mice and can form functional receptors with α3β4*, we also evaluated the role of the α3β4α5* nAChR subtype in nicotine reward and somatic nicotine withdrawal signs by blocking the α3β4* nAChR subtype in α5 nAChR knockout mice with AuIB. AuIB had no significant effect on acute nicotine behaviors, but dose-dependently attenuated nicotine reward and physical withdrawal signs, with no significant effect in affective withdrawal measures. Interestingly, AuIB also attenuated nicotine reward and somatic signs in α5 nAChR knockout mice. This study shows that α3β4* nAChRs mediate nicotine reward and physical nicotine withdrawal, but not acute nicotine behaviors or affective nicotine withdrawal signs in mice. The α5 subunit is not required in the receptor assembly to mediate these effects. Our findings suggest an important role for the α3β4* nAChR subtype in nicotine reward and physical aspects of the nicotine withdrawal syndrome.

  16. Nicotine evokes kinetic tremor by activating the inferior olive via α7 nicotinic acetylcholine receptors.

    PubMed

    Kunisawa, Naofumi; Iha, Higor A; Shimizu, Saki; Tokudome, Kentaro; Mukai, Takahiro; Kinboshi, Masato; Serikawa, Tadao; Ohno, Yukihiro

    2016-11-01

    Nicotinic acetylcholine (nACh) receptors are implicated in the pathogenesis of movement disorders (e.g., tremor) and epilepsy. Here, we performed behavioral and immunohistochemical studies using mice and rats to elucidate the mechanisms underlying nicotine-induced tremor. Treatments of animals with nicotine (0.5-2mg/kg, i.p.) elicited kinetic tremor, which was completely suppressed by the nACh receptor antagonist mecamylamine (MEC). The specific α7 nACh receptor antagonist methyllycaconitine (MLA) also inhibited nicotine-induced tremor, whereas the α4β2 nACh antagonist dihydro-β-erythroidine (DHβE) or the peripheral α3β4 nACh antagonist hexamethonium showed no effects. Mapping analysis of Fos protein expression, a biological marker of neural excitation, revealed that a tremorgenic dose (1mg/kg) of nicotine region-specifically elevated Fos expression in the piriform cortex (PirC), medial habenula, solitary nucleus and inferior olive (IO) among 44 brain regions examined. In addition, similarly to the tremor responses, nicotine-induced Fos expression in the PirC and IO was selectively antagonized by MLA, but not by DHβE. Furthermore, an electrical lesioning of the IO, but not the PirC, significantly suppressed the induction of nicotine tremor. The present results suggest that nicotine elicits kinetic tremor in rodents by activating the IO neurons via α7 nACh receptors.

  17. Nicotine delivery and pharmacologic response from Verve, an oral nicotine delivery product.

    PubMed

    Koszowski, Bartosz; Viray, Lauren C; Stanfill, Stephen B; Lisko, Joseph G; Rosenberry, Zach R; Potts, Jennifer L; Pickworth, Wallace B

    2015-09-01

    Verve, an oral nicotine delivery product (ONDP), was introduced by Nu Mark (Altria Client Group, Richmond VA) for smokers to use in places where smoking is prohibited. This study assessed the effect of this ONDP on plasma nicotine levels, heart rate, product satisfaction, and ability to suppress smoking urge and cigarette cravings. Thirteen daily cigarette smokers [8 men and 5 women; average age 33.4years] attended two laboratory sessions, one occurred after overnight tobacco abstinence. Plasma samples were collected before and after ONDP use and measured for nicotine. In non-abstinent smokers, mean plasma nicotine levels increased from 18.3 to 21.0ng/mL. In abstinent smokers, average nicotine levels increased from 3.1 to 4.5ng/mL. After overnight tobacco abstinence, ONDP use significantly (p<0.01) increased heart rate from 69beats per minute (bpm) to 75bpm; while urge to smoke decreased significantly (p<0.01) from a score of 8.6 to 4.9. Participants indicated moderate product satisfaction that was not changed by tobacco abstinence. Analysis of unused ONDP revealed total nicotine levels of 1.68±0.09mg/disc. Spent ONDP discs were also analyzed to determine % nicotine liberated during chewing; results were 80% in the non-abstinent and 82% in the abstinent conditions (ns). Our study results indicate that ONDP use can increase plasma nicotine levels and heart rate and reduce cigarette cravings in abstinent smokers.

  18. NICOTINE EFFECTS ON THE ACTIVITY OF MICE EXPOSED PRENATALLY TO THE NICOTINIC AGONIST ANATOXIN-A.

    EPA Science Inventory

    Considerable research has shown long-lasting effects of early exposure in experimental animals to nicotine. Anatoxin-a is produced by cyanobacteria and has been shown to be a potent nicotinic agonist. This experiment evaluated the motor activity of adult mice, and their respons...

  19. [Nicotine effects on mitochondria membrane potential: participation of nicotinic acetylcholine receptors].

    PubMed

    Gergalova, G L; Skok, M V

    2011-01-01

    The effect of nicotine on the mouse liver mitochondria was studied by fluorescent flow cytometry. Mice consumed nicotine during 65 days; alternatively, nicotine was added to isolated mitochondria. Mitochondria of nicotine-treated mice had significantly lower basic levels of membrane potential and granularity as compared to those of the control group. Pre-incubation of the isolated mitochondria with nicotine prevented from dissipation of their membrane potential stimulated with 0.8 microM CaCl2 depending on the dose, and this effect was strengthened by the antagonist of alpha7 nicotinic receptors (alpha7 nAChR) methyllicaconitine. Mitochondria of mice intravenously injected with the antibodies against alpha7 nAChR demonstrated lower levels of membrane potential. Introduction of nicotine, choline, acetylcholine or synthetic alpha7 nAChR agonist PNU 282987 into the incubation medium inhibited Ca2+ accumulation in mitochondria, although the doses of agonists were too low to activate the alpha7 nAChR ion channel. It is concluded that nicotine consumption worsens the functional state of mitochondria by affecting their membrane potential and granularity, and this effect, at least in part, is mediated by alpha7 nAChR desensitization.

  20. The nicotine metabolite, cotinine, alters the assembly and trafficking of a subset of nicotinic acetylcholine receptors.

    PubMed

    Fox, Ashley M; Moonschi, Faruk H; Richards, Christopher I

    2015-10-01

    Exposure to nicotine alters the trafficking and assembly of nicotinic receptors (nAChRs), leading to their up-regulation on the plasma membrane. Although the mechanism is not fully understood, nicotine-induced up-regulation is believed to contribute to nicotine addiction. The effect of cotinine, the primary metabolite of nicotine, on nAChR trafficking and assembly has not been extensively investigated. We utilize a pH-sensitive variant of GFP, super ecliptic pHluorin, to differentiate between intracellular nAChRs and those expressed on the plasma membrane to quantify changes resulting from cotinine and nicotine exposure. Similar to nicotine, exposure to cotinine increases the number of α4β2 receptors on the plasma membrane and causes a redistribution of intracellular receptors. In contrast to this, cotinine exposure down-regulates α6β2β3 receptors. We also used single molecule fluorescence studies to show that cotinine and nicotine both alter the assembly of α4β2 receptors to favor the high sensitivity (α4)2(β2)3 stoichiometry.

  1. The Nicotine Metabolite, Cotinine, Alters the Assembly and Trafficking of a Subset of Nicotinic Acetylcholine Receptors*

    PubMed Central

    Fox, Ashley M.; Moonschi, Faruk H.; Richards, Christopher I.

    2015-01-01

    Exposure to nicotine alters the trafficking and assembly of nicotinic receptors (nAChRs), leading to their up-regulation on the plasma membrane. Although the mechanism is not fully understood, nicotine-induced up-regulation is believed to contribute to nicotine addiction. The effect of cotinine, the primary metabolite of nicotine, on nAChR trafficking and assembly has not been extensively investigated. We utilize a pH-sensitive variant of GFP, super ecliptic pHluorin, to differentiate between intracellular nAChRs and those expressed on the plasma membrane to quantify changes resulting from cotinine and nicotine exposure. Similar to nicotine, exposure to cotinine increases the number of α4β2 receptors on the plasma membrane and causes a redistribution of intracellular receptors. In contrast to this, cotinine exposure down-regulates α6β2β3 receptors. We also used single molecule fluorescence studies to show that cotinine and nicotine both alter the assembly of α4β2 receptors to favor the high sensitivity (α4)2(β2)3 stoichiometry. PMID:26269589

  2. Nicotine evokes kinetic tremor by activating the inferior olive via α7 nicotinic acetylcholine receptors.

    PubMed

    Kunisawa, Naofumi; Iha, Higor A; Shimizu, Saki; Tokudome, Kentaro; Mukai, Takahiro; Kinboshi, Masato; Serikawa, Tadao; Ohno, Yukihiro

    2016-11-01

    Nicotinic acetylcholine (nACh) receptors are implicated in the pathogenesis of movement disorders (e.g., tremor) and epilepsy. Here, we performed behavioral and immunohistochemical studies using mice and rats to elucidate the mechanisms underlying nicotine-induced tremor. Treatments of animals with nicotine (0.5-2mg/kg, i.p.) elicited kinetic tremor, which was completely suppressed by the nACh receptor antagonist mecamylamine (MEC). The specific α7 nACh receptor antagonist methyllycaconitine (MLA) also inhibited nicotine-induced tremor, whereas the α4β2 nACh antagonist dihydro-β-erythroidine (DHβE) or the peripheral α3β4 nACh antagonist hexamethonium showed no effects. Mapping analysis of Fos protein expression, a biological marker of neural excitation, revealed that a tremorgenic dose (1mg/kg) of nicotine region-specifically elevated Fos expression in the piriform cortex (PirC), medial habenula, solitary nucleus and inferior olive (IO) among 44 brain regions examined. In addition, similarly to the tremor responses, nicotine-induced Fos expression in the PirC and IO was selectively antagonized by MLA, but not by DHβE. Furthermore, an electrical lesioning of the IO, but not the PirC, significantly suppressed the induction of nicotine tremor. The present results suggest that nicotine elicits kinetic tremor in rodents by activating the IO neurons via α7 nACh receptors. PMID:27506652

  3. Nicotine induces fibrogenic changes in human liver via nicotinic acetylcholine receptors expressed on hepatic stellate cells

    SciTech Connect

    Soeda, Junpei; Morgan, Maelle; McKee, Chad; Mouralidarane, Angelina; Lin, ChingI; Roskams, Tania; Oben, Jude A.

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Cigarette smoke may induce liver fibrosis via nicotine receptors. Black-Right-Pointing-Pointer Nicotine induces proliferation of hepatic stellate cells (HSCs). Black-Right-Pointing-Pointer Nicotine activates hepatic fibrogenic pathways. Black-Right-Pointing-Pointer Nicotine receptor antagonists attenuate HSC proliferation. Black-Right-Pointing-Pointer Nicotinic receptor antagonists may have utility as novel anti-fibrotic agents. -- Abstract: Background and aims: Cigarette smoke (CS) may cause liver fibrosis but possible involved mechanisms are unclear. Among the many chemicals in CS is nicotine - which affects cells through nicotinic acetylcholine receptors (nAChR). We studied the effects of nicotine, and involved pathways, on human primary hepatic stellate cells (hHSCs), the principal fibrogenic cells in the liver. We then determined possible disease relevance by assaying nAChR in liver samples from human non-alcoholic steatohepatitis (NASH). Methods: hHSC were isolated from healthy human livers and nAChR expression analyzed - RT-PCR and Western blotting. Nicotine induction of hHSC proliferation, upregulation of collagen1-{alpha}2 and the pro-fibrogenic cytokine transforming growth factor beta 1 (TGF-{beta}1) was determined along with involved intracellular signaling pathways. nAChR mRNA expression was finally analyzed in whole liver biopsies obtained from patients diagnosed with non-alcoholic steatohepatitis (NASH). Results: hHSCs express muscle type ({alpha}1, {beta}1, delta and epsilon) and neuronal type ({alpha}3, {alpha}6, {alpha}7, {beta}2 and {beta}4) nAChR subunits at the mRNA level. Among these subunits, {alpha}3, {alpha}7, {beta}1 and {epsilon} were predominantly expressed as confirmed by Western blotting. Nicotine induced hHSC proliferation was attenuated by mecamylamine (p < 0.05). Additionally, collagen1-{alpha}2 and TGF-{beta}1 mRNA expression were significantly upregulated by nicotine and inhibited by

  4. Effects of chronic varenicline treatment on nicotine, cocaine, and concurrent nicotine+cocaine self-administration.

    PubMed

    Mello, Nancy K; Fivel, Peter A; Kohut, Stephen J; Carroll, F Ivy

    2014-04-01

    Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal treatment medication would reduce both cigarette smoking and cocaine abuse. Varenicline is a clinically available, partial agonist at α4β2* and α6β2* nicotinic acetylcholine receptors (nAChRs) and a full agonist at α7 nAChRs. Varenicline facilitates smoking cessation in clinical studies and reduced nicotine self-administration, and substituted for the nicotine-discriminative stimulus in preclinical studies. The present study examined the effects of chronic varenicline treatment on self-administration of IV nicotine, IV cocaine, IV nicotine+cocaine combinations, and concurrent food-maintained responding by five cocaine- and nicotine-experienced adult rhesus monkeys (Macaca mulatta). Varenicline (0.004-0.04 mg/kg/h) was administered intravenously every 20 min for 23 h each day for 7-10 consecutive days. Each varenicline treatment was followed by saline-control treatment until food- and drug-maintained responding returned to baseline. During control treatment, nicotine+cocaine combinations maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05-0.001). Varenicline dose-dependently reduced responding maintained by nicotine alone (0.0032 mg/kg/inj) (P<0.05), and in combination with cocaine (0.0032 mg/kg/inj) (P<0.05) with no significant effects on food-maintained responding. However, varenicline did not significantly decrease self-administration of a low dose of nicotine (0.001 mg/kg), cocaine alone (0.0032 and 0.01 mg/kg/inj), or 0.01 mg/kg cocaine combined with the same doses of nicotine. We conclude that varenicline selectively attenuates the reinforcing effects of nicotine alone but not cocaine alone, and its effects on nicotine+cocaine combinations are dependent on the dose of cocaine. PMID:24304823

  5. Nicotine Administration Attenuates Methamphetamine-Induced Novel Object Recognition Deficits

    PubMed Central

    Vieira-Brock, Paula L.; McFadden, Lisa M.; Nielsen, Shannon M.; Smith, Misty D.; Hanson, Glen R.

    2015-01-01

    Background: Previous studies have demonstrated that methamphetamine abuse leads to memory deficits and these are associated with relapse. Furthermore, extensive evidence indicates that nicotine prevents and/or improves memory deficits in different models of cognitive dysfunction and these nicotinic effects might be mediated by hippocampal or cortical nicotinic acetylcholine receptors. The present study investigated whether nicotine attenuates methamphetamine-induced novel object recognition deficits in rats and explored potential underlying mechanisms. Methods: Adolescent or adult male Sprague-Dawley rats received either nicotine water (10–75 μg/mL) or tap water for several weeks. Methamphetamine (4×7.5mg/kg/injection) or saline was administered either before or after chronic nicotine exposure. Novel object recognition was evaluated 6 days after methamphetamine or saline. Serotonin transporter function and density and α4β2 nicotinic acetylcholine receptor density were assessed on the following day. Results: Chronic nicotine intake via drinking water beginning during either adolescence or adulthood attenuated the novel object recognition deficits caused by a high-dose methamphetamine administration. Similarly, nicotine attenuated methamphetamine-induced deficits in novel object recognition when administered after methamphetamine treatment. However, nicotine did not attenuate the serotonergic deficits caused by methamphetamine in adults. Conversely, nicotine attenuated methamphetamine-induced deficits in α4β2 nicotinic acetylcholine receptor density in the hippocampal CA1 region. Furthermore, nicotine increased α4β2 nicotinic acetylcholine receptor density in the hippocampal CA3, dentate gyrus and perirhinal cortex in both saline- and methamphetamine-treated rats. Conclusions: Overall, these findings suggest that nicotine-induced increases in α4β2 nicotinic acetylcholine receptors in the hippocampus and perirhinal cortex might be one mechanism by which

  6. Differential rate responses to nicotine in rat heart: evidence for two classes of nicotinic receptors.

    PubMed

    Ji, Susan; Tosaka, Toshimasa; Whitfield, Bernard H; Katchman, Alexander N; Kandil, Abdurrahman; Knollmann, Bjoern C; Ebert, Steven N

    2002-06-01

    Nicotinic acetylcholine receptors are pentameric, typically being composed of two or more different subunits. To investigate which receptor subtypes are active in the heart, we initiated a series of experiments using an isolated perfused rat heart (Langendorff) preparation. Nicotine administration (100 microM) caused a brief decrease (-7 +/- 2%) followed by a much larger increase (17 +/- 5%) in heart rate that slowly returned to baseline within 10 to 15 min. The nicotine-induced decrease in heart rate could be abolished by an alpha7-specific antagonist, alpha-bungarotoxin (100 nM). In contrast, the nicotine-induced increase in heart rate persisted in the presence of alpha-bungarotoxin. These results suggest that the nicotinic acetylcholine receptors (nAChRs) that mediate the initial decrease in heart rate probably contain alpha7 subunits, whereas those that mediate the increase in heart rate probably do not contain alpha7 subunits. To investigate which subunits may contribute to the nicotine-induced increase in heart rate, we repeated our experiments with cytisine, an agonist at nAChRs that contain beta4 subunits. The cytisine results were similar to those obtained with nicotine, thereby suggesting that the nAChRs on sympathetic nerve terminals in the heart probably contain beta4 subunits. Thus, the results of this study show that pharmacologically distinct nAChRs are responsible for the differential effects of nicotine on heart rate. More specifically, our results suggest that alpha7 subunits participate in the initial nicotine-induced heart rate decrease, whereas beta4 subunits help to mediate the subsequent nicotine-induced rise in heart rate.

  7. Differential effects of non-nicotine tobacco constituent compounds on nicotine self-administration in rats.

    PubMed

    Hall, Brandon J; Wells, Corinne; Allenby, Cheyenne; Lin, Mung Yan; Hao, Ian; Marshall, Lindsey; Rose, Jed E; Levin, Edward D

    2014-05-01

    Tobacco smoking has been shown to be quite addictive in people. However, nicotine itself is a weak reinforcer compared to other commonly abused drugs, leading speculation that other factors contribute to the high prevalence of tobacco addiction in the human population. In addition to nicotine, there are over 5000 chemical compounds that have been identified in tobacco smoke, and more work is needed to ascertain their potential contributions to tobacco's highly addictive properties, or as potential candidates for smoking cessation treatment. In this study, we examined seven non-nicotine tobacco constituent compounds (anabasine, anatabine, nornicotine, myosmine, harmane, norharmane, and tyramine) for their effects on nicotine self-administration behavior in rats. Young adult female Sprague-Dawley rats were allowed to self-administer nicotine (0.03 mg/kg/50 μl infusion) under a fixed ratio-1 schedule of reinforcement. Each self-administration session lasted 45 min. Doses of each tobacco constituent compound were administered subcutaneously 10 min prior to the start of each session in a repeated measures, counterbalanced order two times. Anabasine displayed a biphasic dose-effect function. Pretreatment with 0.02 mg/kg anabasine resulted in a 25% increase in nicotine self-administration, while 2.0mg/kg of anabasine reduced nicotine infusions per session by over 50%. Pretreatment with 2.0mg/kg anatabine also significantly reduced nicotine self-administration by nearly half. These results suggest that some non-nicotine tobacco constituents may enhance or reduce nicotine's reinforcing properties. Also, depending upon the appropriate dose, some of these compounds may also serve as potential smoking cessation agents. PMID:24560911

  8. Donepezil, an acetylcholinesterase inhibitor, attenuates nicotine self-administration and reinstatement of nicotine seeking in rats.

    PubMed

    Kimmey, Blake A; Rupprecht, Laura E; Hayes, Matthew R; Schmidt, Heath D

    2014-07-01

    Nicotine craving and cognitive impairments represent core symptoms of nicotine withdrawal and predict relapse in abstinent smokers. Current smoking cessation pharmacotherapies have limited efficacy in preventing relapse and maintaining abstinence during withdrawal. Donepezil is an acetylcholinesterase inhibitor that has been shown previously to improve cognition in healthy non-treatment-seeking smokers. However, there are no studies examining the effects of donepezil on nicotine self-administration and/or the reinstatement of nicotine-seeking behavior in rodents. The present experiments were designed to determine the effects of acute donepezil administration on nicotine taking and the reinstatement of nicotine-seeking behavior, an animal model of relapse in abstinent human smokers. Moreover, the effects of acute donepezil administration on sucrose self-administration and sucrose seeking were also investigated in order to determine whether donepezil's effects generalized to other reinforced behaviors. Acute donepezil administration (1.0 or 3.0 mg/kg, i.p.) attenuated nicotine, but not sucrose self-administration maintained on a fixed-ratio 5 schedule of reinforcement. Donepezil administration also dose-dependently attenuated the reinstatement of both nicotine- and sucrose-seeking behaviors. Commonly reported adverse effects of donepezil treatment in humans are nausea and vomiting. However, at doses required to attenuate nicotine self-administration in rodents, no effects of donepezil on nausea/malaise as measured by pica were observed. Collectively, these results indicate that increased extracellular acetylcholine levels are sufficient to attenuate nicotine taking and seeking in rats and that these effects are not due to adverse malaise symptoms such as nausea.

  9. Nicotine Recruits Glutamate Receptors to Postsynaptic Sites

    PubMed Central

    Duan, Jing-jing; Lozada, Adrian F.; Gou, Chen-yu; Xu, Jing; Chen, Yuan; Berg, Darwin K.

    2015-01-01

    Cholinergic neurons project throughout the nervous system and activate nicotinic receptors to modulate synaptic function in ways that shape higher order brain function. The acute effects of nicotinic signaling on long-term synaptic plasticity have been well-characterized. Less well understood is how chronic exposure to low levels of nicotine, such as those encountered by habitual smokers, can alter neural connections to promote addiction and other lasting behavioral effects. We show here that chronic exposure of hippocampal neurons in culture to low levels of nicotine recruits AMPA and NMDA receptors to the cell surface and sequesters them at postsynaptic sites. The receptors include GluA2-containing AMPA receptors, which are responsible for most of the excitatory postsynaptic current mediated by AMPA receptors on the neurons, and include NMDA receptors containing GluN1 and GluN2B subunits. Moreover, we find that the nicotine treatment also increases expression of the presynaptic component synapsin 1 and arranges it in puncta juxtaposed to the additional AMPA and NMDA receptor puncta, suggestive of increases in synaptic contacts. Consistent with increased synaptic input, we find that the nicotine treatment leads to an increase in the excitatory postsynaptic currents mediated by AMPA and NMDA receptors. Further, the increases skew the ratio of excitatory-to-inhibitory input the cell receives, and this holds both for pyramidal neurons and inhibitory neurons in the hippocampal CA1 region. The GluN2B-containing NMDA receptor redistribution at synapses is associated with a significant increase in GluN2B phosphorylation at Tyr1472, a site known to prevent GluN2B endocytosis. These results suggest that chronic exposure to low levels of nicotine not only alters functional connections but also is likely to change excitability levels across networks. Further, it may increase the propensity for synaptic plasticity, given the increase in synaptic NMDA receptors. PMID:26365992

  10. Nicotine recruits glutamate receptors to postsynaptic sites.

    PubMed

    Duan, Jing-Jing; Lozada, Adrian F; Gou, Chen-Yu; Xu, Jing; Chen, Yuan; Berg, Darwin K

    2015-09-01

    Cholinergic neurons project throughout the nervous system and activate nicotinic receptors to modulate synaptic function in ways that shape higher order brain function. The acute effects of nicotinic signaling on long-term synaptic plasticity have been well-characterized. Less well understood is how chronic exposure to low levels of nicotine, such as those encountered by habitual smokers, can alter neural connections to promote addiction and other lasting behavioral effects. We show here that chronic exposure of hippocampal neurons in culture to low levels of nicotine recruits AMPA and NMDA receptors to the cell surface and sequesters them at postsynaptic sites. The receptors include GluA2-containing AMPA receptors, which are responsible for most of the excitatory postsynaptic current mediated by AMPA receptors on the neurons, and include NMDA receptors containing GluN1 and GluN2B subunits. Moreover, we find that the nicotine treatment also increases expression of the presynaptic component synapsin 1 and arranges it in puncta juxtaposed to the additional AMPA and NMDA receptor puncta, suggestive of increases in synaptic contacts. Consistent with increased synaptic input, we find that the nicotine treatment leads to an increase in the excitatory postsynaptic currents mediated by AMPA and NMDA receptors. Further, the increases skew the ratio of excitatory-to-inhibitory input that the cell receives, and this holds both for pyramidal neurons and inhibitory neurons in the hippocampal CA1 region. The GluN2B-containing NMDA receptor redistribution at synapses is associated with a significant increase in GluN2B phosphorylation at Tyr1472, a site known to prevent GluN2B endocytosis. These results suggest that chronic exposure to low levels of nicotine not only alters functional connections but also is likely to change excitability levels across networks. Further, it may increase the propensity for synaptic plasticity, given the increase in synaptic NMDA receptors.

  11. Null mutation of the β2 nicotinic acetylcholine receptor subunit attenuates nicotine withdrawal-induced anhedonia in mice.

    PubMed

    Stoker, Astrid K; Marks, Michael J; Markou, Athina

    2015-04-15

    The anhedonic signs of nicotine withdrawal are predictive of smoking relapse rates in humans. Identification of the neurobiological substrates that mediate anhedonia will provide insights into the genetic variations that underlie individual responses to smoking cessation and relapse. The present study assessed the role of β2 nicotinic acetylcholine receptor (nACh receptor) subunits in nicotine withdrawal-induced anhedonia using β2 nACh receptor subunit knockout (β2(-/-)) and wildtype (β2(+/+)) mice. Anhedonia was assessed with brain reward thresholds, defined as the current intensity that supports operant behavior in the discrete-trial current-intensity intracranial self-stimulation procedure. Nicotine was delivered chronically through osmotic minipumps for 28 days (40 mg/kg/day, base), and withdrawal was induced by either administering the broad-spectrum nicotinic receptor antagonist mecamylamine (i.e., antagonist-precipitated withdrawal) in mice chronically treated with nicotine or terminating chronic nicotine administration (i.e., spontaneous withdrawal). Mecamylamine (6 mg/kg, salt) significantly elevated brain reward thresholds in nicotine-treated β2(+/+) mice compared with saline-treated β2(+/+) mice and nicotine-treated β2(-/-) mice. Spontaneous nicotine withdrawal similarly resulted in significant elevations in thresholds in nicotine-withdrawing β2(+/+) mice compared with saline-treated β2(+/+) and nicotine-treated β2(-/-) mice, which remained at baseline levels. These results showed that precipitated and spontaneous nicotine withdrawal-induced anhedonia was attenuated in β2(-/-) mice. The reduced expression of anhedonic signs during nicotine withdrawal in β2(-/-) mice may have resulted from the lack of neuroadaptations in β2 nACh receptor subunit expression and function that may have occurred during either nicotine exposure or nicotine withdrawal in wildtype mice. In conclusion, individuals with genetic variations that result in diminished

  12. E-Cig Liquid Nicotine Containers Often Mislabeled

    MedlinePlus

    ... medlineplus.gov/news/fullstory_160108.html E-Cig Liquid Nicotine Containers Often Mislabeled Also, many aren't ... July 27, 2016 (HealthDay News) -- Containers that hold liquid nicotine for electronic cigarettes may not be labeled ...

  13. Intracerebellar behavioral interactions between nicotine, cotinine and ethanol in mice

    SciTech Connect

    Dar, M.S.; Li, C. )

    1992-02-26

    Using ethanol-induced motor incoordination as the test response as evaluated by rotorod, possible behavioral interactions between ethanol and (-)-nicotine in the cerebellum, one of the key motor area, were investigated. (-)-Nicotine, 5, 1.25, 0.625 ng/100nL intracerebellarly significantly attenuated motor incoordination due to ethanol in a dose-dependent manner. Similarly, (-)-cotinine, a major metabolite of nicotine, 5, 2.5, and 1.25 ng/100nL, significantly but less marked compared to (-)-nicotine attenuated ethanol-induced motor incoordination. The highest, 5 ng/100nL, dose of (-)-nicotine or (-)-cotinine followed by saline instead of ethanol did not alter normal motor coordination. The attenuation of ethanol-induced motor incoordination by (-)-nicotine and (-)- cotinine was blocked by intracerebellar hexamethonium 1 ug/100nL, a purported nicotinic cholinergic antagonist. The data obtained strongly suggest participation of cerebellar nicotinic cholinergic receptor in the ethanol-induced motor incoordination.

  14. Disentangling the nature of the nicotine stimulus.

    PubMed

    Bevins, Rick A; Barrett, Scott T; Polewan, Robert J; Pittenger, Steven T; Swalve, Natashia; Charntikov, Sergios

    2012-05-01

    Learning involving interoceptive stimuli likely plays an important role in many diseases and psychopathologies. Within this area, there has been extensive research investigating the interoceptive stimulus effects of abused drugs. In this pursuit, behavioral pharmacologists have taken advantage of what is known about learning processes and adapted the techniques to investigate the behavioral and receptor mechanisms of drug stimuli. Of particular interest is the nicotine stimulus and the use of the two-lever operant drug discrimination task and the Pavlovian drug discriminated goal-tracking task. There is strong concordance between the two methods when using "standard" testing protocols that minimize learning on test days. For example, ABT-418, nornicotine, and varenicline all fully evoked nicotine-appropriate responding. Notably, research from our laboratory with the discriminated goal-tracking task has used an alternative testing protocol. This protocol assesses stimulus substitution based on how well extinction learning using a non-nicotine ligand transfers back to the nicotine stimulus. These findings challenge conclusions based on more "standard" testing procedures (e.g., ABT-418 is not nicotine-like). As a starting point, we propose Thurstone scaling as a quantitative method for more precisely comparing transfer of extinction across doses, experiments, and investigators. We close with a discussion of future research directions and potential implications of the research for understanding interoceptive stimuli.

  15. Disentangling the nature of the nicotine stimulus✩

    PubMed Central

    Bevins, Rick A.; Barrett, Scott T.; Polewan, Robert J.; Pittenger, Steven T.; Swalve, Natashia; Charntikov, Sergios

    2011-01-01

    Learning involving interoceptive stimuli likely plays an important role in many diseases and psychopathologies. Within this area, there has been extensive research investigating the interoceptive stimulus effects of abused drugs. In this pursuit, behavioral pharmacologists have taken advantage of what is known about learning processes and adapted the techniques to investigate the behavioral and receptor mechanisms of drug stimuli. Of particular interest is the nicotine stimulus and the use of the two-lever operant drug discrimination task and the Pavlovian drug discriminated goal-tracking task. There is strong concordance between the two methods when using “standard” testing protocols that minimize learning on test days. For example, ABT-418, nornicotine, and varenicline all fully evoked nicotine-appropriate responding. Notably, research from our laboratory with the discriminated goal-tracking task has used an alternative testing protocol. This protocol assesses stimulus substitution based on how well extinction learning using a non-nicotine ligand transfers back to the nicotine stimulus. These findings challenge conclusions based on more “standard” testing procedures (e.g., ABT-418 is not nicotine-like). As a starting point, we propose Thurstone scaling as a quantitative method for more precisely comparing transfer of extinction across doses, experiments, and investigators. We close with a discussion of future research directions and potential implications of the research for understanding interoceptive stimuli. PMID:22119845

  16. [Anti-fertility effect of nicotine].

    PubMed

    Arabi, Mehran; Shareghi, Behzad

    2005-05-01

    In recent years, the quality of human sperm and its fertility potential have decreased dramatically. This may suggest that the quality of semen has deteriorated partly due to the effects of increasing toxic factors in the environment. Infertility remains a major problem in society, and recent data show that as many as one in four couples is trying to solve the problem. Male infertility accounts for 40% of infertility cases. Many environmental agents such as tobacco smoke and nicotine and genetic factors have been implicated in the poor sperm function and resultant infertility. The article is a review of the impacts of nicotine on human fertility potential. According to our results, nicotine is proved to be a potent pro-oxidant to the biological samples like spermatozoa population and is able to alter the fertility potential of man by inducing the membrane impairments, altering the GSH metabolism cycle, changing the sperm morphology and motility, and also inducing the DNA fragmentation. Antioxidant supplementation could reverse partially the negative effect of nicotine on sperm functions. However, further studies are necessary to illuminate the other dark sides of nicotinic infertility in human spermatozoa. PMID:15934452

  17. Inside-out neuropharmacology of nicotinic drugs

    PubMed Central

    Henderson, Brandon J.; Lester, Henry A.

    2015-01-01

    Upregulation of neuronal nicotinic acetylcholine receptors (AChRs) is a venerable result of chronic exposure to nicotine; but it is one of several consequences of pharmacological chaperoning by nicotine and by some other nicotinic ligands, especially agonists. Nicotinic ligands permeate through cell membranes, bind to immature AChR oligomers, elicit incompletely understood conformational reorganizations, increase the interaction between adjacent AChR subunits, and enhance the maturation process toward stable AChR pentamers. These changes and stabilizations in turn lead to increases in both anterograde and retrograde traffic within the early secretory pathway. In addition to the eventual upregulation of AChRs at the plasma membrane, other effects of pharmacological chaperoning include modifications to endoplasmic reticulum stress and to the unfolded protein response. Because these processes depend on pharmacological chaperoning within intracellular organelles, we group them as “inside-out pharmacology”. This term contrasts with the better-known, acute, “outside-in” effects of activating and desensitizing plasma membrane AChRs. We review current knowledge concerning the mechanisms and consequences of inside-out pharmacology. PMID:25660637

  18. Perinatal nicotine-induced transgenerational asthma.

    PubMed

    Rehan, Virender K; Liu, Jie; Sakurai, Reiko; Torday, John S

    2013-10-01

    Asthma is a major public health hazard worldwide. Its transgenerational inheritance has been inferred from epidemiological studies. More recently, using nicotine as a proxy for maternal smoking, we have demonstrated that an asthma-like phenotype can be inherited by rat offspring for up to two generations, i.e., multigenerationally, after the initial intrauterine exposure. We hypothesized that asthma transmission to offspring following perinatal nicotine exposure is not restricted up to F2 generation, but it also extends to subsequent generations. To test this hypothesis, using a well-established rat model of nicotine exposure-induced childhood asthma, we determined if perinatal nicotine exposure of F0 gestating dams would transmit asthma transgenerationally to F3 offspring. We now extend our findings to third-generation offspring, including abnormal pulmonary function, particularly as it relates to the occurrence in the upper airway exclusively in males, and to its effects on molecular functional markers (fibronectin and peroxisome proliferator-activated receptor γ), previously shown to be consistent with the asthma phenotype, herein expressed in fibroblasts isolated from the lung. These data, for the first time, demonstrate the transgenerational transmission of the asthma phenotype to F3 offspring following perinatal nicotine exposure of F0 dams. PMID:23911437

  19. Tobacco and Nicotine Product Testing

    PubMed Central

    Biener, Lois; Leischow, Scott J.; Zeller, Mitch R.

    2012-01-01

    Introduction: Tobacco product testing is a critical component of the Family Smoking Prevention and Tobacco Control Act (FSPTCA), which grants the Food and Drug Administration the authority to regulate tobacco products. The availability of methods and measures that can provide accurate data on the relative health risks across types of tobacco products, brands, and subbrands of tobacco products on the validity of any health claims associated with a product, and on how consumers perceive information on products toxicity or risks is crucial for making decisions on the product's potential impact on public health. These tools are also necessary for making assessments of the impact of new indications for medicinal products (other than cessation) but more importantly of tobacco products that may in the future be marketed as cessation tools. Objective: To identify research opportunities to develop empirically based and comprehensive methods and measures for testing tobacco and other nicotine-containing products so that the best science is available when decisions are made about products or policies. Methods: Literature was reviewed to address sections of the FSPTCA relevant to tobacco product evaluation; research questions were generated and then reviewed by a committee of research experts. Results: A research agenda was developed for tobacco product evaluation in the general areas of toxicity and health risks, abuse liability, consumer perception, and population effects. Conclusion: A cohesive, systematic, and comprehensive assessment of tobacco products is important and will require building consensus and addressing some crucial research questions. PMID:21460383

  20. Dopaminergic and cholinergic learning mechanisms in nicotine addiction

    PubMed Central

    Subramaniyan, Manivannan

    2015-01-01

    Nicotine addiction drives tobacco use by one billion people worldwide, causing nearly six million deaths a year. Nicotine binds to nicotinic acetylcholine receptors that are normally activated by the endogenous neurotransmitter acetylcholine. The widespread expression of nicotinic receptors throughout the nervous system accounts for the diverse physiological effects triggered by nicotine. A crucial influence of nicotine is on the synaptic mechanisms underlying learning that contribute to the addiction process. Here, we focus on the acquisition phase of smoking addiction and review animal model studies on how nicotine modifies dopaminergic and cholinergic signaling in key nodes of the reinforcement circuitry: ventral tegmental area, nucleus accumbens (NAc), amygdala, and hippocampus. Capitalizing on mechanisms that subserve natural rewards, nicotine activates midbrain dopamine neurons directly and indirectly, and nicotine causes dopamine release in very broad target areas throughout the brain, including the NAc, amygdala, and hippocampus. In addition, nicotine orchestrates local changes within those target structures, alters the release of virtually all major neurotransmitters, and primes the nervous system to the influence of other addictive drugs. Hence, understanding how nicotine affects the circuitry for synaptic plasticity and learning may aid in developing reasoned therapies to treat nicotine addiction. PMID:26301866

  1. Central administration of nicotine suppresses tracheobronchial cough in anesthetized cats.

    PubMed

    Poliacek, I; Rose, M J; Pitts, T E; Mortensen, A; Corrie, L W; Davenport, P W; Bolser, D C

    2015-02-01

    We tested the hypothesis that nicotine, which acts peripherally to promote coughing, might inhibit reflex cough at a central site. Nicotine was administered via the vertebral artery [intra-arterial (ia)] to the brain stem circulation and by microinjections into a restricted area of the caudal ventral respiratory column in 33 pentobarbital anesthetized, spontaneously breathing cats. The number of coughs induced by mechanical stimulation of the tracheobronchial airways; amplitudes of the diaphragm, abdominal muscle, and laryngeal muscles EMGs; and several temporal characteristics of cough were analyzed after administration of nicotine and compared with those during control and recovery period. (-)Nicotine (ia) reduced cough number, cough expiratory efforts, blood pressure, and heart rate in a dose-dependent manner. (-)Nicotine did not alter temporal characteristics of the cough motor pattern. Pretreatment with mecamylamine prevented the effect of (-)nicotine on blood pressure and heart rate, but did not block the antitussive action of this drug. (+)Nicotine was less potent than (-)nicotine for inhibition of cough. Microinjections of (-)nicotine into the caudal ventral respiratory column produced similar inhibitory effects on cough as administration of this isomer by the ia route. Mecamylamine microinjected in the region just before nicotine did not significantly reduce the cough suppressant effect of nicotine. Nicotinic acetylcholine receptors significantly modulate functions of brain stem and in particular caudal ventral respiratory column neurons involved in expression of the tracheobronchial cough reflex by a mecamylamine-insensitive mechanism.

  2. Nicotine Gum and Behavioral Treatment: A Placebo Controlled Trial.

    ERIC Educational Resources Information Center

    Hall, Sharon M.; And Others

    1987-01-01

    Assigned 139 subjects to intensive behavioral or to low-contact smoking treatment and to 2-milligram nicotine gum or to placebo gum in a 2x2 factorial design. Nicotine gum produced higher abstinence rates than did placebo. Subjects receiving low-contact condition plus nicotine gum had excellent abstinence rates at both 26 weeks and 52 weeks.…

  3. Central administration of nicotine suppresses tracheobronchial cough in anesthetized cats

    PubMed Central

    Rose, M. J.; Pitts, T. E.; Mortensen, A.; Corrie, L. W.; Davenport, P. W.; Bolser, D. C.

    2014-01-01

    We tested the hypothesis that nicotine, which acts peripherally to promote coughing, might inhibit reflex cough at a central site. Nicotine was administered via the vertebral artery [intra-arterial (ia)] to the brain stem circulation and by microinjections into a restricted area of the caudal ventral respiratory column in 33 pentobarbital anesthetized, spontaneously breathing cats. The number of coughs induced by mechanical stimulation of the tracheobronchial airways; amplitudes of the diaphragm, abdominal muscle, and laryngeal muscles EMGs; and several temporal characteristics of cough were analyzed after administration of nicotine and compared with those during control and recovery period. (−)Nicotine (ia) reduced cough number, cough expiratory efforts, blood pressure, and heart rate in a dose-dependent manner. (−)Nicotine did not alter temporal characteristics of the cough motor pattern. Pretreatment with mecamylamine prevented the effect of (−)nicotine on blood pressure and heart rate, but did not block the antitussive action of this drug. (+)Nicotine was less potent than (−)nicotine for inhibition of cough. Microinjections of (−)nicotine into the caudal ventral respiratory column produced similar inhibitory effects on cough as administration of this isomer by the ia route. Mecamylamine microinjected in the region just before nicotine did not significantly reduce the cough suppressant effect of nicotine. Nicotinic acetylcholine receptors significantly modulate functions of brain stem and in particular caudal ventral respiratory column neurons involved in expression of the tracheobronchial cough reflex by a mecamylamine-insensitive mechanism. PMID:25477349

  4. Central administration of nicotine suppresses tracheobronchial cough in anesthetized cats.

    PubMed

    Poliacek, I; Rose, M J; Pitts, T E; Mortensen, A; Corrie, L W; Davenport, P W; Bolser, D C

    2015-02-01

    We tested the hypothesis that nicotine, which acts peripherally to promote coughing, might inhibit reflex cough at a central site. Nicotine was administered via the vertebral artery [intra-arterial (ia)] to the brain stem circulation and by microinjections into a restricted area of the caudal ventral respiratory column in 33 pentobarbital anesthetized, spontaneously breathing cats. The number of coughs induced by mechanical stimulation of the tracheobronchial airways; amplitudes of the diaphragm, abdominal muscle, and laryngeal muscles EMGs; and several temporal characteristics of cough were analyzed after administration of nicotine and compared with those during control and recovery period. (-)Nicotine (ia) reduced cough number, cough expiratory efforts, blood pressure, and heart rate in a dose-dependent manner. (-)Nicotine did not alter temporal characteristics of the cough motor pattern. Pretreatment with mecamylamine prevented the effect of (-)nicotine on blood pressure and heart rate, but did not block the antitussive action of this drug. (+)Nicotine was less potent than (-)nicotine for inhibition of cough. Microinjections of (-)nicotine into the caudal ventral respiratory column produced similar inhibitory effects on cough as administration of this isomer by the ia route. Mecamylamine microinjected in the region just before nicotine did not significantly reduce the cough suppressant effect of nicotine. Nicotinic acetylcholine receptors significantly modulate functions of brain stem and in particular caudal ventral respiratory column neurons involved in expression of the tracheobronchial cough reflex by a mecamylamine-insensitive mechanism. PMID:25477349

  5. Genetic Factors for Enhancement of Nicotine Levels in Cultivated Tobacco.

    PubMed

    Wang, Bingwu; Lewis, Ramsey S; Shi, Junli; Song, Zhongbang; Gao, Yulong; Li, Wenzheng; Chen, Hongxia; Qu, Rongda

    2015-12-02

    Nicotine has practical applications relating to smoking cessation devices and alternative nicotine products. Genetic manipulation for increasing nicotine content in cultivated tobacco (Nicotiana tabacum L.) may be of value for industrial purposes, including the possibility of enhancing the efficiency of nicotine extraction. Biotechnological approaches have been evaluated in connection with this objective, but field-based results are few. Here, we report characterization of two genes encoding basic-helix-loop-helix (bHLH) transcription factors (TFs), NtMYC2a and NtMYC2b from tobacco. Overexpression of NtMYC2a increased leaf nicotine levels in T1 transgenic lines approximately 2.3-fold in greenhouse-grown plants of tobacco cultivar 'NC 95'. Subsequent field testing of T2 and T3 generations of transgenic NtMYC2a overexpression lines showed nicotine concentrations were 76% and 58% higher than control lines, respectively. These results demonstrated that the increased nicotine trait was stably inherited to the T2 and T3 generations, indicating the important role that NtMYC2a plays in regulating nicotine accumulation in N. tabacum and the great potential of NtMYC2a overexpression in tobacco plants for industrial nicotine production. Collected data in this study also indicated a negative feedback inhibition of nicotine biosynthesis. Further enhancement of nicotine accumulation in tobacco leaf may require modification of the processes of nicotine transport and deposition.

  6. Effects of caffeine on persistence and reinstatement of nicotine-seeking behavior in rats: interaction with nicotine-associated cues

    PubMed Central

    Jernigan, Courtney

    2013-01-01

    Rationale Caffeine and nicotine are the most commonly co-used psychostimulants. However, it is still unclear whether caffeine exposure enhances nicotine-seeking behavior. Objective The present study examined the effects of caffeine on nicotine-seeking in rats trained to self-administer nicotine with and without presession administration of caffeine. Methods Male Sprague–Dawley rats were trained to intravenously self-administer nicotine (0.03 mg/kg/infusion, freebase) on a fixed ratio 5 schedule of reinforcement and associate a stimulus cue with each nicotine administration. Five minutes before the sessions, the rats received an intraperitoneal administration of caffeine (5 mg/kg). Extinction tests were conducted under four conditions: presession caffeine administration, response-contingent presentation of nicotine cues, neither condition, or both conditions. Reinstatement tests were conducted after responding was extinguished by withholding presession caffeine, nicotine, and its cues. A separate group of rats trained without presession caffeine exposure was also subjected to the reinstatement tests. Results In the rats trained with presession caffeine exposure, continued caffeine administration sustained nicotine-seeking responses and interacted with nicotine cues to significantly delay the extinction of nicotine-seeking behavior. Readministration of caffeine after extinction effectively reinstated nicotine-seeking behavior. In caffeine-naive rats, caffeine administration did not reinstate extinguished nicotine-seeking behavior but significantly potentiated the cue-induced reinstatement of nicotine-seeking. Conclusion These data demonstrate that caffeine administration sustained and reinstated nicotine-seeking behavior, possibly via its acquired discriminative-stimulus properties predictive of nicotine availability. These findings suggest that smokers who attempt to quit may benefit from stopping caffeine consumption. PMID:21947355

  7. Subchronic nicotine exposure in adolescence induces long-term effects on hippocampal and striatal cannabinoid-CB1 and mu-opioid receptors in rats.

    PubMed

    Marco, Eva M; Granstrem, Oleg; Moreno, Enrique; Llorente, Ricardo; Adriani, Walter; Laviola, Giovanni; Viveros, Maria-Paz

    2007-02-14

    There is evidence for the existence of functional interactions between nicotine and cannabinoids and opioid compounds in adult experimental animals. However, there is scarce information about these relationships in young animals. In the present study we evaluated short and long-term effects of a subchronic nicotine treatment [0.4 mg/kg daily i.p. injections from postnatal day (PND) 34 to PND 43], upon hippocampal and striatal cannabinoid-CB(1) and mu-opioid receptors in Wistar rats of both genders. Rats were sacrificed 2 h after the last nicotine injection (short-term effects, PND 43) or one month later (long-term effects, PND 75). Hippocampal and striatal cannabinoid CB(1) and mu-opioid receptors were quantified by Western blotting. The subchronic nicotine treatment induced a region-dependent long-lasting effect in cannabinoid CB(1) receptor: a significant increase in hippocampal cannabinoid CB(1) receptors and a significant decrease in striatal cannabinoid CB(1) receptors, with these effects being similar in males and females. With respect to mu-opioid receptors, subchronic nicotine induced a significant down-regulation in hippocampal and striatal mu-opioid receptors in the long-term, and within the striatum the effects were more marked in adult males than in females. The present results indicate that juvenile nicotine taking may have implications for the endocannabinoid and endogenous opioid function and for the behaviors served by those systems, this includes possible modification of the response of adults to different psychotropic drugs, i.e. cannabis and morphine/heroin when taken later in life.

  8. r-bPiDI, an α6β2* Nicotinic Receptor Antagonist, Decreases Nicotine-Evoked Dopamine Release and Nicotine Reinforcement.

    PubMed

    Beckmann, Joshua S; Meyer, Andrew C; Pivavarchyk, M; Horton, David B; Zheng, Guangrong; Smith, Andrew M; Wooters, Thomas E; McIntosh, J Michael; Crooks, Peter A; Bardo, Michael T; Dwoskin, Linda P

    2015-10-01

    α6β2* nicotinic acetylcholine receptors (nAChRs) expressed by dopaminergic neurons mediate nicotine-evoked dopamine (DA) release and nicotine reinforcement. α6β2* antagonists inhibit these effects of nicotine, such that α6β2* receptors serve as therapeutic targets for nicotine addiction. The present research assessed the neuropharmacology of 1,10-bis(3-methyl-5,6-dihydropyridin-1(2H)-yl)decane (r-bPiDI), a novel small-molecule, tertiary amino analog of its parent compound, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI). bPiDI was previously shown to inhibit both nicotine-evoked DA release and the reinforcing effects of nicotine. In the current study, r-bPiDI inhibition of [(3)H]nicotine and [(3)H]methyllycaconitine binding sites was evaluated to assess interaction with the recognition binding sites on α4β2* and α7* nAChRs, respectively. Further, r-bPiDI inhibition of nicotine-evoked DA release in vitro in the absence and presence of α-conotoxin MII and following chronic in vivo nicotine administration were determined. The ability of r-bPiDI to decrease nicotine self-administration and food-maintained responding was also assessed. Results show that r-bPiDI did not inhibit [(3)H]nicotine or [(3)H]methyllycaconitine binding, but potently (IC50 = 37.5 nM) inhibited nicotine-evoked DA release from superfused striatal slices obtained from either drug naïve rats or from those repeatedly treated with nicotine. r-bPiDI inhibition of nicotine-evoked DA release was not different in the absence or presence of α-conotoxin MII, indicating that r-bPiDI acts as a potent, selective α6β2* nAChR antagonist. Acute systemic administration of r-bPiDI specifically decreased nicotine self-administration by 75 %, and did not alter food-maintained responding, demonstrating greater specificity relative to bPiDI and bPiDDB, as well as the tertiary amino analog r-bPiDDB. The current work describes the discovery of r-bPiDI, a tertiary amino, α-conotoxin MII-like small

  9. Investigations of Enantiopure Nicotine Haptens Using an Adjuvanting Carrier in Anti-Nicotine Vaccine Development.

    PubMed

    Jacob, Nicholas T; Lockner, Jonathan W; Schlosburg, Joel E; Ellis, Beverly A; Eubanks, Lisa M; Janda, Kim D

    2016-03-24

    Despite efforts to produce suitable smoking cessation aids, addiction to nicotine continues to carry a substantive risk of recidivism. An attractive alternative to current therapies is the pharmacokinetic strategy of antinicotine vaccination. A major hurdle in the development of the strategy has been to elicit a sufficiently high antibody concentration to curb nicotine distribution to the brain. Herein, we detail investigations into a new hapten design, which was able to elicit an antibody response of significantly higher specificity for nicotine. We also explore the use of a mutant flagellin carrier protein with adjuvanting properties. These studies underlie the feasibility of improvement in antinicotine vaccine formulations to move toward clinical efficacy.

  10. NICOTINE EFFECTS ON THE MOTOR ACTIVITY OF MICE EXPOSED PRENATALLY TO THE NICOTINIC AGONIST ANATOXIN-A.

    EPA Science Inventory

    Several studies in the literature have shown that exposure of mice and rats to nicotine early in development alters its effects when the rodents are subsequently challenged with nicotine. Anatoxin-a is a nicotinic agonist produced by several genera of cyanobacteria, and has caus...

  11. Nicotine-motivated behavior in Caenorhabditis elegans requires the nicotinic acetylcholine receptor subunits acr-5 and acr-15.

    PubMed

    Sellings, Laurie; Pereira, Schreiber; Qian, Cheng; Dixon-McDougall, Thomas; Nowak, Christina; Zhao, Bin; Tyndale, Rachel F; van der Kooy, Derek

    2013-03-01

    Signaling at nicotinic acetylcholine receptors in Caenorhabditis elegans controls many behaviors, including egg-laying and locomotor activity. Here, we show that C. elegans approaches a point source of nicotine in a time-, concentration- and age-dependent manner. Additionally, nicotine paired with butanone under starvation conditions prevented the reduced approach to butanone that is observed when butanone is paired with starvation alone and pairing with nicotine generates a preference for the tastes of either sodium or chloride over baseline. These results suggest nicotine acts as a rewarding substance in C. elegans. Furthermore, the nicotinic receptor antagonist mecamylamine, the smoking cessation pharmacotherapy varenicline, mutation of the dop-1 and dop-2 dopamine receptors, and mutations of either acr-5 or acr-15, two nicotinic receptor subunit genes with sequence homology to the mammalian α7 subunit, all reduced the nicotine approach behavior. These two mutants also were defective at associating the presence of nicotine with butanone under starvation conditions and acr-5 mutation could obviate the effect of pairing nicotine with salts. Furthermore, the approach deficit in acr-15 mutants was rescued by selective re-expression in a subset of neurons, but not in muscle. Caenorhabditis elegans may therefore serve as a useful model organism for nicotine-motivated behaviors that could aid in the identification of novel nicotine motivational molecular pathways and consequently the development of novel cessation aids.

  12. Alcohol, nicotine, caffeine, and mental disorders

    PubMed Central

    Crocq, Marc-Antoine

    2003-01-01

    Alcohol, nicotine, and caffeine are the most widely consumed psychotropic drugs worldwide. They are largely consumed by normal individuals, but their use is even more frequent in psychiatric patients, Thus, patients with schizophrenia tend to abuse all three substances. The interrelationships between depression and alcohol are complex. These drugs can all create dependence, as understood in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Alcohol abuse is clearly deleterious to the brain, provoking acute and chronic mental disorders, ranging from intoxication with impairment of cognition, to delirium tremens, halluosis, and dementia. In contrast, the main health consequences of nicotine, notably cancer and cardiovascular disases, lie outside the realm of psychiatry However, the mes of nicotine dependence and motivation to smoke or quit are of concern to psychiatrists. PMID:22033899

  13. Reinstatement and spontaneous recovery of nicotine seeking in rats.

    PubMed

    Shaham, Y; Adamson, L K; Grocki, S; Corrigall, W A

    1997-04-01

    Reinstatement and spontaneous recovery of previously extinguished nicotine-taking behavior were examined in rats. Male subjects were trained to self-administer nicotine (30 microg/kg per infusion, IV; one 60-min session per day for 3 weeks). Extinction sessions were then given for 5-10 days during which saline was substituted for nicotine. Subsequently, in the first set of tests for nicotine seeking, the reinstatement of lever presses that previously delivered nicotine was examined after priming injections of saline and nicotine (75, 150 and 300 microg/kg, SC; and 30 and 60 microg/kg, IV). In the second set of tests for nicotine-seeking, rats were tested after an additional 21-day drug-free period during which they were not exposed to the self-administration chambers (a test for the spontaneous recovery of drug seeking), and after priming injections of nicotine (150 and 300 microg/kg, SC). Reinstatement of extinguished food-reinforced behavior after exposure to nicotine was also determined. Priming injections of nicotine reinstated nicotine seeking regardless of the route of administration. In addition, previously extinguished nicotine seeking recovered spontaneously after a 21-day period during which rats were not exposed to the drug-taking environment. Nicotine also reinstated extinguished food-reinforced behavior in rats with a history of nicotine self-administration, but not in drug-naive rats. The present results extend previous work with opioid and stimulant drugs on reinstatement of drug seeking by the self-administered drug. It also appears that, as with other positive reinforcers, the mere passage of time is a sufficient condition for the spontaneous recovery of extinguished nicotine seeking.

  14. Binding, uptake, and release of nicotine by human gingival fibroblasts

    SciTech Connect

    Hanes, P.J.; Schuster, G.S.; Lubas, S. )

    1991-02-01

    Previous studies of the effects of nicotine on fibroblasts have reported an altered morphology and attachment of fibroblasts to substrates and disturbances in protein synthesis and secretion. This altered functional and attachment response may be associated with changes in the cell membrane resulting from binding of the nicotine, or to disturbances in cell metabolism as a result of high intracellular levels of nicotine. The purpose of the present study, therefore, was to (1) determine whether gingival fibroblasts bound nicotine and if any binding observed was specific or non-specific in nature; (2) determine whether gingival fibroblasts internalized nicotine, and if so, at what rate; (3) determine whether gingival fibroblasts also released nicotine back into the extracellular environment; and (4) if gingival fibroblasts release nicotine intact or as a metabolite. Cultures of gingival fibroblasts were prepared from gingival connective tissue biopsies. Binding was evaluated at 4{degree}C using a mixture of {sup 3}H-nicotine and unlabeled nicotine. Specific binding was calculated as the difference between {sup 3}H-nicotine bound in the presence and absence of unlabeled nicotine. The cells bound 1.44 (+/- 0.42) pmols/10(6) cells in the presence of unlabeled nicotine and 1.66 (+/- 0.55) pmols/10(6) cells in the absence of unlabeled nicotine. The difference was not significant. Uptake of nicotine was measured at 37{degree}C after treating cells with {sup 3}H-nicotine for time periods up to 4 hours. Uptake in pmols/10(6) cells was 4.90 (+/- 0.34) at 15 minutes, 8.30 (+/- 0.75) at 30 minutes, 12.28 (+/- 2.62) at 1 hour and 26.31 (+/- 1.15) at 4 hours.

  15. Estimating the activation energy of the displacement of Mg atoms in the channels of B25C4Mg1.42 crystals

    NASA Astrophysics Data System (ADS)

    Konovalikhin, S. V.; Ponomarev, V. I.

    2016-10-01

    The activation energy of displacement of Mg atoms through channels of B25C4Mg1.42 crystals is estimated using quantum chemical calculations (DFT (B3LYP potential), RHF, and UHF methods, 3-21G basis set) of the element of the structure modeling the channel and location of Mg atoms in it. The changes in the activation energy at the replacement of Mg atoms by Na and Li atoms were estimated. The greatest decreasing in the activation energy was detected for Li atoms. The obtained results can be regarded as a theoretical background for development of conducting systems based on B25C4Mg1.42 crystals.

  16. Blocking α4β2 and α7 nicotinic acetylcholine receptors inhibits the reinstatement of morphine-induced CPP by drug priming in mice.

    PubMed

    Feng, Bin; Xing, Jiang-hao; Jia, Dong; Liu, Shui-bing; Guo, Hong-ju; Li, Xiao-qiang; He, Xiao-sheng; Zhao, Ming-gao

    2011-06-20

    Investigating the interaction between nicotinic and opioid receptors is of great interest for both basic mechanistic and clinical reasons. Morphine and nicotine, two common drugs of abuse, share several behavioral and rewarding properties. However, little is known about the subtypes of nicotinic acetylcholine receptors (nAChR) in the reinstatement of morphine-induced conditioned place preference (CPP). In this study, we found that a non-specific nAChR agonist, nicotine (0.5mg/kg), had no effects on the reinstatement of morphine-induced CPP. However, we found that pretreatment with specific α(4)β(2) and α(7) nAChR subtype antagonists, dihydroxy-β-erithroidine (DHβE, 5mg/kg) and methyllycaconitine (MLA, 4 mg/kg), 20 min prior to administration of morphine, inhibited the reinstatement of morphine-induced CPP by drug priming in mice. Furthermore, depression of the reinstatement of morphine-induced CPP by a single DHβE or MLA treatment lasted at least three days later when the reinstatement was induced by morphine priming. The data suggest that specific nAChR subtypes, i.e., α(4)β(2) and α(7), may contribute to the reinstatement of morphine-induced CPP by drug priming in mice.

  17. Cardiovascular toxicity of nicotine: Implications for electronic cigarette use.

    PubMed

    Benowitz, Neal L; Burbank, Andrea D

    2016-08-01

    The cardiovascular safety of nicotine is an important question in the current debate on the benefits vs. risks of electronic cigarettes and related public health policy. Nicotine exerts pharmacologic effects that could contribute to acute cardiovascular events and accelerated atherogenesis experienced by cigarette smokers. Studies of nicotine medications and smokeless tobacco indicate that the risks of nicotine without tobacco combustion products (cigarette smoke) are low compared to cigarette smoking, but are still of concern in people with cardiovascular disease. Electronic cigarettes deliver nicotine without combustion of tobacco and appear to pose low-cardiovascular risk, at least with short-term use, in healthy users. PMID:27079891

  18. Nicotine effects on skin: are they positive or negative?

    PubMed

    Misery, Laurent

    2004-11-01

    The adverse effects of tobacco on the skin are well known but the role of nicotine is more controversial. Nicotinic receptors are expressed in the skin, on keratinocytes, fibroblasts and blood vessels. Nicotine induces vasoconstriction associated with local hyperaemia. It inhibits inflammation through effects on central and peripheral nervous system and through direct effect on immune cells. It delays wound healing and accelerates skin aging. The role of nicotine on skin diseases remains unclear. Therapeutic effects of nicotine could be possible and this a new stimulating field of research.

  19. High capacity multicomponent hydrogen storage materials: Investigation of the effect of stoichiometry and decomposition conditions on the cycling behaviour of LiBH 4-MgH 2

    NASA Astrophysics Data System (ADS)

    Walker, Gavin S.; Grant, David M.; Price, Tobias C.; Yu, Xuebin; Legrand, Vincent

    LiBH 4-MgH 2 is an attractive reversible hydrogen storage system, it combines two high capacity hydrides (18.3 and 7.6 wt.%, respectively) and the concerted dehydrogenation reaction has a smaller enthalpy change than either species on its own. The latter effect leads to a destabilisation of the hydrided products and results in a lowering of the dehydrogenation temperature. In situ neutron diffraction experiments have been undertaken to characterise the mechanism of decomposition of the LiBD 4-MgD 2 system, with an emphasis on investigating the synergistic effects of the components during cycling under various conditions. This study compares the effect of stoichiometry of the multicomponent system on the cycling mechanism. Results show that LiBD 4-MgD 2 in a 2:1 molar ratio can be reversibly dehydrogenated under low pressures of hydrogen or under vacuum, contrary to earlier reports in the literature, although the reaction was only partially reversed for the 2:1 mixture decomposed under vacuum. This work shows that the reaction pathway was affected by dehydrogenation conditions, but the stoichiometry of the multicomponent system played a minor role.

  20. Prenatal nicotine exposure alters the types of nicotinic receptors that facilitate excitatory inputs to cardiac vagal neurons.

    PubMed

    Huang, Zheng-Gui; Wang, Xin; Evans, Cory; Gold, Allison; Bouairi, Evguenia; Mendelowitz, David

    2004-10-01

    Nicotinic receptors play an important role in modulating the activity of parasympathetic cardiac vagal neurons in the medulla. Previous work has shown nicotine acts via at least three mechanisms to excite brain stem premotor cardiac vagal neurons. Nicotine evokes a direct increase in holding current and facilitates both the frequency and amplitude of glutamatergic neurotransmission to cardiac vagal neurons. This study tests whether these nicotinic receptor-mediated responses are endogenously active, whether alpha4beta2 and alpha7 nicotinic receptors are involved, and whether prenatal exposure to nicotine alters the magnitude of these responses and the types of nicotinic receptors involved. Application of neostigmine (10 microM) significantly increased the holding current, amplitude, and frequency of miniature excitatory postsynaptic current (mEPSC) glutamatergic events in cardiac vagal neurons. In unexposed animals, the nicotine-evoked facilitation of mEPSC frequency, but not mEPSC amplitude or holding current, was blocked by alpha-bungarotoxin (100 nM). Prenatal nicotine exposure significantly exaggerated and altered the types of nicotinic receptors involved in these responses. In prenatal nicotine-exposed animals, alpha-bungarotoxin only partially reduced the increase in mEPSC frequency. In addition, in prenatal nicotine-exposed animals, the increase in holding current was partially dependent on alpha-7 subunit-containing nicotinic receptors, in contrast to unexposed animals in which alpha-bungarotoxin had no effect. These results indicate prenatal nicotine exposure, one of the highest risk factors for sudden infant death syndrome (SIDS), exaggerates the responses and changes the types of nicotinic receptors involved in exciting premotor cardiac vagal neurons. These alterations could be responsible for the pronounced bradycardia that occurs during apnea in SIDS victims.

  1. Electronic cigarettes and nicotine dependence: evolving products, evolving problems.

    PubMed

    Cobb, Caroline O; Hendricks, Peter S; Eissenberg, Thomas

    2015-05-21

    Electronic cigarettes (ECIGs) use an electric heater to aerosolize a liquid that usually contains propylene glycol, vegetable glycerin, flavorants, and the dependence-producing drug nicotine. ECIG-induced nicotine dependence has become an important concern, as some ECIGs deliver very little nicotine while some may exceed the nicotine delivery profile of a tobacco cigarette. This variability is relevant to tobacco cigarette smokers who try to switch to ECIGs. Products with very low nicotine delivery may not substitute for tobacco cigarettes, so that ECIG use is accompanied by little reduced risk of cigarette-caused disease. Products with very high nicotine delivery may make quitting ECIGs particularly difficult should users decide to try. For non-smokers, the wide variability of ECIGs on the market is especially troublesome: low nicotine products may lead them to initiate nicotine self-administration and progress to higher dosing ECIGs or other products, and those that deliver more nicotine may produce nicotine dependence where it was not otherwise present. External regulatory action, guided by strong science, may be required to ensure that population-level nicotine dependence does not rise.

  2. Cortical control of VTA function and influence on nicotine reward.

    PubMed

    Wu, Jie; Gao, Ming; Shen, Jian-Xin; Shi, Wei-Xing; Oster, Andrew M; Gutkin, Boris S

    2013-10-15

    Tobacco use is a major public health problem. Nicotine acts on widely distributed nicotinic acetylcholine receptors (nAChRs) in the brain and excites dopamine (DA) neurons in the ventral tegmental area (VTA). The elicited increase of DA neuronal activity is thought to be an important mechanism for nicotine reward and subsequently the transition to addiction. However, the current understanding of nicotine reward is based predominantly on the data accumulated from in vitro studies, often from VTA slices. Isolated VTA slices artificially terminate communications between neurons in the VTA and other brain regions that may significantly alter nicotinic effects. Consequently, the mechanisms of nicotinic excitation of VTA DA neurons under in vivo conditions have received only limited attention. Building upon the existing knowledge acquired in vitro, it is now time to elucidate the integrated mechanisms of nicotinic reward on intact systems that are more relevant to understanding the action of nicotine or other addictive drugs. In this review, we summarize recent studies that demonstrate the impact of prefrontal cortex (PFC) on the modulation of VTA DA neuronal function and nicotine reward. Based on existing evidence, we propose a new hypothesis that PFC-VTA functional coupling serves as an integration mechanism for nicotine reward. Moreover, addiction may develop due to nicotine perturbing the PFC-VTA coupling and thereby eliminating the PFC-dependent cognitive control over behavior.

  3. Neuroimaging, Genetics and the Treatment of Nicotine Addiction

    PubMed Central

    Ray, Riju; Loughead, James; Wang, Ze; Detre, John; Yang, Edward; Gur, Ruben; Lerman, Caryn

    2008-01-01

    Advances in neuroimaging and genomics provide an unprecedented opportunity to accelerate medication development for nicotine dependence and other addictions. Neuroimaging studies have begun to elucidate the functional neuroanatomy and neurochemistry underlying effects of nicotine and nicotine abstinence. In parallel, genetic studies, including both candidate gene and genome-wide association approaches, are identifying key neurobiological targets and pathways important in addiction to nicotine. To date, only a few neuroimaging studies have explored effects of nicotine or abstinence on brain activity as a function of genotype. Most analyses of genotype are retrospective, resulting in small sample sizes for testing effects of the minor alleles for candidate genes. The purpose of this review is to provide an outline of the work in neuroimaging, genetics, and nicotine dependence, and to explore the potential for increased integration of these approaches to improve nicotine dependence treatment. PMID:18599130

  4. Cholinergic modulation of dopamine pathways through nicotinic acetylcholine receptors.

    PubMed

    de Kloet, Sybren F; Mansvelder, Huibert D; De Vries, Taco J

    2015-10-15

    Nicotine addiction is highly prevalent in current society and is often comorbid with other diseases. In the central nervous system, nicotine acts as an agonist for nicotinic acetylcholine receptors (nAChRs) and its effects depend on location and receptor composition. Although nicotinic receptors are found in most brain regions, many studies on addiction have focused on the mesolimbic system and its reported behavioral correlates such as reward processing and reinforcement learning. Profound modulatory cholinergic input from the pedunculopontine and laterodorsal tegmentum to dopaminergic midbrain nuclei as well as local cholinergic interneuron projections to dopamine neuron axons in the striatum may play a major role in the effects of nicotine. Moreover, an indirect mesocorticolimbic feedback loop involving the medial prefrontal cortex may be involved in behavioral characteristics of nicotine addiction. Therefore, this review will highlight current understanding of the effects of nicotine on the function of mesolimbic and mesocortical dopamine projections in the mesocorticolimbic circuit. PMID:26208783

  5. Structure of neat and hydrated liquid nicotine and laser resonant desorption of clusters from nicotine-water solutions

    NASA Astrophysics Data System (ADS)

    Mihesan, Claudia; Ziskind, Michael; Focsa, Cristian; Seydou, Mahamadou; Lecomte, Frédéric; Schermann, Jean Pierre

    2008-11-01

    The microscopic structures of neat liquid nicotine and nicotine-water mixtures are examined through infrared spectroscopy and laser resonant desorption mass-spectroscopy. The infrared spectra of the solutions are analyzed using DFT calculations of homogenous and mixed hydrogen-bonded clusters. Neat nicotine and hydrated nicotine cluster are experimentally observed through IR laser resonant desorption of a nicotine/water ice mixture followed by laser ionization mass-spectrometry. A sizable fraction of those cluster ions is the result of laser ionization of small neutral clusters already present in the sample.

  6. REINFORCEMENT ENHANCING EFFECTS OF ACUTE NICOTINE VIA ELECTRONIC CIGARETTES

    PubMed Central

    Perkins, Kenneth A.; Karelitz, Joshua L.; Michael, Valerie C.

    2015-01-01

    Background Recent human studies confirm animal research showing that nicotine enhances reinforcement from rewards unrelated to nicotine. These effects of acute nicotine via tobacco smoking may also occur when consumed from non-tobacco products. Methods We assessed acute effects of nicotine via electronic cigarettes (“e-cigarettes”) on responding reinforced by music, video, or monetary rewards, or for no reward (control). In a fully within-subjects design, adult dependent smokers (N=28) participated in three similar experimental sessions, each following overnight abstinence (verified by CO≤10 ppm). Varying only in e-cigarette condition, sessions involved controlled exposure to a nicotine (labeled “36 mg/ml”) or placebo (“0”) e-cigarette, or no e-cigarette use. A fourth session involved smoking one’s own tobacco cigarette brand after no abstinence, specifically to compare responses under typical nicotine satiation with these acute e-cigarette conditions after abstinence. Results Reinforced responding for video reward, but not the other rewards, was greater due to use of the nicotine versus placebo e-cigarette (i.e., nicotine per se), while no differences were found between the placebo e-cigarette and no e-cigarette conditions (i.e., e-cigarette use per se). For nicotine via tobacco smoking, responding compared to the nicotine e-cigarette was similar for video but greater for music, while both video and music reward were enhanced relative to the non-nicotine conditions (placebo and no e-cigarette). Conclusions Acute nicotine from a non-tobacco product has some reinforcement enhancing effects in humans, in a manner partly consistent with nicotine via tobacco smoking and perhaps contributing to the rising popularity of nicotine e-cigarette use. PMID:26070455

  7. Nicotine Activation of α4* Receptors: Sufficient for Reward, Tolerance, and Sensitization

    NASA Astrophysics Data System (ADS)

    Tapper, Andrew R.; McKinney, Sheri L.; Nashmi, Raad; Schwarz, Johannes; Deshpande, Purnima; Labarca, Cesar; Whiteaker, Paul; Marks, Michael J.; Collins, Allan C.; Lester, Henry A.

    2004-11-01

    The identity of nicotinic receptor subtypes sufficient to elicit both the acute and chronic effects of nicotine dependence is unknown. We engineered mutant mice with α4 nicotinic subunits containing a single point mutation, Leu9' --> Ala9' in the pore-forming M2 domain, rendering α4* receptors hypersensitive to nicotine. Selective activation of α4* nicotinic acetylcholine receptors with low doses of agonist recapitulates nicotine effects thought to be important in dependence, including reinforcement in response to acute nicotine administration, as well as tolerance and sensitization elicited by chronic nicotine administration. These data indicate that activation of α4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization.

  8. Nicotine, adolescence, and stress: A review of how stress can modulate the negative consequences of adolescent nicotine abuse.

    PubMed

    Holliday, Erica; Gould, Thomas J

    2016-06-01

    In order to continue the decline of smoking prevalence, it is imperative to identify factors that contribute to the development of nicotine and tobacco addiction, such as adolescent initiation of nicotine use, adolescent stress, and their interaction. This review highlights the biological differences between adolescent and adults in nicotine use and resulting effects, and examines the enduring consequences of adolescent nicotine administration. A review of both clinical and preclinical literature indicates that adolescent, but not adult, nicotine administration leads to increased susceptibility for development of long-lasting impairments in learning and affect. Finally, the role stress plays in normal adolescent development, the deleterious effects stress has on learning and memory, and the negative consequences resulting from the interaction of stress and nicotine during adolescence is reviewed. The review concludes with ways in which future policies could benefit by addressing adolescent stress as a means of reducing adolescent nicotine abuse.

  9. The Oncogenic Functions of Nicotinic Acetylcholine Receptors

    PubMed Central

    Zhao, Yue

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) are ion channels that are expressed in the cell membrane of all mammalian cells, including cancer cells. Recent findings suggest that nAChRs not only mediate nicotine addiction in the brain but also contribute to the development and progression of cancers directly induced by nicotine and its derived carcinogenic nitrosamines whereas deregulation of the nAChRs is observed in many cancers, and genome-wide association studies (GWAS) indicate that SNPs nAChRs associate with risks of lung cancers and nicotine addiction. Emerging evidences suggest nAChRs are posited at the central regulatory loops of numerous cell growth and prosurvival signal pathways and also mediate the synthesis and release of stimulatory and inhibitory neurotransmitters induced by their agonists. Thus nAChRs mediated cell signaling plays an important role in stimulating the growth and angiogenic and neurogenic factors and mediating oncogenic signal transduction during cancer development in a cell type specific manner. In this review, we provide an integrated view of nAChRs signaling in cancer, heightening on the oncogenic properties of nAChRs that may be targeted for cancer treatment. PMID:26981122

  10. The Oncogenic Functions of Nicotinic Acetylcholine Receptors.

    PubMed

    Zhao, Yue

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) are ion channels that are expressed in the cell membrane of all mammalian cells, including cancer cells. Recent findings suggest that nAChRs not only mediate nicotine addiction in the brain but also contribute to the development and progression of cancers directly induced by nicotine and its derived carcinogenic nitrosamines whereas deregulation of the nAChRs is observed in many cancers, and genome-wide association studies (GWAS) indicate that SNPs nAChRs associate with risks of lung cancers and nicotine addiction. Emerging evidences suggest nAChRs are posited at the central regulatory loops of numerous cell growth and prosurvival signal pathways and also mediate the synthesis and release of stimulatory and inhibitory neurotransmitters induced by their agonists. Thus nAChRs mediated cell signaling plays an important role in stimulating the growth and angiogenic and neurogenic factors and mediating oncogenic signal transduction during cancer development in a cell type specific manner. In this review, we provide an integrated view of nAChRs signaling in cancer, heightening on the oncogenic properties of nAChRs that may be targeted for cancer treatment. PMID:26981122

  11. Nicotinic Acetylcholine Receptors in Sensory Cortex

    ERIC Educational Resources Information Center

    Metherate, Raju

    2004-01-01

    Acetylcholine release in sensory neocortex contributes to higher-order sensory function, in part by activating nicotinic acetylcholine receptors (nAChRs). Molecular studies have revealed a bewildering array of nAChR subtypes and cellular actions; however, there is some consensus emerging about the major nAChR subtypes and their functions in…

  12. Nicotine delays puberty in male rat.

    PubMed

    Londonkar, R L; Sonar, A; Patil, S; Patil, S B

    2000-01-01

    Immature male albino rats, 30 days of age, were treated with 0.3 mg nicotine/100 g body weight either orally or intraperitoneally for 30 days. All the animals were autopsied on the 61 st day, by which time they were sexually mature. Testis, epididymis, seminal vesicle, prostate gland and vas deferens were dissected out, weighed, and processed for biochemical and histological studies. Weight of testis and accessory sex organs of nicotine treated group was significantly reduced. The total cholesterol content was increased while protein, DNA and RNA contents were decreased. The acid phosphatase content was also decreased whereas that of alkaline phosphatase was increased. The surface epithelial cell height of accessory sex organs was decreased along with secretory activity. No spermatozoan was observed in the cauda epididymis of intraperitoneal nicotine treated rats. The changes in the testis and accessory sex organs may be due to reduced output of pituitary FSH and LH which are important to initiate the spermatogenesis and steroidogensis. The absence of spermatozoa in the cauda epididymis and reduction in the activities of accessory sex organs indicates the delay caused by nicotine in the attainment of puberty.

  13. Evidence that nicotinic alpha(7) receptors are not involved in the hyperlocomotor and rewarding effects of nicotine.

    PubMed

    Grottick, A J; Trube, G; Corrigall, W A; Huwyler, J; Malherbe, P; Wyler, R; Higgins, G A

    2000-09-01

    Neuronal nicotinic receptors are comprised of combinations of alpha(2-9) and beta(2-4) subunits arranged to form a pentameric receptor. Currently, the principal central nervous system (CNS) subtypes are believed to be alpha(4)beta(2) and a homomeric alpha(7) receptor, although other combinations almost certainly exist. The identity of the nicotinic receptor subtype(s) involved in the rewarding effects of nicotine are unknown. In the present study, using some recently described subtype selective nicotinic agonists and antagonists, we investigated the role of the alpha(7) nicotinic receptor in the mediation of nicotine-induced hyperactivity and self-administration in rats. The alpha(7) receptor agonists AR-R 17779 and DMAC failed to stimulate locomotor activity in both nicotine-nontolerant and -sensitized rats. In contrast, nicotine and the putative alpha(4)beta(2) subtype selective agonist SIB1765F increased activity in both experimental conditions. In nicotine-sensitized rats, the high affinity (including the alpha(4)beta(2) subtype) nicotinic antagonist dihydro-beta-erythroidine (DHbetaE), but not the selective alpha(7) antagonist methyllycaconitine (MLA), antagonized a nicotine-induced hyperactivity. Similarly, DHbetaE, but not MLA, pretreatment reduced nicotine self-administration. Electrophysiology experiments using Xenopus oocytes expressing the human alpha(7) receptor confirmed AR-R 17779 and DMAC to be potent agonists at this site, and further studies demonstrated the ability of systemically administered AR-R 17779 to penetrate into the CNS. Taken together, these results indicate a negligible role of alpha(7) receptors in nicotine-induced hyperlocomotion and reward in the rat, and support the view for an involvement of a member from the high-affinity nicotinic receptor subclass, possibly alpha(4)beta(2). Issues such as drug potency, CNS penetration, and desensitization of the alpha(7) receptor are discussed.

  14. Action of ethanol on responses to nicotine from cerebellar Purkinje neurons: relationship to methyllycaconitine (MLA) inhibition of nicotine responses.

    PubMed

    Yang, X; Criswell, H E; Breese, G R

    1999-08-01

    The effect of ethanol on responses to nicotine from rat cerebellar Purkinje neurons was investigated using extracellular single-unit recording. Systemic administration of ethanol initially enhanced the nicotine-induced inhibition from 50% of the Purkinje neurons. However, irrespective of whether there was an initial enhancement, systemic administration of ethanol antagonized the response to nicotine from the majority of Purkinje neurons. When varying ethanol concentrations were electro-osmotically applied to this neuronal cell type, the responses to nicotine (6/8) were enhanced when a low concentration of ethanol (40 mM) was in the pipette, whereas the majority of nicotine responses (10/11) were antagonized when a higher concentration of ethanol (160 mM) was applied to Purkinje neurons. Thus, the concentration of ethanol presented to the neuron seemed to explain the biphasic consequence of systemically administered ethanol on responses to nicotine. In order to determine whether ethanol affected a specific nACh receptor subtype containing the alpha-7 subunit, it was initially established that the nicotinic antagonists, alpha-bungarotoxin (alpha-BTX) and methyllycaconitine (MLA), which are associated with this subunit, had identical actions on responses to nicotine from Purkinje neurons. When MLA was tested against responses to nicotine from this cell type, MLA antagonized the response to nicotine from 45% (9/20) of the neurons tested. In a direct comparison of the action of ethanol to inhibit responses to nicotine with the action of MLA on the same Purkinje neuron, ethanol inhibited responses to nicotine on all neurons sensitive to MLA. However, ethanol also affected nicotine-induced neural changes from some Purkinje neurons not sensitive to MLA antagonism of nicotine. These data support the supposition that ethanol affects a nACh receptor subtype which has an alpha-7 subunit as well as other nACh receptor subtypes without this specific subunit.

  15. Nicotine-morphine interactions at α4β2, α7 and α3(⁎) nicotinic acetylcholine receptors.

    PubMed

    Talka, Reeta; Salminen, Outi; Whiteaker, Paul; Lukas, Ronald J; Tuominen, Raimo K

    2013-02-15

    Nicotine and opioids share several behavioral and rewarding properties. Although both opioids and nicotine have their own specific mechanism of action, there is empirical and experimental evidence of interactions between these drugs. We studied receptor-level interactions of nicotine and morphine at α4β2, α7 and α3(⁎) nicotinic acetylcholine receptors. [(3)H]epibatidine displacement was used to determine if morphine binds competitively to nicotinic acetylcholine receptors. Functional interactions of morphine and nicotine were studied with calcium fluorometry and (86)Rb(+) efflux assays. Morphine displaced [(3)H]epibatidine from nicotinic agonist binding sites in all cell lines studied. The Ki values for morphine were 13.2μM in SH-EP1-hα4β2 cells, 0.16μM and 126μM in SH-SY5Y cells and 43.7μM in SH-EP1-hα7 cells. In SH-EP1-hα4β2 cells expressing α4β2 nicotinic acetylcholine receptors, morphine acted as a partial agonist of (86)Rb(+) efflux comparable to cytisine (with EC50 values of 53.3μM for morphine and 5.38μM for cytisine). The effect of morphine was attenuated concentration-dependently by the nicotinic antagonist mecamylamine. In the SH-SY5Y cell line expressing several subtypes of nicotinic acetylcholine receptors morphine had an inhibitory effect on nicotine induced (86)Rb(+) ion efflux mediated by α3(⁎) nicotinic acetylcholine receptors. These results suggest that morphine acts as a partial agonist at α4β2 nicotinic acetylcholine receptors and as a weak antagonist at α3(⁎) nicotinic acetylcholine receptors.

  16. Nicotinic activation of laterodorsal tegmental neurons: implications for addiction to nicotine.

    PubMed

    Ishibashi, Masaru; Leonard, Christopher S; Kohlmeier, Kristi A

    2009-11-01

    Identifying the neurological mechanisms underlying nicotine reinforcement is a healthcare imperative, if society is to effectively combat tobacco addiction. The majority of studies of the neurobiology of addiction have focused on dopamine (DA)-containing neurons of the ventral tegmental area (VTA). However, recent data suggest that neurons of the laterodorsal tegmental (LDT) nucleus, which sends cholinergic, GABAergic, and glutamatergic-containing projections to DA-containing neurons of the VTA, are critical to gating normal functioning of this nucleus. The actions of nicotine on LDT neurons are unknown. We addressed this issue by examining the effects of nicotine on identified cholinergic and non-cholinergic LDT neurons using whole-cell patch clamp and Ca(2+)-imaging methods in brain slices from mice (P12-P45). Nicotine applied by puffer pipette or bath superfusion elicited membrane depolarization that often induced firing and TTX-resistant inward currents. Nicotine also enhanced sensitivity to injected current; and, baseline changes in intracellular calcium were elicited in the dendrites of some cholinergic LDT cells. In addition, activity-dependent calcium transients were increased, suggesting that nicotine exposure sufficient to induce firing may lead to enhancement of levels of intracellular calcium. Nicotine also had strong actions on glutamate and GABA-releasing presynaptic terminals, as it greatly increased the frequency of miniature EPSCs and IPSCs to both cholinergic and non-cholinergic neurons. Utilization of nicotinic acetylcholine receptors (nAChR) subunit antagonists revealed that presynaptic, inhibitory terminals on cholinergic neurons were activated by receptors containing alpha 7, beta2, and non-alpha 7 subunits, whereas, presynaptic glutamatergic terminals were activated by nAChRs that comprised non-alpha 7 subunits. We also found that direct nicotinic actions on cholinergic LDT neurons were mediated by receptors containing alpha 7, beta2, and non

  17. Transdermal nicotine absorption handling e-cigarette refill liquids.

    PubMed

    Maina, Giovanni; Castagnoli, Carlotta; Passini, Valter; Crosera, Matteo; Adami, Gianpiero; Mauro, Marcella; Filon, Francesca Larese

    2016-02-01

    The concentrated nicotine in e-cigarette refill liquids can be toxic if inadvertently ingested or absorbed through the skin. Reports of poisonings due to accidental ingestion of nicotine on refill liquids are rapidly increasing, while the evaluation of nicotine dermally absorbed still lacks. For that reason we studied transdermal nicotine absorption after the skin contamination with e-liquid. Donor chambers of eight Franz diffusion cells were filled with 1 mL of 0.8 mg/mL nicotine e-liquid for 24 h. The concentration of nicotine in the receiving phase was determined by high-performance liquid chromatography (LOD:0.1 μg/mL). Nicotine was detectable in receiving solution 2 h after the start of exposure and increased progressively. The medium flux calculated was 4.82 ± 1.05 μg/cm(2)/h with a lag time of 3.9 ± 0.1 h. After 24 h, the nicotine concentration in the receiving compartment was 101.02 ± 22.35 μg/cm(2) corresponding to 3.04 mg of absorbed nicotine after contamination of a skin surface of 100 cm(2). Skin contamination with e-liquid can cause nicotine skin absorption: caution must be paid when handling refill e-liquids.

  18. Nicotine administration enhances negative occasion setting in adolescent rats.

    PubMed

    Meyer, Heidi C; Chodakewitz, Molly I; Bucci, David J

    2016-04-01

    Substantial research has established that exposure to nicotine during adolescence can lead to long-term changes in neural circuitry and behavior. However, relatively few studies have considered the effects of nicotine use on cognition during this critical stage of brain development. This is significant because the influence of nicotine on cognitive performance during adolescence may contribute to the development of regular nicotine use. For example, improvements in cognitive functioning may increase the perceived value of smoking and facilitate impulses to smoke. To address this, the present research tested the effects of nicotine on a form of inhibitory learning during adolescence. Specifically, adolescent rats were exposed to nicotine as they were trained in a negative occasion setting paradigm, in which successful performance depends on learning the conditions under which it is, or is not, appropriate to respond to a target stimulus. Here, we found that nicotine administration enhances negative occasion setting in adolescents. In addition, nicotine increased the amount of orienting behavior directed toward the inhibitory stimulus, suggesting that improvements in this form of behavioral inhibition may be attributed to nicotine-induced increases in attentional processing. These results may help elucidate the factors that contribute to the onset as well as continued use of products containing nicotine during adolescence and provide insight to increase the effectiveness of interventions targeted at reducing the prevalence of adolescent smoking. PMID:26779671

  19. Curcumin improves liver damage in male mice exposed to nicotine.

    PubMed

    Salahshoor, Mohammadreza; Mohamadian, Sabah; Kakabaraei, Seyran; Roshankhah, Shiva; Jalili, Cyrus

    2016-04-01

    The color of turmeric ( jiāng huáng) is because of a substance called curcumin. It has different pharmacological effects, such as antioxidant and anti-inflammatory properties. Nicotine is a major pharmacologically active substance in cigarette smoke. It is mainly metabolized in the liver and causes devastating effects. This study was designed to evaluate the protective role of curcumin against nicotine on the liver in mice. Forty-eight mice were equally divided into eight groups; control (normal saline), nicotine (2.5 mg/kg), curcumin (10, 30, and 60 mg/kg) and curcumin plus nicotine-treated groups. Curcumin, nicotine, and curcumin plus nicotine (once a day) were intraperitoneally injected for 4 weeks. The liver weight and histology, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and serum nitric oxide levels have been studied. The results indicated that nicotine administration significantly decreased liver weight and increased the mean diameter of hepatocyte, central hepatic vein, liver enzymes level, and blood serum nitric oxide level compared with the saline group (p < 0.05). However, curcumin and curcumin plus nicotine administration substantially increased liver weight and decreased the mean diameter of hepatocyte, central hepatic vein, liver enzymes, and nitric oxide levels in all groups compared with the nicotine group (p < 0.05). Curcumin demonstrated its protective effect against nicotine-induced liver toxicity. PMID:27114942

  20. Curcumin improves liver damage in male mice exposed to nicotine

    PubMed Central

    Salahshoor, Mohammadreza; Mohamadian, Sabah; Kakabaraei, Seyran; Roshankhah, Shiva; Jalili, Cyrus

    2015-01-01

    The color of turmeric (薑黃 jiāng huáng) is because of a substance called curcumin. It has different pharmacological effects, such as antioxidant and anti-inflammatory properties. Nicotine is a major pharmacologically active substance in cigarette smoke. It is mainly metabolized in the liver and causes devastating effects. This study was designed to evaluate the protective role of curcumin against nicotine on the liver in mice. Forty-eight mice were equally divided into eight groups; control (normal saline), nicotine (2.5 mg/kg), curcumin (10, 30, and 60 mg/kg) and curcumin plus nicotine-treated groups. Curcumin, nicotine, and curcumin plus nicotine (once a day) were intraperitoneally injected for 4 weeks. The liver weight and histology, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and serum nitric oxide levels have been studied. The results indicated that nicotine administration significantly decreased liver weight and increased the mean diameter of hepatocyte, central hepatic vein, liver enzymes level, and blood serum nitric oxide level compared with the saline group (p < 0.05). However, curcumin and curcumin plus nicotine administration substantially increased liver weight and decreased the mean diameter of hepatocyte, central hepatic vein, liver enzymes, and nitric oxide levels in all groups compared with the nicotine group (p < 0.05). Curcumin demonstrated its protective effect against nicotine-induced liver toxicity. PMID:27114942

  1. Opioid Analgesics and Nicotine: More Than Blowing Smoke.

    PubMed

    Yoon, Jin H; Lane, Scott D; Weaver, Michael F

    2015-09-01

    Practitioners are highly likely to encounter patients with concurrent use of nicotine products and opioid analgesics. Smokers present with more severe and extended chronic pain outcomes and have a higher frequency of prescription opioid use. Current tobacco smoking is a strong predictor of risk for nonmedical use of prescription opioids. Opioid and nicotinic-cholinergic neurotransmitter systems interact in important ways to modulate opioid and nicotine effects: dopamine release induced by nicotine is dependent on facilitation by the opioid system, and the nicotinic-acetylcholine system modulates self-administration of several classes of abused drugs-including opioids. Nicotine can serve as a prime for the use of other drugs, which in the case of the opioid system may be bidirectional. Opioids and compounds in tobacco, including nicotine, are metabolized by the cytochrome P450 enzyme system, but the metabolism of opioids and tobacco products can be complicated. Accordingly, drug interactions are possible but not always clear. Because of these issues, asking about nicotine use in patients taking opioids for pain is recommended. When assessing patient tobacco use, practitioners should also obtain information on products other than cigarettes, such as cigars, pipes, smokeless tobacco, and electronic nicotine delivery systems (ENDS, or e-cigarettes). There are multiple forms of behavioral therapy and pharmacotherapy available to assist patients with smoking cessation, and opioid agonist maintenance and pain clinics represent underutilized opportunities for nicotine intervention programs.

  2. Nicotine induces DNA damage in human salivary glands.

    PubMed

    Ginzkey, Christian; Kampfinger, Katja; Friehs, Gudrun; Köhler, Christian; Hagen, Rudolf; Richter, Elmar; Kleinsasser, Norbert H

    2009-01-10

    The tobacco alkaloid nicotine is responsible for addiction to tobacco and supposed to contribute to tobacco carcinogensis, too. Recently, genotoxic effects of nicotine have been reported in human cells from blood and upper aerodigestive tract. Because of nicotine accumulation in saliva, the study of possible in vitro genotoxic effects of nicotine have been extended to human salivary gland cells. Specimens of parotid glands of 10 tumor patients were obtained from tumor-free tissue. Single cells were prepared by enzymatic digestion immediately after surgery and exposed for 1h to 0.125-4.0mM of nicotine. Possible genotoxic effects were determined by the Comet assay using the % DNA in tail (DT) as a reliable indicator of DNA damage. Nicotine induced a significant dose-dependent increase of DNA migration in parotid gland single-cells. The mean DT was 1.12-fold (0.125mM) to 2.24-fold (4.0mM) higher compared to control. The lowest concentration eliciting significant DNA damage within 1h, 0.25mM nicotine, is only 10-fold higher than maximal concentrations of nicotine reported in saliva after unrestricted smoking. Although conclusive evidence for a carcinogenic potential of nicotine is still lacking, the safety of long-term nicotine replacement therapy should be carefully monitored. PMID:18852035

  3. Reducing the nicotine content to make cigarettes less addictive.

    PubMed

    Benowitz, Neal L; Henningfield, Jack E

    2013-05-01

    Nicotine is highly addictive and is primarily responsible for the maintenance of cigarette smoking. In 1994, Benowitz and Henningfield proposed the idea of federal regulation of the nicotine content of cigarettes such that the nicotine content of cigarettes would be reduced over time, resulting in lower intake of nicotine and a lower level of nicotine dependence. When nicotine levels get very low, cigarettes would be much less addictive. As a result, fewer young people who experiment with cigarettes would become addicted adult smokers and previously addicted smokers would find it easier to quit smoking when they attempt to do so. The regulatory authority to promulgate such a public health strategy was provided by the Family Smoking Prevention and Tobacco Control Act. Although it precludes 'reducing nicotine to zero', the act does not prohibit the Food and Drug Administration from setting standards for cigarette nicotine content that would prevent them from being capable of causing addiction. This paper reviews the assumptions implicit in a nicotine reduction strategy, examines the available data on the feasibility and safety of nicotine reduction, and discusses the public education, surveillance and support services that would be needed for the implementation of such a policy.

  4. Opioid Analgesics and Nicotine: More Than Blowing Smoke.

    PubMed

    Yoon, Jin H; Lane, Scott D; Weaver, Michael F

    2015-09-01

    Practitioners are highly likely to encounter patients with concurrent use of nicotine products and opioid analgesics. Smokers present with more severe and extended chronic pain outcomes and have a higher frequency of prescription opioid use. Current tobacco smoking is a strong predictor of risk for nonmedical use of prescription opioids. Opioid and nicotinic-cholinergic neurotransmitter systems interact in important ways to modulate opioid and nicotine effects: dopamine release induced by nicotine is dependent on facilitation by the opioid system, and the nicotinic-acetylcholine system modulates self-administration of several classes of abused drugs-including opioids. Nicotine can serve as a prime for the use of other drugs, which in the case of the opioid system may be bidirectional. Opioids and compounds in tobacco, including nicotine, are metabolized by the cytochrome P450 enzyme system, but the metabolism of opioids and tobacco products can be complicated. Accordingly, drug interactions are possible but not always clear. Because of these issues, asking about nicotine use in patients taking opioids for pain is recommended. When assessing patient tobacco use, practitioners should also obtain information on products other than cigarettes, such as cigars, pipes, smokeless tobacco, and electronic nicotine delivery systems (ENDS, or e-cigarettes). There are multiple forms of behavioral therapy and pharmacotherapy available to assist patients with smoking cessation, and opioid agonist maintenance and pain clinics represent underutilized opportunities for nicotine intervention programs. PMID:26375198

  5. Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits.

    PubMed

    Vieira-Brock, Paula L; McFadden, Lisa M; Nielsen, Shannon M; Ellis, Jonathan D; Walters, Elliot T; Stout, Kristen A; McIntosh, J Michael; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

    2015-12-01

    Repeated methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of Parkinson's disease. Many METH abusers smoke cigarettes and thus self-administer nicotine; yet few studies have investigated the effects of nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that nicotine can be neuroprotective, perhaps owing to effects involving α4β2 and α6β2 nicotinic acetylcholine receptors (nAChRs). This study revealed that oral nicotine exposure beginning in adolescence [postnatal day (PND) 40] through adulthood [PND 96] attenuated METH-induced striatal dopaminergic deficits when METH was administered at PND 89. This protection did not appear to be due to nicotine-induced alterations in METH pharmacokinetics. Short-term (i.e., 21-day) high-dose nicotine exposure also protected when administered from PND 40 to PND 61 (with METH at PND 54), but this protective effect did not persist. Short-term (i.e., 21-day) high-dose nicotine exposure did not protect when administered postadolescence (i.e., beginning at PND 61, with METH at PND 75). However, protection was engendered if the duration of nicotine exposure was extended to 39 days (with METH at PND 93). Autoradiographic analysis revealed that nicotine increased striatal α4β2 expression, as assessed using [(125)I]epibatidine. Both METH and nicotine decreased striatal α6β2 expression, as assessed using [(125)I]α-conotoxin MII. These findings indicate that nicotine protects against METH-induced striatal dopaminergic deficits, perhaps by affecting α4β2 and/or α6β2 expression, and that both age of onset and duration of nicotine exposure affect this protection.

  6. Synthesis, crystal structure and magnetic properties of the two polymorphs of novel S=1 osmate; Li4MgOsO6

    NASA Astrophysics Data System (ADS)

    Nguyen, Phoung-Hieu T.; Kemei, Moureen C.; Tan, Malinda S.; Derakhshan, Shahab

    2016-10-01

    Li4MgOsO6 was synthesized by two different solid-state reaction procedures. The crystal structures were determined by X-ray powder diffraction technique and it was revealed that Li4MgOsO6 crystallizes in two different crystal symmetries in ordered rock salt structure type, namely monoclinic C2/m and orthorhombic Fddd. The unit cell constants for the monoclinic system are a=5.1074(4) Å, b=8.8182(4) Å, c=5.0902(2) Å, and β=109.845(4)° and those of the orthorhombic structure are a=5.8485(1) Å, b=8.3821(1) Å, and c=17.6212(3) Å. In both systems, Os6+ ions reside exclusively in a specific crystallographic position while Li+ and Mg2+ ions exhibit mix occupancy. The temperature dependent magnetic susceptibility data for both S=1 osmate systems do not support the occurrence of any magnetic transition down to 2 K. The Curie-Weiss fit to the paramagnetic regime of the magnetic susceptibility data reveal highly negative θ value (-114.81 K and -121.87 K for C2/m and for Fddd systems, respectively), which are indicative of predominant antiferromagnetic (AFM) interactions in both systems. The experimental effective magnetic moment (μeff) value for the monoclinic phase is 2.13 μB and that of the orthorhombic system is 2.34 μB. Due to the rather strong AFM interactions and lack of magnetic transition down to 2 K, both of these novel osmates are placed in the class of highly frustrated magnets. Low temperature magnetic susceptibility (below 2 K) and dynamic magnetic properties studies (μsr studies) are in order to better understand the magnetic ground states of these two polymorphs of Li4MgOsO6.

  7. The Sensory Impact of Nicotine on Noradrenergic and Dopaminergic Neurons of the Nicotine Reward - Addiction Neurocircuitry

    PubMed Central

    Rose, Jed E; Dehkordi, Ozra; Manaye, Kebreten F; Millis, Richard M; Cianaki, Salman Ameri; Jayam-Trouth, Annapurni

    2016-01-01

    The sensory experience of smoking is a key component of nicotine addiction known to result, in part, from stimulation of nicotinic acetylcholine receptors (nAChRs) at peripheral sensory nerve endings. Such stimulation of nAChRs is followed by activation of neurons at multiple sites in the mesocorticolimbic reward pathways. However, the neurochemical profiles of CNS cells that mediate the peripheral sensory impact of nicotine remain unknown. In the present study in mice, we first used c-Fos immunohistochemistry to identify CNS cells stimulated by nicotine (NIC, 40 μg/kg, IP) and by a peripherally-acting analog of nicotine, nicotine pyrrolidine methiodide (NIC-PM, 30 μg/kg, IP). Sequential double-labelling was then performed to determine whether noradrenergic and dopaminergic neurons of the nicotine reward-addiction circuitry were primary targets of NIC and NIC-PM. Double-labelling of NIC and/or NIC-PM activated c-Fos immunoreactive cells with tyrosine hydroxylase (TH) showed no apparent c-Fos expression by the dopaminergic cells of the ventral tegmental area (VTA). With the exception of sparse numbers of TH immunoreactive D11 cells, dopamine-containing neurons in other areas of the reward-addiction circuitry, namely periaqueductal gray, and dorsal raphe, were also devoid of c-Fos immunoreactivity. Noradrenergic neurons of locus coeruleus (LC), known to innervate VTA, were activated by both NIC and NIC-PM. These results demonstrate that noradrenergic neurons of LC are among the first structures that are stimulated by single acute IP injection of NIC and NIC-PM. Dopaminergic neurons of VTA and other CNS sites, did not respond to acute IP administration of NIC or NIC-PM by induction of c-Fos. PMID:27347434

  8. Nicotine increases GABAergic input on rat dorsal raphe serotonergic neurons through alpha7 nicotinic acetylcholine receptor.

    PubMed

    Hernández-Vázquez, F; Chavarría, K; Garduño, J; Hernández-López, S; Mihailescu, S P

    2014-12-15

    The dorsal raphe nucleus (DRN) contains large populations of serotonergic (5-HT) neurons. This nucleus receives GABAergic inhibitory afferents from many brain areas and from DRN interneurons. Both GABAergic and 5-HT DRN neurons express functional nicotinic acetylcholine receptors (nAChRs). Previous studies have demonstrated that nicotine increases 5-HT release and 5-HT DRN neuron discharge rate by stimulating postsynaptic nAChRs and by increasing glutamate and norepinephrine release inside DRN. However, the influence of nicotine on the GABAergic input to 5-HT DRN neurons was poorly investigated. Therefore, the aim of this work was to determine the effect of nicotine on GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) of 5-HT DRN neurons and the subtype of nAChR(s) involved in this response. Experiments were performed in coronal slices obtained from young Wistar rats. GABAergic sIPSCs were recorded from post hoc-identified 5-HT DRN neurons with the whole cell voltage patch-clamp technique. Administration of nicotine (1 μM) increased sIPSC frequency in 72% of identified 5-HT DRN neurons. This effect was not reproduced by the α4β2 nAChR agonist RJR-2403 and was not influenced by TTX (1 μM). It was mimicked by the selective agonist for α7 nAChR, PNU-282987, and exacerbated by the positive allosteric modulator of the same receptor, PNU-120596. The nicotine-induced increase in sIPSC frequency was independent on voltage-gated calcium channels and dependent on Ca(2+)-induced Ca(2+) release (CICR). These results demonstrate that nicotine increases the GABAergic input to most 5-HT DRN neurons, by activating α7 nAChRs and producing CICR in DRN GABAergic terminals.

  9. Nicotine increases GABAergic input on rat dorsal raphe serotonergic neurons through alpha7 nicotinic acetylcholine receptor.

    PubMed

    Hernández-Vázquez, F; Chavarría, K; Garduño, J; Hernández-López, S; Mihailescu, S P

    2014-12-15

    The dorsal raphe nucleus (DRN) contains large populations of serotonergic (5-HT) neurons. This nucleus receives GABAergic inhibitory afferents from many brain areas and from DRN interneurons. Both GABAergic and 5-HT DRN neurons express functional nicotinic acetylcholine receptors (nAChRs). Previous studies have demonstrated that nicotine increases 5-HT release and 5-HT DRN neuron discharge rate by stimulating postsynaptic nAChRs and by increasing glutamate and norepinephrine release inside DRN. However, the influence of nicotine on the GABAergic input to 5-HT DRN neurons was poorly investigated. Therefore, the aim of this work was to determine the effect of nicotine on GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) of 5-HT DRN neurons and the subtype of nAChR(s) involved in this response. Experiments were performed in coronal slices obtained from young Wistar rats. GABAergic sIPSCs were recorded from post hoc-identified 5-HT DRN neurons with the whole cell voltage patch-clamp technique. Administration of nicotine (1 μM) increased sIPSC frequency in 72% of identified 5-HT DRN neurons. This effect was not reproduced by the α4β2 nAChR agonist RJR-2403 and was not influenced by TTX (1 μM). It was mimicked by the selective agonist for α7 nAChR, PNU-282987, and exacerbated by the positive allosteric modulator of the same receptor, PNU-120596. The nicotine-induced increase in sIPSC frequency was independent on voltage-gated calcium channels and dependent on Ca(2+)-induced Ca(2+) release (CICR). These results demonstrate that nicotine increases the GABAergic input to most 5-HT DRN neurons, by activating α7 nAChRs and producing CICR in DRN GABAergic terminals. PMID:25231613

  10. Ventral hippocampal alpha 7 nicotinic receptor blockade and chronic nicotine effects on memory performance in the radial-arm maze.

    PubMed

    Bettany, J H; Levin, E D

    2001-12-01

    Chronic nicotine administration has been shown to significantly improve working memory. Nicotinic involvement in memory function critically involves the ventral hippocampus. Local ventral hippocampal infusions of the nicotinic antagonists mecamylamine, dihydro-beta-erythroidine (DH beta E) and methyllycaconitine (MLA) significantly impair working memory. The impairment caused by hippocampal infusion of the alpha 4 beta 2 antagonist DH beta E is reversed by chronic systemic nicotine. This study determined the interaction of chronic systemic nicotine with acute ventral hippocampal infusions of the alpha 7 antagonist MLA. Adult female Sprague-Dawley rats were trained on an 8-arm radial maze working memory task. Then they underwent ventral hippocampal cannulation and received sc implants of minipumps delivering nicotine (0 or 5 mg/kg/day for 28 days). Acute ventral hippocampal infusions of MLA (0, 4.88, 14.64 and 43.92 microg/side) were given during 3-4 weeks of chronic nicotine. MLA caused a significant dose-related memory impairment. In the rats not receiving nicotine, the 14.64 and 43.92 microg/side MLA doses caused significant memory impairment. Chronic systemic nicotine exposure did not block the MLA-induced memory impairment. Comparing the current results with MLA with previous results with DH beta E, equimolar ventral hippocampal DH beta E more effectively impaired memory than MLA, but the DH beta E-induced impairment was more effectively reversed by chronic systemic nicotine administration.

  11. A multi-route model of nicotine-cotinine pharmacokinetics, pharmacodynamics and brain nicotinic acetylcholine receptor binding in humans.

    PubMed

    Teeguarden, Justin G; Housand, Conrad J; Smith, Jordan N; Hinderliter, Paul M; Gunawan, Rudy; Timchalk, Charles A

    2013-02-01

    The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the development and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.

  12. Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine.

    PubMed

    Perez, Erika; Quijano-Cardé, Natalia; De Biasi, Mariella

    2015-09-01

    Alcohol and nicotine are among the top causes of preventable death in the United States. Unfortunately, people who are dependent on alcohol are more likely to smoke than individuals in the general population. Similarly, smokers are more likely to abuse alcohol. Alcohol and nicotine codependence affects health in many ways and leads to poorer treatment outcomes in subjects who want to quit. This study examined the interaction of alcohol and nicotine during withdrawal and compared abstinence symptoms during withdrawal from one of the two drugs only vs both. Our results indicate that simultaneous withdrawal from alcohol and nicotine produces physical symptoms that are more severe and last longer than those experienced during withdrawal from one of the two drugs alone. In animals experiencing withdrawal after chronic ethanol treatment, acute nicotine exposure was sufficient to prevent abstinence symptoms. Similarly, symptoms were prevented when alcohol was injected acutely in mice undergoing nicotine withdrawal. These experiments provide evidence for the involvement of the nicotinic cholinergic system in alcohol withdrawal. Furthermore, the outcomes of intracranial microinfusions of mecamylamine, a nonselective nicotinic receptor antagonist, highlight a major role for the nicotinic receptors expressed in medial habenula and interpeduncular nucleus during withdrawal. Overall, the data support the notion that modulating the nicotinic cholinergic system might help to maintain long-term abstinence from alcohol.

  13. A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans

    SciTech Connect

    Teeguarden, Justin G.; Housand, Conrad; Smith, Jordan N.; Hinderliter, Paul M.; Gunawan, Rudy; Timchalk, Charles

    2013-02-01

    The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the development and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.

  14. Neonatal Nicotine Exposure Increases Excitatory Synaptic Transmission and Attenuates Nicotine-stimulated GABA release in the Adult Rat Hippocampus

    PubMed Central

    Damborsky, Joanne C.; Griffith, William H.; Winzer-Serhan, Ursula H.

    2014-01-01

    Developmental exposure to nicotine has been linked to long-lasting changes in synaptic transmission which may contribute to behavioral abnormalities seen in offspring of women who smoke during pregnancy. Here, we examined the long-lasting effects of developmental nicotine exposure on glutamatergic and GABAergic neurotransmission, and on acute nicotine-induced glutamate and GABA release in the adult hippocampus, a structure important in cognitive and emotional behaviors. We utilized a chronic neonatal nicotine treatment model to administer nicotine (6 mg/kg/day) to rat pups from postnatal day (P) 1–7, a period that falls developmentally into the third human trimester. Using whole-cell voltage clamp recordings from CA1 pyramidal neurons in hippocampal slices, we measured excitatory and inhibitory postsynaptic currents in neonatally control- and nicotine-treated young adult males. Neonatal nicotine exposure significantly increased AMPA receptor-mediated spontaneous and evoked excitatory signaling, with no change in glutamate release probability in adults. Conversely, there was no increase in spontaneous GABAergic neurotransmission in nicotine-males. Chronic neonatal nicotine treatment had no effect on acute nicotine-stimulated glutamate release in adults, but acute nicotine-stimulated GABA release was significantly attenuated. Thus, neonatal nicotine exposure results in a persistent net increase in excitation and a concurrent loss of nicotinic acetylcholine receptor (nAChR)-mediated regulation of presynaptic GABA but not glutamate release, which would exacerbate excitation following endogenous or exogenous nAChR activation. Our data underscore an important role for nAChRs in hippocampal excitatory synapse development, and suggest selective long-term changes at specific presynaptic nAChRs which together could explain some of the behavioral abnormalities associated with maternal smoking. PMID:24950455

  15. Galantamine, an acetylcholinesterase inhibitor and positive allosteric modulator of nicotinic acetylcholine receptors, attenuates nicotine taking and seeking in rats.

    PubMed

    Hopkins, Thomas J; Rupprecht, Laura E; Hayes, Matthew R; Blendy, Julie A; Schmidt, Heath D

    2012-09-01

    Current smoking cessation pharmacotherapies have limited efficacy in preventing relapse and maintaining abstinence during withdrawal. Galantamine is an acetylcholinesterase inhibitor that also acts as a positive allosteric modulator of nicotinic acetylcholine receptors. Galantamine has recently been shown to reverse nicotine withdrawal-induced cognitive impairments in mice, which suggests that galantamine may function to prevent relapse in human smokers. However, there are no studies examining whether galantamine administration modulates nicotine self-administration and/or reinstatement of nicotine seeking in rodents. The present experiments were designed to determine the effects of galantamine administration on nicotine taking and reinstatement of nicotine-seeking behavior, an animal model of relapse. Moreover, the effects of galantamine on sucrose-maintained responding and sucrose seeking were also examined to determine whether galantamine's effects generalized to other reinforced behaviors. An inverted U-shaped dose-response curve was obtained when animals self-administered different unit doses of nicotine with the highest responding for 0.03 mg/kg per infusion of nicotine. Acute galantamine administration (5.0 mg/kg, i.p.) attenuated nicotine self-administration when animals were maintained on either a fixed-ratio 5 (FR5) or progressive ratio (PR) schedule of reinforcement. Galantamine administration also attenuated the reinstatement of nicotine-seeking behavior. No significant effects of galantamine on sucrose self-administration or sucrose reinstatement were noted. Acetylcholinesterase inhibitors have also been shown to produce nausea and vomiting in humans. However, at doses required to attenuate nicotine self-administration, no effects of galantamine on nausea/malaise as measured by pica were noted. These results indicate that increased extracellular acetylcholine levels and/or nicotinic acetylcholine receptor stimulation is sufficient to attenuate

  16. High-affinity α4β2 nicotinic receptors mediate the impairing effects of acute nicotine on contextual fear extinction.

    PubMed

    Kutlu, Munir Gunes; Holliday, Erica; Gould, Thomas J

    2016-02-01

    Previously, studies from our lab have shown that while acute nicotine administered prior to training and testing enhances contextual fear conditioning, acute nicotine injections prior to extinction sessions impair extinction of contextual fear. Although there is also strong evidence showing that the acute nicotine's enhancing effects on contextual fear conditioning require high-affinity α4β2 nicotinic acetylcholine receptors (nAChRs), it is unknown which nAChR subtypes are involved in the acute nicotine-induced impairment of contextual fear extinction. In this study, we investigated the effects of acute nicotine administration on contextual fear extinction in knock-out (KO) mice lacking α4, β2 or α7 subtypes of nAChRs and their wild-type (WT) littermates. Both KO and WT mice were first trained and tested for contextual fear conditioning and received a daily contextual extinction session for 4 days. Subjects received intraperitoneal injections of nicotine (0.18 mg/kg) or saline 2-4 min prior to each extinction session. Our results showed that the mice that lack α4 and β2 subtypes of nAChRs showed normal contextual fear extinction but not the acute nicotine-induced impairment while the mice that lack the α7 subtype showed both normal contextual extinction and nicotine-induced impairment of contextual extinction. In addition, control experiments showed that acute nicotine-induced impairment of contextual fear extinction persisted when nicotine administration was ceased and repeated acute nicotine administrations alone did not induce freezing behavior in the absence of context-shock learning. These results clearly demonstrate that high-affinity α4β2 nAChRs are necessary for the effects of acute nicotine on contextual fear extinction.

  17. High-affinity α4β2 nicotinic receptors mediate the impairing effects of acute nicotine on contextual fear extinction.

    PubMed

    Kutlu, Munir Gunes; Holliday, Erica; Gould, Thomas J

    2016-02-01

    Previously, studies from our lab have shown that while acute nicotine administered prior to training and testing enhances contextual fear conditioning, acute nicotine injections prior to extinction sessions impair extinction of contextual fear. Although there is also strong evidence showing that the acute nicotine's enhancing effects on contextual fear conditioning require high-affinity α4β2 nicotinic acetylcholine receptors (nAChRs), it is unknown which nAChR subtypes are involved in the acute nicotine-induced impairment of contextual fear extinction. In this study, we investigated the effects of acute nicotine administration on contextual fear extinction in knock-out (KO) mice lacking α4, β2 or α7 subtypes of nAChRs and their wild-type (WT) littermates. Both KO and WT mice were first trained and tested for contextual fear conditioning and received a daily contextual extinction session for 4 days. Subjects received intraperitoneal injections of nicotine (0.18 mg/kg) or saline 2-4 min prior to each extinction session. Our results showed that the mice that lack α4 and β2 subtypes of nAChRs showed normal contextual fear extinction but not the acute nicotine-induced impairment while the mice that lack the α7 subtype showed both normal contextual extinction and nicotine-induced impairment of contextual extinction. In addition, control experiments showed that acute nicotine-induced impairment of contextual fear extinction persisted when nicotine administration was ceased and repeated acute nicotine administrations alone did not induce freezing behavior in the absence of context-shock learning. These results clearly demonstrate that high-affinity α4β2 nAChRs are necessary for the effects of acute nicotine on contextual fear extinction. PMID:26688111

  18. Biodegradation of nicotine by a newly isolated Pseudomonas stutzeri JZD

    NASA Astrophysics Data System (ADS)

    Petricevic, Jelena; Gujanicic, Vera; Radic, Danka; Jovicic Petrovic, Jelena; Jovic, Jelena; Raicevic, Vera

    2013-04-01

    The tobacco-manufacturing process and all activities that use tobacco, produce solid or liquid wastes with high concentrations of nicotine. Nicotine is a significant toxic waste product in tobacco industry. This waste is classified as 'toxic and hazardous' by European Union regulations when the nicotine content exceeds 500 milligrams per kilogram dry weight. Therefore, there is a major environmental requirement to remove nicotine from tobacco wastes. Bioremediation techniques which involve nicotine degradation by microorganisms have attracted attention during the last years, because microorganisms have the potential to reduce nicotine levels in tobacco and to detoxify tobacco wastes. The aim of this study is isolation and identification of nicotine degraded bacteria and optimization of nicotine degradation in laboratory conditions. An aerobic bacterial strain capable of effectively degrading nicotine was isolated from the tobacco industry waste, Serbia. After isolation, the liquid culture was spread onto the solid plates of the nicotine inorganic salt medium using the dilution plate method. Cell morphology of strain was observed by a light microscope and physiological characteristics were determined by Api technique and sequence analyzes of 16S rDNA. This isolate was identified as Pseudomonas stutzeri based on morphology, physiological characteristics, and Apiweb technique. Comparison with sequences available in data library showed the 99% similarity with 16S rDNA gene sequence of the species Pseudomonas stutzeri ( GenBank Acc. No. CP003725). We analyzed the effect of initial nicotine concentration (1g/L, 1.5 g/L, 2.5 g/L) on microbial activity in aim to optimize biodegradation. The effect of cultivation temperature (25°C; 30°C; 37°C) on nicotine degradation by P. stutzeri was evaluated after 24 h of cultivation, with 1.5 g/L nicotine added as the sole carbon source. Effect of biodegradation has depended on initial concentration. During incubation, number of

  19. [A review of the effects of nicotine on schizophrenia].

    PubMed

    Bidzan, Leszek

    2007-01-01

    It is increasingly appreciated that amongst psychiatric cigarette smokers, those with schizophrenia have elevated rates of smoking compared to the general population. Nicotine seems to improve cognitive functions critically affected in schizophrenia. There is substantial evidence that nicotine could be used by patients with schizophrenia as a "self-medication" to improve deficits in attention, cognition, and information processing. Perhaps nicotine has influence on intensity of side effects of antipsychotic medication. Nicotine treatment modulates both dopaminergic and glutamatergic neurotransmission, and these effects are specific both to brain region and functional system. Understanding how and why schizophrenic individuals use nicotine may lead to the development of new treatments for both schizophrenia and nicotine dependence. PMID:18421928

  20. Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal.

    PubMed

    Watkins, S S; Koob, G F; Markou, A

    2000-02-01

    The neurobiology of nicotine addiction is reviewed within the context of neurobiological and behavioral theories postulated for other drugs of abuse. The roles of various neurotransmitter systems, including acetylcholine, dopamine, serotonin, glutamate, gamma-aminobutyric acid, and opioid peptides in acute nicotine reinforcement and withdrawal from chronic administration are examined followed by a discussion of potential neuroadaptations within these neurochemical systems that may lead to the development of nicotine dependence. The link between nicotine administration, depression and schizophrenia are also discussed. Finally, a theoretical model of the neurobiological mechanisms underlying acute nicotine withdrawal and protracted abstinence involves alterations within dopaminergic, serotonergic, and stress systems that are hypothesized to contribute to the negative affective state associated with nicotine abstinence.

  1. The role of nicotinic acid metabolites in flushing and hepatotoxicity.

    PubMed

    Stern, Ralph H

    2007-07-01

    Flushing and hepatotoxicity are important adverse effects of nicotinic acid. This article reviews the role of metabolism of nicotinic acid in the production of these side effects. The suggestion that nicotinic acid (NUA) formation produces flushing is traced to a correlation of flushing with NUA C(max) (maximal concentration) and the observation that aspirin inhibits NUA formation and flushing. The former does not establish causation and the latter can be explained by inhibition of prostaglandin formation. Recent characterization of the GPR109A receptor that mediates prostaglandin release by Langerhans cells to produce flushing has shown nicotinic acid, not NUA, is responsible. The suggestion that nicotinamide metabolites produce hepatotoxicity is not supported by any data. The mechanism of hepatotoxicity is unknown and a toxic metabolite of nicotinic acid has not been identified. Different nicotinic acid formulations produce different metabolite patterns due to nonlinear pharmacokinetics, but there is no evidence that these differences have any clinical importance. PMID:21291680

  2. In vivo and in vitro alteration of nicotine metabolism by the major metabolite of phenytoin.

    PubMed

    Lubawy, W C; Kostenbauder, H B; McGovren, J P

    1978-02-01

    The influence of hydroxyphentoin (HPPH), the major metabolite of phenytoin, on the in vitro and in vivo metabolism of nicotine was examined. In rat liver 9,000 g supernatant HPPH decreased the appearance of cotinine from nicotine by 65% while not influencing the disappearance of nicotine or the appearance of nicotine-l'-N-oxide. In vivo, HPPH inhibited both nicotine elimination and cotinine formation but did not affect nicotin-l'-N-oxide formation. PMID:25464

  3. Pathogenesis of Abdominal Aortic Aneurysms: Role of Nicotine and Nicotinic Acetylcholine Receptors

    PubMed Central

    Li, Zong-Zhuang; Dai, Qiu-Yan

    2012-01-01

    Inflammation, proteolysis, smooth muscle cell apoptosis, and angiogenesis have been implicated in the pathogenesis of abdominal aortic aneurysms (AAAs), although the well-defined initiating mechanism is not fully understood. Matrix metalloproteinases (MMPs) such as MMP-2 and -9 and other proteinases degrading elastin and extracellular matrix are the critical pathogenesis of AAAs. Among the risk factors of AAAs, cigarette smoking is an irrefutable one. Cigarette smoke is practically involved in various aspects of the AAA pathogenesis. Nicotine, a major alkaloid in tobacco leaves and a primary component in cigarette smoke, can stimulate the MMPs expression by vascular SMCs, endothelial cells, and inflammatory cells in vascular wall and induce angiogenesis in the aneurysmal tissues. However, for the inflammatory and apoptotic processes in the pathogenesis of AAAs, nicotine seems to be moving in just the opposite direction. Additionally, the effects of nicotine are probably dose dependent or associated with the exposure duration and may be partly exerted by its receptors—nicotinic acetylcholine receptors (nAChRs). In this paper, we will mainly discuss the pathogenesis of AAAs involving inflammation, proteolysis, smooth muscle cell apoptosis and angiogenesis, and the roles of nicotine and nAChRs. PMID:22529515

  4. Harm perception of nicotine products in college freshmen.

    PubMed

    Smith, Stephanie Y; Curbow, Barbara; Stillman, Frances A

    2007-09-01

    This study examined the association of sociodemographic characteristics and smoking behaviors (i.e., cigarette, cigar, and waterpipe) with nicotine product harm perception in college freshmen. Students were asked to compare the perceived harmfulness of 11 nicotine-delivering products with that of a regular cigarette. Data were from a cross-sectional Internet survey conducted during the spring 2004 semester at a private university (N = 411). Binomial logistic regression was used to determine the association between sociodemographic and behavioral factors with nicotine product harm perception. A statistically significant association was found between nicotine product harm perception and sex, race, income, citizenship, and smoking behavior (p< or =.05). Regarding the three medicinal nicotine replacement therapies, 19.6% of respondents incorrectly perceived the nicotine patch to be as harmful as or more harmful than a regular cigarette; corresponding values were 24.1% for nicotine gum and 52.9% for nicotine inhaler. Respondents incorrectly perceived the following smoked tobacco products to be less harmful than regular cigarettes: ultra-light cigarettes (40.4%), waterpipe (37%), light cigarettes (35.2%), cigarillos (17.4%), and cigars (16.9%). Regarding smokeless nicotine products, 89.3% of respondents incorrectly perceived dip and chew to be as harmful as or more harmful than regular cigarettes; corresponding values were 36.2% for nicotine lollipops and 35.2% for nicotine water. Our findings reveal misperceptions about nicotine product harmfulness and underscore the importance of developing a science base to inform policies and educate consumers about these products. PMID:17763115

  5. Harm perception of nicotine products in college freshmen.

    PubMed

    Smith, Stephanie Y; Curbow, Barbara; Stillman, Frances A

    2007-09-01

    This study examined the association of sociodemographic characteristics and smoking behaviors (i.e., cigarette, cigar, and waterpipe) with nicotine product harm perception in college freshmen. Students were asked to compare the perceived harmfulness of 11 nicotine-delivering products with that of a regular cigarette. Data were from a cross-sectional Internet survey conducted during the spring 2004 semester at a private university (N = 411). Binomial logistic regression was used to determine the association between sociodemographic and behavioral factors with nicotine product harm perception. A statistically significant association was found between nicotine product harm perception and sex, race, income, citizenship, and smoking behavior (p< or =.05). Regarding the three medicinal nicotine replacement therapies, 19.6% of respondents incorrectly perceived the nicotine patch to be as harmful as or more harmful than a regular cigarette; corresponding values were 24.1% for nicotine gum and 52.9% for nicotine inhaler. Respondents incorrectly perceived the following smoked tobacco products to be less harmful than regular cigarettes: ultra-light cigarettes (40.4%), waterpipe (37%), light cigarettes (35.2%), cigarillos (17.4%), and cigars (16.9%). Regarding smokeless nicotine products, 89.3% of respondents incorrectly perceived dip and chew to be as harmful as or more harmful than regular cigarettes; corresponding values were 36.2% for nicotine lollipops and 35.2% for nicotine water. Our findings reveal misperceptions about nicotine product harmfulness and underscore the importance of developing a science base to inform policies and educate consumers about these products.

  6. Effects of nicotine given into the brain of fowls

    PubMed Central

    Marley, E.; Seller, T.J.

    1974-01-01

    1 The effects of nicotine, given into the IIIrd ventricle of adult conscious fowls (Gallus domesticus) or infused into various brain regions of conscious young chicks, were tested on behaviour, electrocortical activity, respiratory rate and body temperature. Its effects given intraventricularly or applied externally to the brain-stem of anaesthetized fowls were also examined. 2 After intraventricular nicotine, fowls squatted for 3 to 5 min with eyes closed, electrocortical activity resembling that during sleep but with superimposed spike activity. Following this, fowls reawakened and tachypnoea developed, together with partial abduction of the wings from the trunk, the back becoming horizontal and the tail flexed. These effects were prevented by pempidine. 3 Intraventricular nicotine suppressed or, less commonly, reduced operant key-pecking, an effect unrelated linearly to dose. 4 Intraventricular nicotine given to fowls anaesthetized with chloralose produced brief apnoea, followed by increased amplitude of respiratory excursion for about 5 minutes. Respiratory rate accelerated slightly but tachypnoea did not develop. Nicotine applied directly to the ventral brain-stem increased respiratory amplitude in three out of seven fowls. 5 In anaesthetized fowls, intraventricular nicotine raised blood pressure for 2 to 3 min, an effect prolonged up to 70 min by acute bilateral vagotomy, whereas pressor effects of intravenous nicotine were extended merely two to three fold. Dividing the spinal cord at C2 prevented pressor effects of intraventricular nicotine; those of intravenous nicotine were unaltered. 6 In young chicks, nicotine infused into the diencephalon, telencephalon and myelencephalon induced effects similar to those observed immediately after intraventricular nicotine, i.e. chicks squatted with closed eyes but recovered within 3 to 5 minutes. Simultaneously, electrocortical activity changed from an alert to the sleep pattern, usually with superimposed `spike

  7. Nicotine addiction through a neurogenomic prism

    PubMed Central

    Caron, Lorraine; Karkazis, Katrina; Raffin, Thomas A.; Swan, Gary; Koenig, Barbara A.

    2008-01-01

    Studies are under way to examine the neurogenetic factors contributing to smoking behaviors. The combined approaches of genomics, molecular biology, neuroscience, and pharmacology are expected to fuel developments in pharmacogenetics, to create new genetic tests, and ultimately to provide the basis for innovative strategies for smoking cessation and prevention. The emergence of a neurogenomic understanding of nicotine addiction is likely to induce fundamental changes in popular, clinical, and public health views of smoking, which could significantly shape existing practices and policies to reduce tobacco use. Still a nascent area of research, nicotine addiction provides an excellent case study through which to anticipate key ethical and policy issues in both behavioral genetics and the neurogenomics of addictive behaviors. PMID:16036275

  8. Effects of maternal nicotine on breastfeeding infants

    PubMed Central

    Primo, Cândida Caniçali; Ruela, Priscilla Bôa F.; Brotto, Léia Damasceno de A.; Garcia, Telma Ribeiro; Lima, Eliane de Fátima

    2013-01-01

    OBJECTIVE To assess scientific evidence about the effects of maternal nicotine on infant by an integrative review. DATA SOURCES Studies published in Portuguese, English and Spanish, from 1990 to 2009, with abstracts available in the Latin American Health Sciences Literature (Lilacs) and Medical Literature Analysis and Retrieval System On-Line (Medline) databases. The descriptors were: "breastfeeding", "lactation" and "smoking". DATA SYNTHESIS The main identified effects of nicotine on infants were: changes in sleep and wakefulness patterns; reduction of iodine supply; hystopathological damage on liver and lung; intracellular oxidative damage; reduction of pancreatic ß cells; and decreased glucose tolerance. CONCLUSIONS It is recommended to inform mothers about harmful chemicals contained in cigarettes that can be secreted into breast milk. They should be strongly encouraged to stop smoking during lactation. PMID:24142324

  9. Effects of maternal nicotine on breastfeeding infants.

    PubMed

    Primo, Cândida Caniçali; Ruela, Priscilla Bôa F; Brotto, Léia Damasceno de A; Garcia, Telma Ribeiro; Lima, Eliane de Fátima

    2013-09-01

    OBJECTIVE To assess scientific evidence about the effects of maternal nicotine on infant by an integrative review. DATA SOURCES Studies published in Portuguese, English and Spanish, from 1990 to 2009, with abstracts available in the Latin American Health Sciences Literature (Lilacs) and Medical Literature Analysis and Retrieval System On-Line (Medline) databases. The descriptors were: "breastfeeding", "lactation" and "smoking". DATA SYNTHESIS The main identified effects of nicotine on infants were: changes in sleep and wakefulness patterns; reduction of iodine supply; hystopathological damage on liver and lung; intracellular oxidative damage; reduction of pancreatic ß cells; and decreased glucose tolerance. CONCLUSIONS It is recommended to inform mothers about harmful chemicals contained in cigarettes that can be secreted into breast milk. They should be strongly encouraged to stop smoking during lactation. PMID:24142324

  10. Synthesis and biodistribution of radioiodinated nicotine analogs

    SciTech Connect

    Chan, S.M.; Basmadjian, G.P.; Marten, D.F.; Sadek, S.; Magarian, R.A.; Grunder, J.R.; Ice, R.D.

    1984-01-01

    The authors reported previously on the synthesis and biodistribution of radioiodinated 5-iodonicotine. In their continuous effort to search for a potential brain as well as adrenal medulla imaging agent, the authors synthesized four radioiodinated nicotine analogs. The labeled compounds were prepared by brominating nicotinic acid, and reacting the acylated product with the appropriate amines to give the respective amides which were then reduced with diborane to the amines. I-125 labeling was done by halogen exchange. Biodistribution studies performed in female Sprague-Dawley rats showed that all these compounds were taken up rapidly by the brain and the adrenal. The highest uptake of all these compounds in both organs occurred at 2 minutes after tail vein injections. The organ:blood ratios at 2 minutes and the T/sub 1/3/ (min.) of radioactivity in these organs were compared.

  11. In vitro study of nicotine release from smokeless tobacco.

    PubMed

    Nasr, M M; Reepmeyer, J C; Tang, Y

    1998-01-01

    Four brands (Copenhagen Snuff, Skoal Bandit Classic, Skoal Wintergreen Long Cut, and Skoal Wintergreen Fine Cut) of smokeless tobacco products were tested for their rate of nicotine release into artificial saliva via direct contact or through a dialysis bag. Nicotine was determined by reversed-phase liquid chromatography. When samples were in direct contact with artificial saliva, most of the nicotine was released from the tobacco in the first minute. Nicotine release from Skoal Bandit Classic, marketed as smokeless tobacco in a sachet, was slower with the sachet intact than without the sachet. When smokeless tobacco and artificial saliva were placed inside a dialysis bag, nicotine release was much slower and primarily depended upon the permeability of the dialysis membrane. Although total nicotine was lowest for Skoal Bandit Classic, little difference was seen in nicotine release rates among the brands tested. When smokeless tobacco was placed in dialysis bags with artificial saliva outside, a significant difference was seen in rates of nicotine migration through the membrane. In this model, nicotine release from Copenhagen Snuff was much faster than from Skoal Bandit Classic with or without the sachet. This difference may be related to the pH of the smokeless tobacco products.

  12. Revisiting the Effect of Nicotine on Interval Timing

    PubMed Central

    Daniels, Carter W.; Watterson, Elizabeth; Garcia, Raul; Mazur, Gabriel J.; Brackney, Ryan J.; Sanabria, Federico

    2015-01-01

    This paper reviews the evidence for nicotine-induced acceleration of the internal clock when timing in the seconds-to-minutes timescale, and proposes an alternative explanation to this evidence: that nicotine reduces the threshold for responses that result in more reinforcement. These two hypotheses were tested in male Wistar rats using a novel timing task. In this task, rats were trained to seek food at one location after 8 s since trial onset and at a different location after 16 s. Some rats received the same reward at both times (group SAME); some received a larger reward at 16 s (group DIFF). Steady baseline performance was followed by 3 days of subcutaneous nicotine administration (0.3 mg/kg), baseline recovery, and an antagonist challenge (mecamylamine, 1.0 mg/kg). Nicotine induced a larger, immediate reduction in latencies to switch (LTS) in group DIFF than in group SAME. This effect was sustained throughout nicotine administration. Mecamylamine administration and discontinuation of nicotine rapidly recovered baseline performance. These results support a response-threshold account of nicotinic disruption of timing performance, possibly mediated by nicotinic acetylcholine receptors. A detailed analysis of the distribution of LTSs suggests that anomalous effects of nicotine on LTS dispersion may be due to loss of temporal control of behavior. PMID:25637907

  13. Estimation of personal exposure to ambient nicotine in daily environment.

    PubMed

    Muramatsu, M; Umemura, S; Fukui, J; Arai, T; Kira, S

    1987-01-01

    To evaluate the actual exposure level of nonsmokers to environmental tobacco smoke (ETS) in their daily life, the exposure level of ambient nicotine was measured with a nicotine personal monitor carried by a nonsmoker. Average exposure levels of nicotine, even in such smoky places as cars, coffee shops and pubs, were less than 45 micrograms/m3. As a result of all-day monitoring, the highest amount of nicotine inhaled in a day was estimated, in this study, to be up to 310 micrograms, equivalent to actively smoking 0.31 ordinary cigarettes. PMID:3679553

  14. Stable isotope studies of nicotine kinetics and bioavailability

    SciTech Connect

    Benowitz, N.L.; Jacob, P. 3d.; Denaro, C.; Jenkins, R. )

    1991-03-01

    The stable isotope-labeled compound 3',3'-dideuteronicotine was used to investigate the disposition kinetics of nicotine in smokers, the systemic absorption of nicotine from cigarette smoke, and the bioavailability of nicotine ingested as oral capsules. Blood levels of labeled nicotine could be measured for 9 hours after a 30-minute intravenous infusion. Analysis of disposition kinetics in 10 healthy men revealed a multiexponential decline after the end of an infusion, with an elimination half-life averaging 203 minutes. This half-life was longer than that previously reported, indicating the presence of a shallow elimination phase. Plasma clearance averaged 14.6 ml/min/kg. The average intake of nicotine per cigarette was 2.29 mg. A cigarette smoke-monitoring system that directly measured particulate matter in smoke was evaluated in these subjects. Total particulate matter, number of puffs on the cigarette, total puff volume, and time of puffing correlated with the intake of nicotine from smoking. The oral bioavailability of nicotine averaged 44%. This bioavailability is higher than expected based on the systemic clearance of nicotine and suggests that there may be significant extrahepatic metabolism of nicotine.

  15. Modulation of cerebral microvascular permeability by endothelial nicotinic acetylcholine receptors.

    PubMed

    Hawkins, Brian T; Egleton, Richard D; Davis, Thomas P

    2005-07-01

    Nicotine increases the permeability of the blood-brain barrier in vivo. This implies a possible role for nicotinic acetylcholine receptors in the regulation of cerebral microvascular permeability. Expression of nicotinic acetylcholine receptor subunits in cerebral microvessels was investigated with immunofluorescence microscopy. Positive immunoreactivity was found for receptor subunits alpha3, alpha5, alpha7, and beta2, but not subunits alpha4, beta3, or beta4. Blood-brain barrier permeability was assessed via in situ brain perfusion with [14C]sucrose. Nicotine increased the rate of sucrose entry into the brain from 0.3 +/- 0.1 to 1.1 +/- 0.2 microl.g(-1).min(-1), as previously described. This nicotine-induced increase in blood-brain barrier permeability was significantly attenuated by both the blood-brain barrier-permeant nicotinic antagonist mecamylamine and the blood-brain barrier-impermeant nicotinic antagonist hexamethonium to 0.5 +/- 0.2 and 0.3 +/- 0.2 microl.g(-1).min(-1), respectively. These data suggest that nicotinic acetylcholine receptors expressed on the cerebral microvascular endothelium mediate nicotine-induced changes in blood-brain barrier permeability.

  16. Nicotinic modulation of serotonergic activity in the dorsal raphe nucleus.

    PubMed

    Hernandez-Lopez, Salvador; Garduño, Julieta; Mihailescu, Stefan

    2013-01-01

    Cholinergic signaling mediated by nicotinic receptors has been associated to a large number of physiological and behavioral processes such as learning, memory, attention, food-intake and mood disorders. Although it is well established that many nicotinic actions are mediated through an increase in serotonin (5-HT) release, the physiological mechanisms by which nicotine produces these effects are still unclear. The dorsal raphe nucleus (DRN) contains the major amount of 5-HT neurons projecting to different parts of the brain. DRN also contains nicotinic acetylcholine receptors (nAChRs) located at somatic and presynaptic elements. Nicotine produces both inhibitory and excitatory effects on different subpopulations of 5-HT DRN neurons. In this review, we describe the presynaptic and postsynaptic mechanisms by which nicotine increases the excitability of DRN neurons as well as the subtypes of nAChRs involved. We also describe the inhibitory effects of nicotine and the role of 5-HT1A receptors in this effect. These nicotinic actions modulate the activity of different neuronal subpopulations in the DRN, changing the 5-HT tone in the brain areas where these groups of neurons project. Some of the physiological implications of nicotine-induced 5-HT release are discussed. PMID:24021594

  17. Sensory reinforcement-enhancing effects of nicotine via smoking.

    PubMed

    Perkins, Kenneth A; Karelitz, Joshua L

    2014-12-01

    As has been found in nicotine research on animals, research on humans has shown that acute nicotine enhances reinforcement from rewards unrelated to nicotine intake, but this effect may be specific to rewards from stimuli that are "sensory" in nature. We assessed acute effects of nicotine via smoking on responding for music or video rewards (sensory), for monetary reward (nonsensory), or for no reward (control), to gauge the generalizability of nicotine's reinforcement-enhancing effects. Using a fully within-subjects design, dependent smokers (N = 20) participated in 3 similar experimental sessions, each following overnight abstinence (verified by carbon monoxide <10 ppm) and varying only in the smoking condition. Sessions involved no smoking or smoking "denicotinized" ("denic;" 0.05 mg) or nicotine (0.6 mg) Quest brand cigarettes in controlled fashion prior to responding on a simple operant computer task for each reward separately using a progressive ratio schedule. The reinforcing effects of music and video rewards, but not money, were significantly greater due to the nicotine versus denic cigarette (i.e., nicotine per se), whereas there were no differences between denic cigarette smoking and no smoking (i.e., smoking behavior per se), except for no reward. These effects were not influenced by withdrawal relief from either cigarette. Results that generalize from an auditory to a visual reward confirm that acute nicotine intake per se enhances the reinforcing value of sensory rewards, but its effects on the value of other (perhaps nonsensory) types of rewards may be more modest.

  18. The metabolism of [14C]nicotine in the cat

    PubMed Central

    Turner, D. M.

    1969-01-01

    The metabolism of [2′-14C]nicotine given as an intravenous injection in small doses to anaesthetized and unanaesthetized cats has been studied. A method is described for the quantitative determination of [14C]nicotine and [14C]cotinine in tissues and body fluids. Nanogram amounts of these compounds have been detected. After a single dose of 40μg. of [14C]nicotine/kg., 55% of the injected radioactivity was excreted in the urine within 24hr., but only 1% of this radioactivity was unchanged nicotine. [14C]Nicotine is metabolized extremely rapidly, [14C]cotinine appearing in the blood within 2·5min. of intravenous injection. [14C]Nicotine accumulates rapidly in the brain and 15min. after injection 90% of the radioactivity still represents [14C]nicotine. Metabolites of [14C]nicotine have been identified in liver and urine extracts. [14C]Nicotine-1′-oxide has been detected in both liver and urine. PMID:5360723

  19. Estradiol promotes the rewarding effects of nicotine in female rats.

    PubMed

    Flores, Rodolfo J; Pipkin, Joseph A; Uribe, Kevin P; Perez, Adriana; O'Dell, Laura E

    2016-07-01

    It is presently unclear whether ovarian hormones, such as estradiol (E2), promote the rewarding effects of nicotine in females. Thus, we compared extended access to nicotine intravenous self-administration (IVSA) in intact male, intact female, and OVX female rats (Study 1) as well as OVX females that received vehicle or E2 supplementation (Study 2). The E2 supplementation procedure involved a 4-day injection regimen involving 2 days of vehicle and 2 days of E2 administration. Two doses of E2 (25 or 250μg) were assessed in separate groups of OVX females in order to examine the dose-dependent effects of this hormone on the rewarding effects of nicotine. The rats were given 23-hour access to nicotine IVSA using an escalating dose regimen (0.015, 0.03, and 0.06mg/kg/0.1mL). Each dose was self-administered for 4 days with 3 intervening days of nicotine abstinence. The results revealed that intact females displayed higher levels of nicotine intake as compared to males. Also, intact females displayed higher levels of nicotine intake versus OVX females. Lastly, our results revealed that OVX rats that received E2 supplementation displayed a dose-dependent increase in nicotine intake as compared to OVX rats that received vehicle. Together, our results suggest that the rewarding effects of nicotine are enhanced in female rats via the presence of the ovarian hormone, E2.

  20. 27 CFR 21.119 - Nicotine solution.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... nicotine; 3.6 avoirdupois ounces of methylene blue, U.S.P.; water sufficient to make 100 gallons. (b) Color..., with 50 ml of a standard color solution containing 5 grams of CuSO4·5H2 O, C.P. in 100 ml of water. The... with a suitable bulb tube, 50 ml of 0.1 N NaOH added and the mixture distilled in a current of...

  1. 27 CFR 21.119 - Nicotine solution.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... nicotine; 3.6 avoirdupois ounces of methylene blue, U.S.P.; water sufficient to make 100 gallons. (b) Color..., with 50 ml of a standard color solution containing 5 grams of CuSO4·5H2 O, C.P. in 100 ml of water. The... with a suitable bulb tube, 50 ml of 0.1 N NaOH added and the mixture distilled in a current of...

  2. 27 CFR 21.119 - Nicotine solution.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... nicotine; 3.6 avoirdupois ounces of methylene blue, U.S.P.; water sufficient to make 100 gallons. (b) Color..., with 50 ml of a standard color solution containing 5 grams of CuSO4·5H2 O, C.P. in 100 ml of water. The... with a suitable bulb tube, 50 ml of 0.1 N NaOH added and the mixture distilled in a current of...

  3. 27 CFR 21.119 - Nicotine solution.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... nicotine; 3.6 avoirdupois ounces of methylene blue, U.S.P.; water sufficient to make 100 gallons. (b) Color..., with 50 ml of a standard color solution containing 5 grams of CuSO4·5H2 O, C.P. in 100 ml of water. The... with a suitable bulb tube, 50 ml of 0.1 N NaOH added and the mixture distilled in a current of...

  4. 27 CFR 21.119 - Nicotine solution.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... nicotine; 3.6 avoirdupois ounces of methylene blue, U.S.P.; water sufficient to make 100 gallons. (b) Color..., with 50 ml of a standard color solution containing 5 grams of CuSO4·5H2 O, C.P. in 100 ml of water. The... with a suitable bulb tube, 50 ml of 0.1 N NaOH added and the mixture distilled in a current of...

  5. Nicotine response genetics in the zebrafish

    PubMed Central

    Petzold, Andrew M.; Balciunas, Darius; Sivasubbu, Sridhar; Clark, Karl J.; Bedell, Victoria M.; Westcot, Stephanie E.; Myers, Shelly R.; Moulder, Gary L.; Thomas, Mark J.; Ekker, Stephen C.

    2009-01-01

    Tobacco use is predicted to result in over 1 billion deaths worldwide by the end of the 21st century. How genetic variation contributes to the observed differential predisposition in the human population to drug dependence is unknown. The zebrafish (Danio rerio) is an emerging vertebrate model system for understanding the genetics of behavior. We developed a nicotine behavioral assay in zebrafish and applied it in a forward genetic screen using gene-breaking transposon mutagenesis. We used this method to molecularly characterize bdav/cct8 and hbog/gabbr1.2 as mutations with altered nicotine response. Each have a single human ortholog, identifying two points for potential scientific, diagnostic, and drug development for nicotine biology and cessation therapeutics. We show this insertional method generates mutant alleles that are reversible through Cre-mediated recombination, representing a conditional mutation system for the zebrafish. The combination of this reporter-tagged insertional mutagen approach and zebrafish provides a powerful platform for a rich array of questions amenable to genetic-based scientific inquiry, including the basis of behavior, epigenetics, plasticity, stress, memory, and learning. PMID:19858493

  6. Nicotine and cannabinoids: parallels, contrasts and interactions.

    PubMed

    Viveros, Maria-Paz; Marco, Eva M; File, Sandra E

    2006-01-01

    After a brief outline of the nicotinic and cannabinoid systems, we review the interactions between the pharmacological effects of nicotine and cannabis, two of the most widely used drugs of dependence. These drugs are increasingly taken in combination, particularly among the adolescents and young adults. The review focuses on addiction-related processes, gateway and reverse gateway theories of addiction and therapeutic implications. It then reviews studies on the important period of adolescence, an area that is in urgent need of further investigation and in which the importance of sex differences is emerging. Three other areas of research, which might be particularly relevant to the onset and/or maintenance of dependence, are then reviewed. Firstly, the effects of the two drugs on anxiety-related behaviours are discussed and then their effects on food intake and cognition, two areas in which they have contrasting effects. Certain animal studies suggest that reinforcing effects are likely to be enhanced by joint consumption of nicotine and cannabis, as also may be anxiolytic effects. If this was the case in humans, the latter might be viewed as an advantage particularly by adolescent girls, although the increased weight gain associated with cannabis would be a disadvantage. The two drugs also have opposite effects on cognition and the possibility of long-lasting cognitive impairments resulting from adolescent consumption of cannabis is of particular concern.

  7. Advances in nicotine research in Addiction Biology.

    PubMed

    Bernardi, Rick E

    2015-09-01

    The aim of Addiction Biology is to advance our understanding of the action of drugs of abuse and addictive processes via the publication of high-impact clinical and pre-clinical findings resulting from behavioral, molecular, genetic, biochemical, neurobiological and pharmacological research. As of 2013, Addiction Biology is ranked number 1 in the category of Substance Abuse journals (SCI). Occasionally, Addiction Biology likes to highlight via review important findings focused on a particular topic and recently published in the journal. The current review summarizes a number of key publications from Addiction Biology that have contributed to the current knowledge of nicotine research, comprising a wide spectrum of approaches, both clinical and pre-clinical, at the cellular, molecular, systems and behavioral levels. A number of findings from human studies have identified, using imaging techniques, alterations in common brain circuits, as well as morphological and network activity changes, associated with tobacco use. Furthermore, both clinical and pre-clinical studies have characterized a number of mechanistic targets critical to understanding the effects of nicotine and tobacco addiction. Together, these findings will undoubtedly drive future studies examining the dramatic impact of tobacco use and the development of treatments to counter nicotine dependence. PMID:25997723

  8. Advances in nicotine research in Addiction Biology.

    PubMed

    Bernardi, Rick E

    2015-09-01

    The aim of Addiction Biology is to advance our understanding of the action of drugs of abuse and addictive processes via the publication of high-impact clinical and pre-clinical findings resulting from behavioral, molecular, genetic, biochemical, neurobiological and pharmacological research. As of 2013, Addiction Biology is ranked number 1 in the category of Substance Abuse journals (SCI). Occasionally, Addiction Biology likes to highlight via review important findings focused on a particular topic and recently published in the journal. The current review summarizes a number of key publications from Addiction Biology that have contributed to the current knowledge of nicotine research, comprising a wide spectrum of approaches, both clinical and pre-clinical, at the cellular, molecular, systems and behavioral levels. A number of findings from human studies have identified, using imaging techniques, alterations in common brain circuits, as well as morphological and network activity changes, associated with tobacco use. Furthermore, both clinical and pre-clinical studies have characterized a number of mechanistic targets critical to understanding the effects of nicotine and tobacco addiction. Together, these findings will undoubtedly drive future studies examining the dramatic impact of tobacco use and the development of treatments to counter nicotine dependence.

  9. Nicotine content and delivery across tobacco products.

    PubMed

    Djordjevic, Mirjana V; Doran, Kelly A

    2009-01-01

    Nicotine is the principal alkaloid in both commercial and homemade products (e.g., cigarettes, smokeless tobacco, bidis, waterpipes) followed by nornicotine, anabasine, anatabine, and many other basic substances that contain a cyclic nitrogenous nucleus. Tobacco types, leaf position on the plant, agricultural practices, fertilizer treatment, and degree of ripening are among some prominent factors that determine the levels of alkaloids in tobacco leaf. From a random examination of 152 cultivated varieties of Nicotiana tabacum, a range of alkaloid variation between 0.17 and 4.93% was determined. In fact, every step in tobacco production that affects plant metabolism will influence the level of alkaloid content to a certain degree. Depending on blending recipe, type and amount of additives, and product design, all types of tobacco products contain a very wide range of nicotine concentration. However, the ultimate emission of nicotine to the user, exposure, and psychophar-macological effects depend not only on the content and emission, but also on the relationship between the product and the user. PMID:19184646

  10. Nicotine content and delivery across tobacco products.

    PubMed

    Djordjevic, Mirjana V; Doran, Kelly A

    2009-01-01

    Nicotine is the principal alkaloid in both commercial and homemade products (e.g., cigarettes, smokeless tobacco, bidis, waterpipes) followed by nornicotine, anabasine, anatabine, and many other basic substances that contain a cyclic nitrogenous nucleus. Tobacco types, leaf position on the plant, agricultural practices, fertilizer treatment, and degree of ripening are among some prominent factors that determine the levels of alkaloids in tobacco leaf. From a random examination of 152 cultivated varieties of Nicotiana tabacum, a range of alkaloid variation between 0.17 and 4.93% was determined. In fact, every step in tobacco production that affects plant metabolism will influence the level of alkaloid content to a certain degree. Depending on blending recipe, type and amount of additives, and product design, all types of tobacco products contain a very wide range of nicotine concentration. However, the ultimate emission of nicotine to the user, exposure, and psychophar-macological effects depend not only on the content and emission, but also on the relationship between the product and the user.

  11. Impairment of contextual fear extinction by chronic nicotine and withdrawal from chronic nicotine is associated with hippocampal nAChR upregulation.

    PubMed

    Kutlu, Munir Gunes; Oliver, Chicora; Huang, Peng; Liu-Chen, Lee-Yuan; Gould, Thomas J

    2016-10-01

    Chronic nicotine and withdrawal from chronic nicotine have been shown to be major modulators of fear learning behavior. Moreover, recent studies from our laboratory have shown that acute nicotine impaired fear extinction and safety learning in mice. However, the effects of chronic nicotine and withdrawal on fear extinction are unknown. Therefore, the current experiments were conducted to investigate the effects of chronic nicotine as well as withdrawal from chronic nicotine on contextual fear extinction in mice. C57BL6/J mice were given contextual fear conditioning training and retention testing during chronic nicotine administration. Mice then received contextual fear extinction either during chronic nicotine or during withdrawal from chronic nicotine. Our results showed that contextual fear extinction was impaired both during chronic nicotine administration and subsequent withdrawal. However, it was also observed that the effects of prior chronic nicotine disappeared after 72 h in withdrawal, a timeline that closely matches with the timing of the chronic nicotine-induced upregulation of hippocampal nicotinic acetylcholine receptor (nAChR) density. Additional experiments found that 4 days, but not 1 day, of continuous nicotine administration upregulated hippocampal nAChRs and impaired contextual fear extinction. These effects disappeared following 72 h withdrawal. Overall, these experiments provide a potential link between nicotine-induced upregulation of hippocampal nAChRs and fear extinction deficits observed in patients with anxiety disorders, which may lead to advancements in the pharmacological treatment methods for this disorder. PMID:27378334

  12. Variation in the α 5 nicotinic acetylcholine receptor subunit gene predicts cigarette smoking intensity as a function of nicotine content.

    PubMed

    Macqueen, D A; Heckman, B W; Blank, M D; Janse Van Rensburg, K; Park, J Y; Drobes, D J; Evans, D E

    2014-02-01

    A single-nucleotide polymorphism (SNP) in the α5 nicotinic acetylcholine receptor subunit gene, rs16969968, has been repeatedly associated with both smoking and respiratory health phenotypes. However, there remains considerable debate as to whether associations with lung cancer are mediated through effects on smoking behavior. Preclinical studies suggest that α5 receptor subunit expression and function may have a direct role in nicotine titration during self administration. The present study investigated the association of CHRNA5 polymorphisms and smoking topography in 66 smokers asked to smoke four nicotine-containing (nicotine yield=0.60 mg) and four placebo (nicotine yield <0.05 mg) cigarettes, during separate experimental sessions. Genotype at rs16969968 predicted nicotine titration, with homozygotes for the major allele (G:G) displaying significantly reduced puff volume in response to nicotine, whereas minor allele carriers (A:G or A:A) produced equivalent puff volumes for placebo and nicotine cigarettes. The present results suggest that puff volume may be a more powerful objective phenotype of smoking behavior than self-reported cigarettes per day and nicotine dependence. Further, these results suggest that the association between rs16969968 and lung cancer may be mediated by the quantity of smoke inhaled.

  13. Nicotine and endogenous opioids: neurochemical and pharmacological evidence.

    PubMed

    Hadjiconstantinou, Maria; Neff, Norton H

    2011-06-01

    Although the mesolimbic dopamine hypothesis is the most influential theory of nicotine reward and reinforcement, there has been a consensus that other neurotransmitter systems contribute to the addictive properties of nicotine as well. In this regard, the brain opioidergic system is of interest. Striatum is rich in opioid peptides and opioid receptors, and striatal opioidergic neurons are engaged in a bidirectional communication with midbrain dopaminergic neurons, closely regulating each other's activity. Enkephalins and dynorphins exert opposing actions on dopaminergic neurons, increasing and decreasing dopamine release respectively, and are components of circuits promoting positive or negative motivational and affective states. Moreover, dopamine controls the synthesis of striatal enkephalins and dynorphins. Evidence suggests that opioidergic function is altered after nicotine and endogenous opioids are involved in nicotine's behavioral effects. 1) The synthesis and release of β-endorphin, met-enkephalin and dynorphin in brain, especially nucleus accumbens (NAc), are altered after acute or chronic nicotine treatment and during nicotine withdrawal. 2) Although opioid receptor binding and mRNA do not appear to change in the striatum during nicotine withdrawal, the activity of κ-opioid (KOPr) and δ-opioid (DOPr) receptors is attenuated in NAc. 3) The nicotine withdrawal syndrome reminisces that of opiates, and naloxone precipitates some of its somatic, motivational, and affective signs. 4) Genetic and pharmacological studies indicate that μ-opioid (MOPr) receptors are mainly involved in nicotine reward, while DOPrs contribute to the emotional and KOPrs to the aversive responses of nicotine. 5) Finally, MOPrs and enkephalin, but not β-endorphin or dynorphin, are necessary for the physical manifestations of nicotine withdrawal. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

  14. Environmental fate and effects of nicotine released during cigarette production.

    PubMed

    Seckar, Joel A; Stavanja, Mari S; Harp, Paul R; Yi, Yongsheng; Garner, Charles D; Doi, Jon

    2008-07-01

    A variety of test methods were used to study the gradation, bioaccumulation, and toxicity of nicotine. Studies included determination of the octanol-water partition coefficient, conversion to CO2 in soil and activated sludge, and evaluation of the effects on microbiological and algal inhibition as well as plant germination and root elongation. The partitioning of nicotine between octanol and water indicated that nicotine will not bioaccumulate regardless of the pH of the medium. The aqueous and soil-based biodegradation studies indicated that nicotine is readily biodegradable in both types of media. The microbiological inhibition and aquatic and terrestrial toxicity tests indicated that nicotine has low toxicity. The U.S. Environmental Protection Agency Persistence, Bioaccumulation, and Toxicity Profiler model, based on the structure of nicotine and the predictive rates of hydroxyl radical and ozone reactions, estimated an atmospheric half-life of less than 5.0 h. Using this value in the Canadian Environmental Modeling Center level III model, the half-life of nicotine was estimated as 3.0 d in water and 0.5 d in soil. This model also estimated nicotine discharge into the environment; nicotine would be expected to be found predominantly in water (93%), followed by soil (4%), air (3%), and sediment (0.4%). Using the estimated nicotine concentrations in water, soil, and sediment and the proper median effective concentrations derived from the algal growth, biomass inhibition, and buttercrunch lettuce (Lactuca sativa) seed germination and root elongation studies, hazard quotients of between 10(-7) and 10(-8) were calculated, providing further support for the conclusion that the potential for nicotine toxicity to aquatic and terrestrial species in the environment is extremely low.

  15. Environmental fate and effects of nicotine released during cigarette production.

    PubMed

    Seckar, Joel A; Stavanja, Mari S; Harp, Paul R; Yi, Yongsheng; Garner, Charles D; Doi, Jon

    2008-07-01

    A variety of test methods were used to study the gradation, bioaccumulation, and toxicity of nicotine. Studies included determination of the octanol-water partition coefficient, conversion to CO2 in soil and activated sludge, and evaluation of the effects on microbiological and algal inhibition as well as plant germination and root elongation. The partitioning of nicotine between octanol and water indicated that nicotine will not bioaccumulate regardless of the pH of the medium. The aqueous and soil-based biodegradation studies indicated that nicotine is readily biodegradable in both types of media. The microbiological inhibition and aquatic and terrestrial toxicity tests indicated that nicotine has low toxicity. The U.S. Environmental Protection Agency Persistence, Bioaccumulation, and Toxicity Profiler model, based on the structure of nicotine and the predictive rates of hydroxyl radical and ozone reactions, estimated an atmospheric half-life of less than 5.0 h. Using this value in the Canadian Environmental Modeling Center level III model, the half-life of nicotine was estimated as 3.0 d in water and 0.5 d in soil. This model also estimated nicotine discharge into the environment; nicotine would be expected to be found predominantly in water (93%), followed by soil (4%), air (3%), and sediment (0.4%). Using the estimated nicotine concentrations in water, soil, and sediment and the proper median effective concentrations derived from the algal growth, biomass inhibition, and buttercrunch lettuce (Lactuca sativa) seed germination and root elongation studies, hazard quotients of between 10(-7) and 10(-8) were calculated, providing further support for the conclusion that the potential for nicotine toxicity to aquatic and terrestrial species in the environment is extremely low. PMID:18399728

  16. Discovering the mechanisms underlying serotonin (5-HT)2A and 5-HT2C receptor regulation following nicotine withdrawal in rats.

    PubMed

    Zaniewska, Magdalena; Alenina, Natalia; Wydra, Karolina; Fröhler, Sebastian; Kuśmider, Maciej; McCreary, Andrew C; Chen, Wei; Bader, Michael; Filip, Małgorzata

    2015-08-01

    We have previously demonstrated that nicotine withdrawal produces depression-like behavior and that serotonin (5-HT)2A/2C receptor ligands modulate that mood-like state. In the present study we aimed to identify the mechanisms (changes in radioligand binding, transcription or RNA-editing) related to such a behavioral outcome. Rats received vehicle or nicotine (0.4 mg/kg, s.c.) for 5 days in home cages. Brain 5-HT2A/2C receptors were analyzed on day 3 of nicotine withdrawal. Nicotine withdrawal increased [(3)H]ketanserin binding to 5-HT2A receptors in the ventral tegmental area and ventral dentate gyrus, yet decreased binding in the nucleus accumbens shell. Reduction in [(3)H]mesulergine binding to 5-HT2C receptors was seen in the ventral dentate gyrus. Profound decrease in the 5-HT2A receptor transcript level was noted in the hippocampus and ventral tegmental area. Out of five 5-HT2C receptor mRNA editing sites, deep sequencing data showed a reduction in editing at the E site and a trend toward reduction at the C site in the hippocampus. In the ventral tegmental area, a reduction for the frequency of CD 5-HT2C receptor transcript was seen. These results show that the reduction in the 5-HT2A receptor transcript level may be an auto-regulatory response to the increased receptor density in the hippocampus and ventral tegmental area during nicotine withdrawal, while decreased 5-HT2C receptor mRNA editing may explain the reduction in receptor labeling in the hippocampus. Serotonin (5-HT)2A/2C receptor ligands alleviate depression-like state in nicotine-withdrawn rats. Here, we show that the reduction in 5-HT2A receptor transcript level may be an auto-regulatory response to the increased receptor number in the hippocampus and ventral tegmental area during nicotine withdrawal, while attenuated 5-HT2C receptor mRNA editing in the hippocampus might explain reduced inverse agonist binding to 5-HT2C receptor and suggest a shift toward a population of more active receptors. 5

  17. Impact of nicotine metabolism on nicotine's pharmacological effects and behavioral responses: insights from a Cyp2a(4/5)bgs-null mouse.

    PubMed

    Li, Lei; Jia, Kunzhi; Zhou, Xin; McCallum, Sarah E; Hough, Lindsay B; Ding, Xinxin

    2013-12-01

    Nicotine metabolism is believed to affect not only nicotine's pharmacological effects but also nicotine addiction. As a key step toward testing this hypothesis, we have studied nicotine metabolism and nicotine's pharmacological and behavioral effects in a novel knockout mouse model [named Cyp2a(4/5)bgs-null] lacking a number of cytochrome P450 genes known to be or possibly involved in nicotine metabolism, including two Cyp2a and all Cyp2b genes. We found that, compared with wild-type mice, the Cyp2a(4/5)bgs-null mice showed >90% decreases in hepatic microsomal nicotine oxidase activity in vitro, and in rates of systemic nicotine clearance in vivo. Further comparisons of nicotine metabolism between Cyp2a(4/5)bgs-null and Cyp2a5-null mice revealed significant roles of both CYP2A5 and CYP2B enzymes in nicotine clearance. Compared with the behavioral responses in wild-type mice, the decreases in nicotine metabolism in the Cyp2a(4/5)bgs-null mice led to prolonged nicotine-induced acute pharmacological effects, in that null mice showed enhanced nicotine hypothermia and antinociception. Furthermore, we found that the Cyp2a(4/5)bgs-null mice developed a preference for nicotine in a conditioned place preference test, a commonly used test of nicotine's rewarding effects, at a nicotine dose that was 4-fold lower than what was required by wild-type mice. Thus, CYP2A/2B-catalyzed nicotine clearance affects nicotine's behavioral response as well as its acute pharmacological effects in mice. This result provides direct experimental support of the findings of pharmacogenetic studies that suggest linkage between rates of nicotine metabolism and smoking behavior in humans.

  18. Time-course of extracellular nicotine and cotinine levels in rat brain following administration of nicotine: effects of route and ethanol coadministration

    PubMed Central

    Katner, Simon N.; Toalston, Jamie E.; Smoker, Michael P.; Rodd, Zachary A.; McBride, William J.

    2015-01-01

    Rationale Nicotine and ethanol are commonly coabused drugs, and nicotine-laced ethanol products are growing in popularity. However, little is known about time-course changes in extracellular nicotine and cotinine levels in rat models of ethanol and nicotine coabuse. Objectives The objective of the present study was to determine the time-course changes in brain levels of nicotine and cotinine following subcutaneous (SC) and intragastric (IG) nicotine administration in alcohol-preferring (P) and Wistar rats. Methods In vivo microdialysis was used to collect dialysate samples from the nucleus accumbens shell (NACsh) for nicotine and cotinine determinations, following SC administration of (−)-nicotine (0.18, 0.35, and 0.70 mg/kg) in female P and Wistar rats or IG administration of (−)-nicotine (0.35 and 0.70 mg/kg) in 15 % (v/v) ethanol or water in female P rats. Results SC nicotine produced nicotine and cotinine dialysate levels as high as 51 and 14 ng/ml, respectively. IG administration of 15 % EtOH + 0.70 mg/kg nicotine in P rats resulted in maximal nicotine and cotinine dialysate levels of 19 and 14 ng/ml, respectively, whereas administration of 0.70 mg/kg nicotine in water resulted in maximal nicotine and cotinine levels of 21 and 25 ng/ml, respectively. Nicotine and cotinine levels were detectable within the first 15 and 45 min, respectively, after IG administration. Conclusions Overall, the results of this study suggest that nicotine is rapidly adsorbed and produces relevant extracellular brain concentrations of nicotine and its pharmacologically active metabolite, cotinine. The persisting high brain concentrations of cotinine may contribute to nicotine addiction. PMID:25038869

  19. Impact of nicotine metabolism on nicotine's pharmacological effects and behavioral responses: insights from a Cyp2a(4/5)bgs-null mouse.

    PubMed

    Li, Lei; Jia, Kunzhi; Zhou, Xin; McCallum, Sarah E; Hough, Lindsay B; Ding, Xinxin

    2013-12-01

    Nicotine metabolism is believed to affect not only nicotine's pharmacological effects but also nicotine addiction. As a key step toward testing this hypothesis, we have studied nicotine metabolism and nicotine's pharmacological and behavioral effects in a novel knockout mouse model [named Cyp2a(4/5)bgs-null] lacking a number of cytochrome P450 genes known to be or possibly involved in nicotine metabolism, including two Cyp2a and all Cyp2b genes. We found that, compared with wild-type mice, the Cyp2a(4/5)bgs-null mice showed >90% decreases in hepatic microsomal nicotine oxidase activity in vitro, and in rates of systemic nicotine clearance in vivo. Further comparisons of nicotine metabolism between Cyp2a(4/5)bgs-null and Cyp2a5-null mice revealed significant roles of both CYP2A5 and CYP2B enzymes in nicotine clearance. Compared with the behavioral responses in wild-type mice, the decreases in nicotine metabolism in the Cyp2a(4/5)bgs-null mice led to prolonged nicotine-induced acute pharmacological effects, in that null mice showed enhanced nicotine hypothermia and antinociception. Furthermore, we found that the Cyp2a(4/5)bgs-null mice developed a preference for nicotine in a conditioned place preference test, a commonly used test of nicotine's rewarding effects, at a nicotine dose that was 4-fold lower than what was required by wild-type mice. Thus, CYP2A/2B-catalyzed nicotine clearance affects nicotine's behavioral response as well as its acute pharmacological effects in mice. This result provides direct experimental support of the findings of pharmacogenetic studies that suggest linkage between rates of nicotine metabolism and smoking behavior in humans. PMID:24045421

  20. Differential expression of the beta4 neuronal nicotinic receptor subunit affects tolerance development and nicotinic binding sites following chronic nicotine treatment

    PubMed Central

    Meyers, Erin E.; Loetz, Esteban C.; Marks, Michael J.

    2015-01-01

    The role of neuronal nicotinic acetylcholine receptors (nAChR) containing the β4 subunit in tolerance development and nicotinic binding site levels following chronic nicotine treatment was investigated. Mice differing in expression of the β4 nAChR subunit [wild-type (β4++), heterozygote (β4+−) and null mutant (β4−−)] were chronically treated for 10 days with nicotine (0, 0.5, 1.0, 2.0 or 4.0 mg/kg/hr) by constant intravenous infusion. Chronic nicotine treatment elicited dose-dependent tolerance development. β4−− mice developed significantly more tolerance than either β4++ or β4+− mice which was most evident following treatment with 4.0 mg/kg/hr nicotine. Subsets of [125I]-epibatidine binding were measured in several brain regions. Deletion of the β4 subunit had little effect on initial levels of cytisine-sensitive [125I]-epibatidine binding (primarily α4β2-nAChR sites) or their response (generally increased binding) to chronic nicotine treatment. In contrast, β4 gene-dose-dependent decreases in expression 5IA-85380 resistant [125I]-epibatidine binding sites (primarily β4*-nAChR) were observed. While these β4*nAChR sites were generally resistant to regulation by chronic nicotine treatment, significant increases in binding were noted for habenula and hindbrain. Comparison of previously published tolerance development in β2−− mice (less tolerance) to that of β4−− mice (more tolerance) supports a differential role for these receptor subtypes in regulating tolerance following chronic nicotine treatment. PMID:25560939

  1. Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors.

    PubMed

    Yohn, Nicole L; Turner, Jill R; Blendy, Julie A

    2014-05-01

    Although nicotine mediates its effects through several nicotinic acetylcholine receptor (nAChR) subtypes, it remains to be determined which nAChR subtypes directly mediate heightened anxiety during withdrawal. Relative success in abstinence has been found with the nAChR partial agonist varenicline (Chantix; Pfizer, Groton, CT); however, treatment with this drug fails to alleviate anxiety in individuals during nicotine withdrawal. Therefore, it is hypothesized that success can be found by the repurposing of other nAChR partial agonists for cessation therapies that target anxiety. It is noteworthy that the selective partial agonists for α4β2, ABT-089 [2-methyl-3-[2(S)-pyrrolidinylmethoxy]pyridine], and α7, ABT-107 [5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole] (AbbVie, North Chicago, IL), have not been evaluated as possible therapeutics for nicotine cessation. Therefore, we examined the effect of ABT-089 and ABT-107 on anxiety during withdrawal from nicotine in the novelty-induced hypophagia (NIH) paradigm. We found that short-term administration of ABT-089 and ABT-107 alleviate anxiety-like behavior during withdrawal from nicotine while long-term administration of ABT-089 but not ABT-107 reduces anxiety-like behavior during withdrawal. After behavioral testing, brains were harvested and β2-containing nAChRs were measured using [(3)H]epibaditine. ABT-089 and ABT-107 do not upregulate nAChRs, which is in contrast to the upregulation of nAChRs observed after nicotine. Furthermore, ABT-089 is anxiogenic in nicotine naive animals, suggesting that the effects on anxiety are specifically related to the nicotine-dependent state. Together, these studies identify additional nAChR partial agonists that may aid in the rational development of smoking cessation aids.

  2. Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors.

    PubMed

    Yohn, Nicole L; Turner, Jill R; Blendy, Julie A

    2014-05-01

    Although nicotine mediates its effects through several nicotinic acetylcholine receptor (nAChR) subtypes, it remains to be determined which nAChR subtypes directly mediate heightened anxiety during withdrawal. Relative success in abstinence has been found with the nAChR partial agonist varenicline (Chantix; Pfizer, Groton, CT); however, treatment with this drug fails to alleviate anxiety in individuals during nicotine withdrawal. Therefore, it is hypothesized that success can be found by the repurposing of other nAChR partial agonists for cessation therapies that target anxiety. It is noteworthy that the selective partial agonists for α4β2, ABT-089 [2-methyl-3-[2(S)-pyrrolidinylmethoxy]pyridine], and α7, ABT-107 [5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole] (AbbVie, North Chicago, IL), have not been evaluated as possible therapeutics for nicotine cessation. Therefore, we examined the effect of ABT-089 and ABT-107 on anxiety during withdrawal from nicotine in the novelty-induced hypophagia (NIH) paradigm. We found that short-term administration of ABT-089 and ABT-107 alleviate anxiety-like behavior during withdrawal from nicotine while long-term administration of ABT-089 but not ABT-107 reduces anxiety-like behavior during withdrawal. After behavioral testing, brains were harvested and β2-containing nAChRs were measured using [(3)H]epibaditine. ABT-089 and ABT-107 do not upregulate nAChRs, which is in contrast to the upregulation of nAChRs observed after nicotine. Furthermore, ABT-089 is anxiogenic in nicotine naive animals, suggesting that the effects on anxiety are specifically related to the nicotine-dependent state. Together, these studies identify additional nAChR partial agonists that may aid in the rational development of smoking cessation aids. PMID:24627467

  3. N(N)-nicotinic blockade as an acute human model of autonomic failure

    NASA Technical Reports Server (NTRS)

    Jordan, J.; Shannon, J. R.; Black, B. K.; Lance, R. H.; Squillante, M. D.; Costa, F.; Robertson, D.

    1998-01-01

    Pure autonomic failure has been conceptualized as deficient sympathetic and parasympathetic innervation. Several recent observations in chronic autonomic failure, however, cannot be explained simply by loss of autonomic innervation, at least according to our current understanding. To simulate acute autonomic failure, we blocked N(N)-nicotinic receptors with intravenous trimethaphan (6+/-0.4 mg/min) in 7 healthy subjects (4 men, 3 women, aged 32+/-3 years, 68+/-4 kg, 171+/-5 cm). N(N)-Nicotinic receptor blockade resulted in near-complete interruption of sympathetic and parasympathetic efferents as indicated by a battery of autonomic function tests. With trimethaphan, small postural changes from the horizontal were associated with significant blood pressure changes without compensatory changes in heart rate. Gastrointestinal motility, pupillary function, saliva production, and tearing were profoundly suppressed with trimethaphan. Plasma norepinephrine level decreased from 1.1+/-0.12 nmol/L (180+/-20 pg/mL) at baseline to 0.23+/-0.05 nmol/L (39+/-8 pg/mL) with trimethaphan (P<.001). There was a more than 16-fold increase in plasma vasopressin (P<.01) and no change in plasma renin activity. We conclude that blockade of N(N)-cholinergic receptors is useful to simulate the hemodynamic alterations of acute autonomic failure in humans. The loss of function with acute N(N)-cholinergic blockade is more complete than in most cases of chronic autonomic failure. This difference may be exploited to elucidate the contributions of acute denervation and chronic adaptation to the pathophysiology of autonomic failure. N(N)-Cholinergic blockade may also be applied to study human cardiovascular physiology and pharmacology in the absence of confounding baroreflexes.

  4. Sex differences in nicotine self-administration in rats during progressive unit dose reduction: Implications for nicotine regulation policy

    PubMed Central

    Grebenstein, Patricia; Burroughs, Danielle; Zhang, Yan; LeSage, Mark G.

    2013-01-01

    Reducing the nicotine content in tobacco products is being considered by the FDA as a policy to reduce the addictiveness of tobacco products. Understanding individual differences in response to nicotine reduction will be critical to developing safe and effective policy. Animal and human research demonstrating sex differences in the reinforcing effects of nicotine suggests that males and females may respond differently to nicotine-reduction policies. However, no studies have directly examined sex differences in the effects of nicotine unit-dose reduction on nicotine self-administration (NSA) in animals. The purpose of the present study was to examine this issue in a rodent self-administration model. Male and female rats were trained to self-administer nicotine (0.06 mg/kg) under an FR 3 schedule during daily 23 h sessions. Rats were then exposed to saline extinction and reacquisition of NSA, followed by weekly reductions in the unit dose (0.03 to 0.00025 mg/kg) until extinction levels of responding were achieved. Males and females were compared with respect to baseline levels of intake, resistance to extinction, degree of compensatory increases in responding during dose reduction, and the threshold reinforcing unit dose of nicotine. Exponential demand-curve analysis was also conducted to compare the sensitivity of males and females to increases in the unit price (FR/unit dose) of nicotine (i.e., elasticity of demand or reinforcing efficacy). Females exhibited significantly higher baseline intake and less compensation than males. However, there were no sex differences in the reinforcement threshold or elasticity of demand. Dose–response relationships were very well described by the exponential demand function (r2 values > 0.96 for individual subjects). These findings suggest that females may exhibit less compensatory smoking in response to nicotine reduction policies, even though their nicotine reinforcement threshold and elasticity of demand may not differ from

  5. L-theanine inhibits nicotine-induced dependence via regulation of the nicotine acetylcholine receptor-dopamine reward pathway.

    PubMed

    Di, Xiaojing; Yan, Jingqi; Zhao, Yan; Chang, Yanzhong; Zhao, Baolu

    2012-12-01

    In this study, the inhibitory effect of L-theanine, an amino acid derivative of tea, on the rewarding effects of nicotine and its underlying mechanisms of action were studied. We found that L-theanine inhibited the rewarding effects of nicotine in a conditioned place preference (CPP) model of the mouse and reduced the excitatory status induced by nicotine in SH-SY5Y cells to the same extent as the nicotine receptor inhibitor dihydro-beta-erythroidine (DHβE). Further studies using high performance liquid chromatography, western blotting and immunofluorescence staining analyses showed that L-theanine significantly inhibited nicotine-induced tyrosine hydroxylase (TH) expression and dopamine production in the midbrain of mice. L-theanine treatment also reduced the upregulation of the α(4), β(2) and α(7) nicotine acetylcholine receptor (nAChR) subunits induced by nicotine in mouse brain regions that related to the dopamine reward pathway, thus decreasing the number of cells that could react to nicotine. In addition, L-theanine treatment inhibited nicotine-induced c-Fos expression in the reward circuit related areas of the mouse brain. Knockdown of c-Fos by siRNA inhibited the excitatory status of cells but not the upregulation of TH induced by nicotine in SH-SY5Y cells. Overall, the present study showed that L-theanine reduced the nicotine-induced reward effects via inhibition of the nAChR-dopamine reward pathway. These results may offer new therapeutic strategies for treatment of tobacco addiction.

  6. Sex differences in nicotine self-administration in rats during progressive unit dose reduction: implications for nicotine regulation policy.

    PubMed

    Grebenstein, Patricia; Burroughs, Danielle; Zhang, Yan; LeSage, Mark G

    2013-12-01

    Reducing the nicotine content in tobacco products is being considered by the FDA as a policy to reduce the addictiveness of tobacco products. Understanding individual differences in response to nicotine reduction will be critical to developing safe and effective policy. Animal and human research demonstrating sex differences in the reinforcing effects of nicotine suggests that males and females may respond differently to nicotine-reduction policies. However, no studies have directly examined sex differences in the effects of nicotine unit-dose reduction on nicotine self-administration (NSA) in animals. The purpose of the present study was to examine this issue in a rodent self-administration model. Male and female rats were trained to self-administer nicotine (0.06mg/kg) under an FR 3 schedule during daily 23h sessions. Rats were then exposed to saline extinction and reacquisition of NSA, followed by weekly reductions in the unit dose (0.03 to 0.00025mg/kg) until extinction levels of responding were achieved. Males and females were compared with respect to baseline levels of intake, resistance to extinction, degree of compensatory increases in responding during dose reduction, and the threshold reinforcing unit dose of nicotine. Exponential demand-curve analysis was also conducted to compare the sensitivity of males and females to increases in the unit price (FR/unit dose) of nicotine (i.e., elasticity of demand or reinforcing efficacy). Females exhibited significantly higher baseline intake and less compensation than males. However, there were no sex differences in the reinforcement threshold or elasticity of demand. Dose-response relationships were very well described by the exponential demand function (r(2) values>0.96 for individual subjects). These findings suggest that females may exhibit less compensatory smoking in response to nicotine reduction policies, even though their nicotine reinforcement threshold and elasticity of demand may not differ from males

  7. [New prospects of nicotine dependence treatment--vaccines].

    PubMed

    Goniewicz, Maciej Lukasz; Koszowski, Bartosz; Czogała, Jan; Zymełka, Anna

    2006-01-01

    Smoking is considered to be one of the main threats to health in many societies around the world. Despite carrying out numerous large-scale campaigns promoting a healthy life-style and stimulant avoidance, nicotine dependence still concerns a huge group of people. What is more, almost half of the population is exposed to passive contact with tobacco smoke. At present, there is a whole range of pharmaceutical and non-pharmaceutical means of fighting nicotine dependence. The dramatic development of medical sciences in recent years, especially of the fields connected with biotechnology, resulted in working out of a new method of nicotinism treatment--antinicotinic vaccines. The starting point for working out of such drugs was the mechanism of nicotine action on central nervous system. The idea behind the vaccine is to prevent nicotine from passing through the blood-brain barrier. Nicotine molecules, due to their size and lipophilic character, can easily enter the brain. The mechanism of the antinicotinic vaccine's action consists in producing specific antibodies, which combined with nicotine in the bloodstream are to create immune complexes big enough not to enter the brain. Currently, clinical trails of three vaccines are being carried out: TA-NIC (Xenova Group, UK), NicVAX (NABI Biopharmaceuticals, USA), CYT002-NicQb (Cytos Biotechnology, Switzerland). The results indicate that this form of treatment is interesting when it comes to its effectiveness and in the future may become a routine method of nicotine dependence treatment. PMID:17288232

  8. Nicotinamide metabolism in ferns: formation of nicotinic acid glucoside.

    PubMed

    Ashihara, Hiroshi; Yin, Yuling; Watanabe, Shin

    2011-03-01

    The metabolic fate of [carbonyl-(14)C]nicotinamide was investigated in 9 fern species, Psilotum nudum, Angiopteris evecta, Lygodium japonicum, Acrostichum aureum, Asplenium antiquum, Diplazium subsinuatum, Thelypteris acuminate, Blechnum orientale and Crytomium fortune. All fern species produce a large quantity of nicotinic acid glucoside from [(14)C]nicotinamide, but trigonelline formation is very low. Increases in the release of (14)CO(2) with incubation time was accompanied by decreases in [carboxyl-(14)C]nicotinic acid glucoside. There was slight stimulation of nicotinic acid glucoside formation by 250 mM NaCl in mature leaves of the mangrove fern, Acrostichum aureum, but it is unlikely that this compound acts as a compatible solute. Nicotinamide and nicotinic acid salvage for pyridine nucleotide synthesis was detected in all fern species, although this activity was always less than nicotinic acid glucoside synthesis. Predominant formation of nicotinic acid glucoside is characteristic of nicotinic acid metabolism in ferns. This reaction appears to act as a detoxication mechanism, removing excess nicotinic acid.

  9. Pathophysiological effects of nicotine on the pancreas: an update.

    PubMed

    Chowdhury, Parimal; MacLeod, Stewart; Udupa, Kodetthor B; Rayford, Phillip L

    2002-07-01

    Epidemiological evidence strongly suggests an association between cigarette smoking and pancreatic diseases. It is well recognized that nicotine, a major component in cigarette smoke, is an addictive agent and, therefore, reinforces smoking behavior. The current review update focuses on the genetics of nicotine dependence and its role on the development of pancreatic diseases. The role of smoking and nicotine in pancreatitis and pancreatic cancer development is also discussed. Exposure of laboratory animals to nicotine clearly supports the notion that nicotine can induce pancreatic injury. The mechanism by which nicotine induces such effects is perhaps mediated via signal transduction pathways in the pancreatic acinar cell, leading to enhanced levels of intracellular calcium release, resulting in cytotoxicity and eventual cell death. The induction of pancreatic injury by nicotine may also involve activation and expression of protooncogene, H-ras, which can increase cytosolic calcium via second messenger pathways. Development of pancreatic carcinoma in cigarette smokers as observed in human populations may be the result of activation and mutation of the H-ras gene. A possible pathogenetic mechanism of nicotine in the pancreas activating multiple signal transduction pathways is schematically summarized in Figure 1.

  10. Free radical production in nicotine treated pancreatic tissue.

    PubMed

    Wetscher, G J; Bagchi, M; Bagchi, D; Perdikis, G; Hinder, P R; Glaser, K; Hinder, R A

    1995-05-01

    The ability of nicotine to induce oxidative stress in the pancreatic tissue of rats was investigated. Homogenized pancreatic tissue of Sprague-Dawley rats was incubated with nicotine in a dose of 200 ng/mg protein/ml for 15, 30, 45, and 60 min or was incubated for 30 min with nicotine in a dose of 50, 100, 200, 400, and 800 ng/mg protein/ml. Pancreatic tissue was also incubated with 200 ng/mg protein/ml nicotine with or without the scavengers superoxide dismutase (SOD), catalase, SOD+catalase, inactivated SOD, inactivated catalase, or albumin. Incubation with 0.9% NaCl served as control. There was a positive correlation between the duration of nicotine incubation and chemiluminescence (r = 0.6) or lipid peroxidation (r = 0.71) and also between the nicotine dose and chemiluminescence (r = 0.54) or lipid peroxidation (r = 0.66). Thirty minutes incubation of pancreatic tissue with nicotine in a dose of 200 ng/mg protein/ml increased chemiluminescence 5 fold and lipid peroxidation 2.5 fold. This response was dampened by SOD or catalase and abolished by SOD+catalase. Inactivated enzymes or albumin had no scavenging effect. These results demonstrate that nicotine causes oxidative stress to the pancreatic tissue of rats. PMID:7797095

  11. Extending the role of associative learning processes in nicotine addiction.

    PubMed

    Bevins, Rick A; Palmatier, Matthew I

    2004-09-01

    Compulsive smoking is a worldwide public health problem. Although research has confirmed the importance of associative learning processes in nicotine addiction, therapies targeting nicotine-associated cues still have a high relapse rate. Most theories conceptualize nicotine as an 'outcome' that reinforces behaviors and/or changes the affective value of stimuli. Albeit important, this view does not capture the complexity of associative processes involved in nicotine addiction. For example, nicotine serves as a conditional stimulus acquiring new appetitive/affective properties when paired with a non-drug reward. Also, nicotine functions as an occasion setter that participates in higher-order associative processes that likely permit a more pervasive influence of conditioned cues that are resistant to typically cue-exposure therapy techniques. Finally, nicotine appears to amplify the salience of other stimuli that have some incentive value resulting in enhanced nicotine self-administration and conditioned reinforcement processes. Future smoking intervention strategies should take into consideration these additional associative learning processes.

  12. The pyrolysis of (-)-(S)-nicotine: racemization and decomposition.

    PubMed

    Clayton, Peter; Lu, Annhelen; Bishop, Louise

    2010-05-01

    The pyrolytic behaviour of (-)-(S)-nicotine in methanol was investigated using on-line pyrolysis GC/MS to establish whether racemization to the R(+) antipode occurs and to identify other products of pyrolysis. The conditions used included pyrolysing the sample for 15 seconds in an atmosphere of 9% oxygen in nitrogen (275 ml/min total flow) across the temperature range of 200 degrees C-1000 degrees C. A chiral Cyclodex-B analytical column (30 m x 0.25 mm i.d. x 0.25 microm film thickness) was used to separate the enantiomers of nicotine, although the two enantiomer peaks were not baseline resolved. The results of the experiment shows that there is no increase in (+)-(R)-nicotine levels across a wide temperature range. This suggests that the elevated levels of (+)-R-nicotine observed in tobacco smoke (compared to tobacco leaf material) are not due to the pyrolytic auto-racemization of (-)-(S)-nicotine but are a result of more complex interactions between (-)-(S)-nicotine and other smoke components. The pyrolysis of isotopically labelled nicotine established that nicotine undergoes thermal decomposition to beta-nicotyrine which in turn may decompose to other products.

  13. Educating Smokers about Their Cigarettes and Nicotine Medications

    ERIC Educational Resources Information Center

    Bansal-Travers, Maansi; Cummings, K. Michael; Hyland, Andrew; Brown, Anthony; Celestino, Paula

    2010-01-01

    The objective of this study was to test the efficacy of specially designed educational materials to correct misperceptions held by smokers about nicotine, nicotine medications, low tar cigarettes, filters and product ingredients. To accomplish this, 682 New York State Smokers' Quitline callers were randomized to one of two groups: control group…

  14. How Prepared Are Psychiatry Residents for Treating Nicotine Dependence?

    ERIC Educational Resources Information Center

    Prochaska, Judith J.; Fromont, Sebastien C.; Hall, Sharon M.

    2005-01-01

    Objective: Nicotine dependence is the most prevalent substance abuse disorder among adult psychiatric patients and a leading cause of death and disability. The authors examined the extent to which psychiatry residents are prepared to treat nicotine dependence in clinical practice. Methods: Residents from five psychiatry residency programs in…

  15. A Critical Evaluation of Nicotine Replacement Therapy for Teenage Smokers.

    ERIC Educational Resources Information Center

    Patten, Christi A.

    2000-01-01

    Evaluates the appropriateness and feasibility of nicotine replacement therapy (NRT) in teenage smokers. Available forms of NRT, theoretical rationale and efficacy of NRT, ethical considerations, and the feasibility of NRT in teenage smokers are addressed. Several characteristics similar to adult nicotine dependent smokers have been found in teen…

  16. The Smoking Gun in Nicotine-Induced Anorexia

    PubMed Central

    Rubinstein, Marcelo; Low, Malcolm J.

    2013-01-01

    Hypothalamic proopiomelanocortin (POMC) neurons are the major source of anorectic melanocortin peptides in the brain. A recent study (Mineur et al., 2011) demonstrates that nicotine directly stimulates arcuate POMC neurons through nicotinic acetylcholinergic α3β4 receptors, suggesting a new mechanism to understand the inverse relationship between tobacco smoking and body weight. PMID:21803282

  17. Decreasing Nicotine Content Reduces Subjective and Physiological Effects of Smoking

    PubMed Central

    Penetar, David M.; Lindsey, Kimberly P.; Peters, Erica N.; Juliano, Trisha M.; Lukas, Scott E.

    2013-01-01

    Objective Assessment of the subjective and physiological effects of smoking cigarettes with different machine-smoked nicotine yields. Methods Eight volunteers rated the characteristics of cigarettes with varying levels of nicotine (Quest®). At 30 minute intervals, participants smoked one of three different Quest® brand cigarettes in a counterbalanced order (reported machine-smoked nicotine yield: 0.6 mg, 0.3 mg, or 0.05 mg). Smoking satisfaction and sensations were measured on a cigarette evaluation questionnaire. A mood questionnaire measured self-reported subjective changes in ‘happy’, ‘stimulated’, ‘anxious’, ‘desire to smoke’, and ‘desire not to smoke’. Heart rate and skin temperature were recorded continuously. Results As nicotine yield decreased, cigarettes produced smaller changes in subjective ratings on the evaluation questionnaire with the placebo nicotine cigarette always rated lower or less potent than the other two cigarettes evaluated. Heart rate was significantly increased by the reduced nicotine cigarettes, but was not affected by the nicotine-free cigarette. Conclusion These results indicate that machine-smoked yield is an important determinant of both the subjective and physiological effects of smoking. The use of reduced and nicotine free cigarettes in smoking cessation programs remains to be evaluated. PMID:25253991

  18. Neurotensin agonist attenuates nicotine potentiation to cocaine sensitization.

    PubMed

    Fredrickson, Paul; Boules, Mona; Stennett, Bethany; Richelson, Elliott

    2014-03-01

    Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a "gateway drug". Neurotensin (NT) is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13) analog, blocks behavioral sensitization (an animal model for psychostimulant addiction) to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control) followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine. PMID:25379267

  19. Public Support for Mandated Nicotine Reduction in Cigarettes

    PubMed Central

    Abrams, David B.; Niaura, Raymond S.; Richardson, Amanda; Vallone, Donna M.

    2013-01-01

    Objectives. We assessed public support for a potential Food and Drug Administration (FDA)–mandated reduction in cigarette nicotine content. Methods. We used nationally representative data from a June 2010 cross-sectional survey of US adults (n = 2649) to obtain weighted point estimates and correlates of support for mandated nicotine reduction. We also assessed the potential role of political ideology in support of FDA regulation of nicotine. Results. Nearly 50% of the public supported mandated cigarette nicotine reduction, with another 28% having no strong opinion concerning this potential FDA regulation. Support for nicotine reduction was highest among Hispanics, African Americans, and those with less than a high school education. Among smokers, the odds of supporting FDA nicotine regulation were 2.77 times higher among smokers who intended to quit in the next 6 months than among those with no plans to quit. Conclusions. Mandating nicotine reduction in cigarettes to nonaddictive levels may reduce youth initiation and facilitate adult cessation. The reasons behind nicotine regulation need to be communicated to the public to preempt tobacco industry efforts to impede such a regulation. PMID:23327262

  20. Discriminating nicotine and non-nicotine containing e-liquids using infrared spectroscopy.

    PubMed

    Deconinck, E; Bothy, J L; Barhdadi, S; Courselle, P

    2016-02-20

    In a few countries, including Belgium, nicotine-containing e-cigarettes and e-liquids are considered medicines, and therefore cannot freely be sold, but should be distributed in a pharmacy. The fact that in the neighbouring countries these products are freely available, poses a problem for custom personnel, the more the nicotine content of the products is not always labelled, especially when they are bought through internet. Therefore there is a need for easy-to-use equipment and methods to perform a first on site screening of intercepted samples, both for border control as to check label compliance of the sample. The use of attenuated total reflectance-infrared spectroscopy (ATR-IR) and near infrared spectroscopy (NIR), combined with chemometrics was evaluated for the discrimination between nicotine containing and non-nicotine containing samples. It could be concluded that both ATR-IR and NIR could be used for the discrimination when combined with the appropriate chemometric techniques. The presented techniques do not need sample preparation and result in models with a minimum of false negative samples. If a large enough training set can be established the interpretation can be fully automated, making the presented approach suitable for on-site screening of e-liquid samples. PMID:26771132

  1. Nicotinic acetylcholine receptors controlling attention: behavior, circuits and sensitivity to disruption by nicotine.

    PubMed

    Poorthuis, Rogier B; Mansvelder, Huibert D

    2013-10-15

    Attention is a central cognitive function that enables long-term engagement in a task and suppression of irrelevant information to obtain future goals. The prefrontal cortex (PFC) is the main link in integrating emotional and motivational state of an animal to regulate top-down attentional processes. Acetylcholine modulates PFC neuronal networks by activating nicotinic acetylcholine receptors (nAChRs) to support attention. However, how neuronal activity changes in the PFC during attention and which nAChR subtypes mediate this is only rudimentarily understood, but progress is being made. Recently, exciting new insights were obtained in the dynamics of cholinergic signaling in the PFC and modes of acetylcholine transmission via nAChRs in the cortex. In addition, mechanisms are uncovered on how the PFC circuitry is regulated by nAChRs. Novel studies show that endogenous activation of nAChRs in the PFC plays a central role in controlling attention. Here, we review current insights into how different subtypes of nAChRs expressed by distinct types of neurons in the PFC circuitry shape attention. In addition we discuss the impact of nicotine on the cholinergic system and prefrontal cortical circuits. Low concentrations of nicotine, as experienced by smokers, interfere with cholinergic signaling. In the long-term exposure to nicotine during adolescence leads to maladaptive adaptations of the PFC circuitry, which ultimately leads to a decrement in attention performance, again emphasizing the importance of nAChRs in attention.

  2. Nicotinic, glutamatergic and dopaminergic synaptic transmission and plasticity in the mesocorticolimbic system: focus on nicotine effects.

    PubMed

    Pistillo, Francesco; Clementi, Francesco; Zoli, Michele; Gotti, Cecilia

    2015-01-01

    Cigarette smoking is currently the leading cause of preventable deaths and disability throughout the world, being responsible for about five million premature deaths/year. Unfortunately, fewer than 10% of tobacco users who try to stop smoking actually manage to do so. The main addictive agent delivered by cigarette smoke is nicotine, which induces psychostimulation and reward, and reduces stress and anxiety. The use of new technologies (including optogenetics) and the development of mouse models characterised by cell-specific deletions of receptor subtype genes or the expression of gain-of-function nAChR subunits has greatly increased our understanding of the molecular mechanisms and neural substrates of nicotine addiction first revealed by classic electrophysiological, neurochemical and behavioural approaches. It is now becoming clear that various aspects of nicotine dependence are mediated by close interactions of the glutamatergic, dopaminergic and γ-aminobutyric acidergic systems in the mesocorticolimbic system. This review is divided into two parts. The first provides an updated overview of the circuitry of the ventral tegmental area, ventral striatum and prefrontal cortex, the neurotransmitter receptor subtypes expressed in these areas, and their physiological role in the mesocorticolimbic system. The second will focus on the molecular, functional and behavioural mechanisms involved in the acute and chronic effects of nicotine on the mesocorticolimbic system.

  3. A pilot study on nicotine residues in houses of electronic cigarette (e-cigarette) users, tobacco smokers, and non-users of nicotine-containing products

    PubMed Central

    Bush, Derek; Goniewicz, Maciej L.

    2015-01-01

    Background Nicotine deposited on the surfaces has been shown to react with airborne chemicals leading to formation of carcinogens and contributing to thirdhand exposure. While prior studies revealed nicotine residues in tobacco smokers' homes, none have examined the nicotine residue in electronic cigarette (e-cigarette) users' homes. Methods We measured nicotine on the surfaces in households of 8 e-cigarette users, 6 cigarette smokers, and 8 non-users of nicotine-containing products in Western New York, USA. Three surface wipe samples were taken from the floor, wall and window. Nicotine was extracted from the wipes and analyzed using gas chromatography. Results Half of the e-cigarette users' homes had detectable levels of nicotine on surfaces whereas nicotine was found in all of the tobacco cigarette smokers' homes. Trace amounts of nicotine were also detected in half of the homes of non-users of nicotine-containing products. Nicotine levels in e-cigarette users homes was significantly lower than that found in cigarette smokers homes (average concentration 7.7±17.2 vs. 1,303±2,676 μg/m2; p<0.05). There was no significant difference in the amount of nicotine in homes of e-cigarette users and non-users (p>0.05). Conclusions Nicotine is a common contaminant found on indoor surfaces. Using e-cigarettes indoors leads to significantly less thirdhand exposure to nicotine compared to smoking tobacco cigarettes. PMID:25869751

  4. Roles of nicotinic acetylcholine receptor β subunits in function of human α4-containing nicotinic receptors

    PubMed Central

    Wu, Jie; Liu, Qiang; Yu, Kewei; Hu, Jun; Kuo, Yen-Ping; Segerberg, Marsha; St John, Paul A; Lukas, Ronald J

    2006-01-01

    Naturally expressed nicotinic acetylcholine receptors (nAChR) containing α4 subunits (α4*-nAChR) in combination with β2 subunits (α4β2-nAChR) are among the most abundant, high-affinity nicotine binding sites in the mammalian brain. β4 subunits are also richly expressed and colocalize with α4 subunits in several brain regions implicated in behavioural responses to nicotine and nicotine dependence. Thus, α4β4-nAChR also may exist and play important functional roles. In this study, properties were determined of human α4β2- and α4β4-nAChR heterologously expressed de novo in human SH-EP1 epithelial cells. Whole-cell currents mediated via human α4β4-nAChR have ∼4-fold higher amplitude than those mediated via human α4β2-nAChR and exhibit much slower acute desensitization and functional rundown. Nicotinic agonists induce peak whole-cell current responses typically with higher functional potency at α4β4-nAChR than at α4β2-nAChR. Cytisine and lobeline serve as full agonists at α4β4-nAChR but are only partial agonists at α4β2-nAChR. However, nicotinic antagonists, except hexamethonium, have comparable affinities for functional α4β2- and α4β4-nAChR. Whole-cell current responses show stronger inward rectification for α4β2-nAChR than for α4β4-nAChR at a positive holding potential. Collectively, these findings demonstrate that human nAChR β2 or β4 subunits can combine with α4 subunits to generate two forms of α4*-nAChR with distinctive physiological and pharmacological features. Diversity in α4*-nAChR is of potential relevance to nervous system function, disease, and nicotine dependence. PMID:16825297

  5. Knowledge and Perceptions about Nicotine, Nicotine Replacement Therapies and Electronic Cigarettes among Healthcare Professionals in Greece

    PubMed Central

    Moysidou, Anastasia; Farsalinos, Konstantinos E.; Voudris, Vassilis; Merakou, Kyriakoula; Kourea, Kallirrhoe; Barbouni, Anastasia

    2016-01-01

    Introduction. The purpose of this study was to evaluate the knowledge and perceptions of Greek healthcare professionals about nicotine, nicotine replacement therapies and electronic cigarettes. Methods. An online survey was performed, in which physicians and nurses working in private and public healthcare sectors in Athens-Greece were asked to participate through email invitations. A knowledge score was calculated by scoring the correct answers to specific questions with 1 point. Results. A total of 262 healthcare professionals were included to the analysis. Most had daily contact with smokers in their working environment. About half of them considered that nicotine has an extremely or very important contribution to smoking-related disease. More than 30% considered nicotine replacement therapies equally or more addictive than smoking, 76.7% overestimated their smoking cessation efficacy and only 21.0% would recommend them as long-term smoking substitutes. For electronic cigarettes, 45.0% considered them equally or more addictive than smoking and 24.4% equally or more harmful than tobacco cigarettes. Additionally, 35.5% thought they involve combustion while the majority responded that nicotine in electronic cigarettes is synthetically produced. Only 14.5% knew about the pending European regulation, but 33.2% have recommended them to smokers in the past. Still, more than 40% would not recommend electronic cigarettes to smokers unwilling or unable to quit smoking with currently approved medications. Cardiologists and respiratory physicians, who are responsible for smoking cessation therapy in Greece, were even more reluctant to recommend electronic cigarettes to this subpopulation of smokers compared to all other participants. The knowledge score of the whole study sample was 7.7 (SD: 2.4) out of a maximum score of 16. Higher score was associated with specific physician specialties. Conclusions. Greek healthcare professionals appear to overestimate the adverse effects

  6. Locomotion induced by ventral tegmental microinjections of a nicotinic agonist.

    PubMed

    Museo, E; Wise, R A

    1990-03-01

    Bilateral microinjections of the nicotinic agonist cytisine (0.1, 1 or 10 nanomoles per side) into the ventral tegmental area increased locomotor activity. This increase in locomotion was antagonized by mecamylamine (2 mg/kg, IP), a nicotinic antagonist that readily crosses the blood-brain barrier, and by pimozide (0.3 mg/kg, IP), a central dopaminergic antagonist. Hexamethonium (2 mg/kg, IP), a nicotinic antagonist that, unlike mecamylamine, does not cross the blood-brain barrier, had no effect; this suggests that mecamylamine's attenuation of cytisine-induced locomotor activity resulted from a blockade of central and not peripheral nicotinic receptors. The data support the notion that nicotinic and dopaminergic substrates interact at the level of the VTA to produce increases in locomotor activity.

  7. Biosynthesis of trigonelline from nicotinate mononucleotide in mungbean seedlings.

    PubMed

    Zheng, Xin-Qiang; Matsui, Ayu; Ashihara, Hiroshi

    2008-01-01

    To determine the biosynthetic pathway to trigonelline, the metabolism of [carboxyl-(14)C]nicotinate mononucleotide (NaMN) and [carboxyl-(14)C]nicotinate riboside (NaR) in protein extracts and tissues of embryonic axes from germinating mungbeans (Phaseolus aureus) was investigated. In crude cell-free protein extracts, in the presence of S-adenosyl-L-methionine, radioactivity from [(14)C]NaMN was incorporated into NaR, nicotinate and trigonelline. Activities of NaMN nucleotidase, NaR nucleosidase and trigonelline synthase were also observed in the extracts. Exogenously supplied [(14)C]NaR, taken up by embryonic axes segments, was readily converted to nicotinate and trigonelline. It is concluded that the NaMN-->NaR-->nicotinate-->trigonelline pathway is operative in the embryonic axes of mungbean seedlings. This result suggests that trigonelline is synthesised not only from NAD but also via the de novo biosynthetic pathway of pyridine nucleotides. PMID:17888466

  8. Nicotinic cholinergic receptors in rat brain. Annual report No. 2

    SciTech Connect

    Kellar, K.J.

    1985-05-13

    We have conducted experiments to determine if 3H acetylcholine (3Hach) nicotinic recognition sites are located presynaptically on catecholamine and/or serotonin axons. Lesions of these axons by intraventricular injections of neurotoxins resulted in marked decreases in 3Hach binding sites in the striatum and hypothalamus, but not in the cortex or thalamus. These results indicate that 3Hach nicotinic binding sites are located on catecholamine and serotonin axons in specific areas of the brain. In other experiments, we determined that repeated administration of nicotine results in enhanced behavioral responses to a subsequent injection of nicotine, and that there appears to be a correlation between the enhanced response to nicotine and increased 3Hach binding sites in cerebral cortex.

  9. Historical and Current Perspective on Tobacco use and Nicotine Addiction

    PubMed Central

    Dani, John A.; Balfour, David J.K.

    2011-01-01

    Although the addictive influence of tobacco was recognized very early, the modern concepts of nicotine addiction have relied on knowledge of cholinergic neurotransmission and nicotinic acetylcholine receptors (nAChRs). The discovery of the “receptive substance” by Langley, that would turn out to be nAChRs, and “Vagusstoff” (acetylcholine) by Loewi, coincided with an exciting time when the concept of chemical synaptic transmission was being formulated. More recently, the application of more powerful techniques and the study of animal models that replicate key features of nicotine dependence have led to important advancements in our understanding of molecular, cellular, and systems mechanisms of nicotine addiction. In this Review, we present a historical perspective and overview of the research that has led to our present understanding of nicotine addiction. PMID:21696833

  10. The β3 subunit of the nicotinic acetylcholine receptor: Modulation of gene expression and nicotine consumption.

    PubMed

    Kamens, Helen M; Miyamoto, Jill; Powers, Matthew S; Ro, Kasey; Soto, Marissa; Cox, Ryan; Stitzel, Jerry A; Ehringer, Marissa A

    2015-12-01

    Genetic factors explain approximately half of the variance in smoking behaviors, but the molecular mechanism by which genetic variation influences behavior is poorly understood. SNPs in the putative promoter region of CHRNB3, the gene that encodes the β3 subunit of the nicotinic acetylcholine receptor (nAChR), have been repeatedly associated with nicotine behaviors. In this work we sought to identify putative function of three SNPs in the promoter region of CHRNB3 on in vitro gene expression. Additionally, we used β3 null mutant mice as a model of reduced gene expression to assess the effects on nicotine behaviors. The effect of rs13277254, rs6474413, and rs4950 on reporter gene expression was examined using a luciferase reporter assay. A major and minor parent haplotype served as the background on which alleles at the three SNPs were flipped onto different backgrounds (e.g. minor allele on major haplotype background). Constructs were tested in three human cell lines: BE(2)-C, SH-SY5Y and HEK293T. In all cell types the major haplotype led to greater reporter gene expression compared to the minor haplotype, and results indicate that this effect is driven by rs6474413. Moreover, mice lacking the β3 subunit showed reduced voluntary nicotine consumption compared that of wildtype animals. These data provide evidence that the protective genetic variant at rs6474413 identified in human genetic studies reduces gene expression and that decreased β3 gene expression in mice reduces nicotine intake. This work contributes to our understanding of the molecular mechanisms that contribute to the human genetic associations of tobacco behaviors.

  11. The therapeutic promise of positive allosteric modulation of nicotinic receptors.

    PubMed

    Uteshev, Victor V

    2014-03-15

    In the central nervous system, deficits in cholinergic neurotransmission correlate with decreased attention and cognitive impairment, while stimulation of neuronal nicotinic acetylcholine receptors improves attention, cognitive performance and neuronal resistance to injury as well as produces robust analgesic and anti-inflammatory effects. The rational basis for the therapeutic use of orthosteric agonists and positive allosteric modulators (PAMs) of nicotinic receptors arises from the finding that functional nicotinic receptors are ubiquitously expressed in neuronal and non-neuronal tissues including brain regions highly vulnerable to traumatic and ischemic types of injury (e.g., cortex and hippocampus). Moreover, functional nicotinic receptors do not vanish in age-, disease- and trauma-related neuropathologies, but their expression and/or activation levels decline in a subunit- and brain region-specific manner. Therefore, augmenting the endogenous cholinergic tone by nicotinic agents is possible and may offset neurological impairments associated with cholinergic hypofunction. Importantly, because neuronal damage elevates extracellular levels of choline (a selective agonist of α7 nicotinic acetylcholine receptors) near the site of injury, α7-PAM-based treatments may augment pathology-activated α7-dependent auto-therapies where and when they are most needed (i.e., in the penumbra, post-injury). Thus, nicotinic-PAM-based treatments are expected to augment the endogenous cholinergic tone in a spatially and temporally restricted manner creating the potential for differential efficacy and improved safety as compared to exogenous orthosteric nicotinic agonists that activate nicotinic receptors indiscriminately. In this review, I will summarize the existing trends in therapeutic applications of nicotinic PAMs.

  12. Adolescent nicotine exposure disrupts context conditioning in adulthood in rats.

    PubMed

    Spaeth, Andrea M; Barnet, Robert C; Hunt, Pamela S; Burk, Joshua A

    2010-10-01

    Despite the prevalence of smoking among adolescents, few studies have assessed the effects of adolescent nicotine exposure on learning in adulthood. In particular, it remains unclear whether adolescent nicotine exposure has effects on hippocampus-dependent learning that persist into adulthood. The present experiment examined whether there were effects of adolescent nicotine exposure on context conditioning, a form of learning dependent on the integrity of the hippocampus, when tested during adulthood. Rats were exposed to nicotine during adolescence (postnatal days [PD] 28-42) via osmotic minipump (0, 3.0 or 6.0mg/kg/day). Context conditioning occurred in early adulthood (PD 65-70). Animals were exposed to an experimental context and were given 10 unsignaled footshocks or no shock. Additional groups were included to test the effects of adolescent nicotine on delay conditioning, a form of learning that is not dependent upon the hippocampus. Conditioning was assessed using a lick suppression paradigm. For animals in the context conditioning groups, adolescent nicotine resulted in significantly less suppression of drinking in the presence of context cues compared with vehicle-pretreated animals. For animals in the delay conditioning groups, there was a trend for adolescent nicotine (3.0mg/kg/day) to suppress drinking compared to vehicle-pretreated animals. There were no differences in extinction of contextual fear or cued fear between rats previously exposed to vehicle or nicotine. The data indicate that adolescent nicotine administration impairs context conditioning when animals are trained and tested as adults. The present data suggest that adolescent nicotine exposure may disrupt hippocampus-dependent learning when animals are tested during adulthood.

  13. Incorporation of Nicotine into Silicone Coatings for Marine Applications

    NASA Astrophysics Data System (ADS)

    Jaramillo, Sandy Tuyet

    PDMS-based marine coatings presently used are limited by their inability to mitigate microfouling which limits their application to high speed vessels. PDMS coatings are favored when viable, due to their foul release properties of macrofouling organisms. Natural products have been investigated for antifouling properties for potential use in these marine antifouling coatings but few have incorporated natural products into coatings or coating systems. The purpose of the research was to establish the corrosion inhibiting properties of nicotine and to incorporate nicotine, a biodegradable and readily available natural product, into a PDMS coating to demonstrate the use of a natural product in a coating for marine applications. The corrosion inhibiting properties of nicotine was examined using potentiodynamic polarization scans, material characterization techniques such as scanning electron microscopy, energy dispersive spectroscopy and X-ray diffraction, quartz crystal microbalance and electrochemical impedance spectroscopy. Nicotine was determined to be an anodic corrosion inhibitor for mild steel immersed in simulated seawater with the ability to precipitate a protective calcium carbonate film. Electrochemical impedance spectroscopy was used to evaluate the performance of the developed nicotine incorporated coatings on mild steel immersed in simulated seawater over 21 days of immersion. The coatings with 2 wt.% of nicotine incorporated in the coating with a ratio of 1:30 of additional platinum catalyst to nicotine exhibited the best performance for intact coatings. This coating had the most favorable balance of the amount of nicotine and platinum catalyst of all the coatings evaluated. Overall, all nicotine incorporated coatings had a performance improvement when compared to the control PDMS coating. Of the nicotine incorporated coatings that were tested with an artificial pin-hole defect, the 2PDMS coating also exhibited the best performance with significant

  14. Electronic Cigarettes Are a Source of Thirdhand Exposure to Nicotine

    PubMed Central

    Lee, Lily

    2015-01-01

    Introduction: Substances remaining on the surfaces in areas where people have smoked contribute to thirdhand exposure. Nicotine from tobacco smoke has been shown to react with oxidizing chemicals in the air to form secondary pollutants, such as carcinogenic nitrosamines. While prev ious studies have demonstrated thirdhand exposure to nicotine from tobacco smoke, none have investigated whether nicotine from electronic cigarettes (e-cigarettes) can also be deposited on various surfaces. Methods: Three brands of e-cigarettes were refilled with varying nicotine concentrations. We released 100 puffs from each product directly into an exposure chamber. Surface wipe samples were taken from 5 indoor 100cm2 surfaces (window, walls, floor, wood, and metal) pre- and post-release of vapors. Nicotine was extracted from the wipes and was analyzed using gas chromatography. Results: Three of the 4 experiments showed significant increases in the amount of nicotine on all five surfaces. The floor and glass windows had the greatest increases in nicotine, on average by a factor of 47 and 6, respectively (p < .05). The average amount of nicotine deposited on a floor during each experiment was 205 μg/m2 and varied from limit of quantitation to 550 μg/m2. Conclusions: This study indicates that there is a risk for thirdhand exposure to nicotine from e-cigarettes. Thirdhand exposure levels differ depending on the surface and the e-cigarette brand. Future research should explore the potential risks of thirdhand exposure to carcinogens formed from the nicotine that is released from e-cigarettes. PMID:25173774

  15. COMPARISON OF NICOTINIC ANTAGONISTS IN BLOCKING THE EFFECT OF ANATOXIN-A AND NICOTINE ON THE MOTOR ACTIVITY OF RATS.

    EPA Science Inventory

    Anatoxin-a is a potent nicotinic agonist produced by many species and genera of cyanobacteria. Previous research showed that both anatoxin-a and nicotine produce dose-related decreases in the motor activity of rats. The two toxins differed, however, in their effects with weekly a...

  16. Comparison of nicotine pharmacokinetics in healthy Japanese male smokers following application of the transdermal nicotine patch and cigarette smoking.

    PubMed

    Sobue, Satoshi; Sekiguchi, Kaneo; Kikkawa, Hironori; Akasaki, Moriaki; Irie, Shin

    2006-05-01

    Transdermal nicotine patch (TNP) contains approximately 16.6 and 24.9 mg of nicotine per 20 and 30 cm2 (TNP-20 and TNP-30). The aims of the study are to investigate linearity of nicotine pharmacokinetics after single application of different strengths of TNP and to directly compare plasma nicotine concentrations with those during cigarette smoking. Twelve healthy Japanese male smokers were randomly allocated to 1 of 2 cohorts consisting of 6 subjects each. Cohort 1 subjects received 1 sheet of TNP-20 (TNP-20x1) in period 1, and 2 sheets of TNP-20 (TNP-20x2) in period 3. Cohort 2 subjects were received 1 sheet of TNP-30 (TNP-30x1) in period 2, and smoked a total of 12 cigarettes at 1 h intervals in period 4. Each TNP was applied to the upper arm for 16 h. After TNP-20x1 or TNP-20x2 treatment in cohort 1, the amount of nicotine delivered from TNP (Dose) was proportional to surface area of TNP. Cmax and AUC of nicotine increased with the surface area (Dose), and tmax, t(1/2), CL/F and percentage of dose excreted in urine were almost the same between both treatments. These suggest the linear pharmacokinetics of nicotine in proportion to the surface area and Dose following single application of TNP in identical subjects. In cohort 2, the plasma nicotine concentrations after TNP-30x1 treatment were approximately half those just before each smoking.

  17. Long-term Nicotine Replacement Therapy

    PubMed Central

    Schnoll, Robert A.; Goelz, Patricia M.; Veluz-Wilkins, Anna; Blazekovic, Sonja; Powers, Lindsay; Leone, Frank T.; Gariti, Peter; Wileyto, E. Paul; Hitsman, Brian

    2015-01-01

    IMPORTANCE The US Food and Drug Administration adopted labeling for nicotine patches to allow use beyond the standard 8 weeks. This decision was based in part on data showing increased efficacy for 24 weeks of treatment. Few studies have examined whether the use of nicotine patches beyond 24 weeks provides additional therapeutic benefit. OBJECTIVE To compare 8 (standard), 24 (extended), and 52 (maintenance) weeks of nicotine patch treatment for promoting tobacco abstinence. DESIGN, SETTING, AND PARTICIPANTS We recruited 525 treatment-seeking smokers for a randomized clinical trial conducted from June 22, 2009, through April 15, 2014, through 2 universities. INTERVENTIONS Smokers received 12 smoking cessation behavioral counseling sessions and were randomized to 8, 24, or 52 weeks of nicotine patch treatment. MAIN OUTCOMES AND MEASURES The primary outcome was 7-day point prevalence abstinence, confirmed with breath levels of carbon monoxide at 6 and 12 months (intention to treat). RESULTS At 24 weeks, 21.7% of participants in the standard treatment arm were abstinent, compared with 27.2% of participants in the extended and maintenance treatment arms (χ 2 = 1.98; P = .17). In a multivariate model controlled for covariates, participants in the extended and maintenance treatment arms reported significantly greater abstinence rates at 24 weeks compared with participants in the standard treatment arm (odds ratio [OR], 1.70 [95% CI, 1.03-2.81]; P = .04), had a longer duration of abstinence until relapse (β = 21.30 [95% CI, 10.30-32.25]; P < .001), reported smoking fewer cigarettes per day if not abstinent (mean [SD], 5.8 [5.3] vs 6.4 [5.1] cigarettes per day; β = 0.43 [95% CI, 0.06-0.82]; P = .02), and reported more abstinent days (mean [SD], 80.5 [38.1] vs 68.2 [43.7] days; OR, 1.55 [95% CI, 1.06-2.26]; P = .02). At 52 weeks, participants in the maintenance treatment arm did not report significantly greater abstinence rates compared with participants in the standard

  18. Crystal structure of human nicotinic acid phosphoribosyltransferase.

    PubMed

    Marletta, Ada Serena; Massarotti, Alberto; Orsomando, Giuseppe; Magni, Giulio; Rizzi, Menico; Garavaglia, Silvia

    2015-01-01

    Nicotinic acid phosphoribosyltransferase (EC 2.4.2.11) (NaPRTase) is the rate-limiting enzyme in the three-step Preiss-Handler pathway for the biosynthesis of NAD. The enzyme catalyzes the conversion of nicotinic acid (Na) and 5-phosphoribosyl-1-pyrophosphate (PRPP) to nicotinic acid mononucleotide (NaMN) and pyrophosphate (PPi). Several studies have underlined the importance of NaPRTase for NAD homeostasis in mammals, but no crystallographic data are available for this enzyme from higher eukaryotes. Here, we report the crystal structure of human NaPRTase that was solved by molecular replacement at a resolution of 2.9 Å in its ligand-free form. Our structural data allow the assignment of human NaPRTase to the type II phosphoribosyltransferase subfamily and reveal that the enzyme consists of two domains and functions as a dimer with the active site located at the interface of the monomers. The substrate-binding mode was analyzed by molecular docking simulation and provides hints into the catalytic mechanism. Moreover, structural comparison of human NaPRTase with the other two human type II phosphoribosyltransferases involved in NAD biosynthesis, quinolinate phosphoribosyltransferase and nicotinamide phosphoribosyltransferase, reveals that while the three enzymes share a conserved overall structure, a few distinctive structural traits can be identified. In particular, we show that NaPRTase lacks a tunnel that, in nicotinamide phosphoribosiltransferase, represents the binding site of its potent and selective inhibitor FK866, currently used in clinical trials as an antitumoral agent. PMID:26042198

  19. A C. elegans model of nicotine-dependent behavior: regulation by TRP-family channels.

    PubMed

    Feng, Zhaoyang; Li, Wei; Ward, Alex; Piggott, Beverly J; Larkspur, Erin R; Sternberg, Paul W; Xu, X Z Shawn

    2006-11-01

    Nicotine, the primary addictive substance in tobacco, induces profound behavioral responses in mammals, but the underlying genetic mechanisms are not well understood. Here we develop a C. elegans model of nicotine-dependent behavior. We show that worms exhibit behavioral responses to nicotine that parallel those observed in mammals, including acute response, tolerance, withdrawal, and sensitization. These nicotine responses require nicotinic acetylcholine receptor (nAChR) family genes that are known to mediate nicotine dependence in mammals, suggesting functional conservation of nAChRs in nicotine responses. Importantly, we find that mutant worms lacking TRPC (transient receptor potential canonical) channels are defective in their response to nicotine and that such a defect can be rescued by a human TRPC channel, revealing an unexpected role for TRPC channels in regulating nicotine-dependent behavior. Thus, C. elegans can be used to characterize known genes as well as to identify new genes regulating nicotine responses.

  20. Functional Upregulation of α4* Nicotinic Acetylcholine Receptors in VTA GABAergic Neurons Increases Sensitivity to Nicotine Reward.

    PubMed

    Ngolab, Jennifer; Liu, Liwang; Zhao-Shea, Rubing; Gao, Guangping; Gardner, Paul D; Tapper, Andrew R

    2015-06-01

    Chronic nicotine exposure increases sensitivity to nicotine reward during a withdrawal period, which may facilitate relapse in abstinent smokers, yet the molecular neuroadaptation(s) that contribute to this phenomenon are unknown. Interestingly, chronic nicotine use induces functional upregulation of nicotinic acetylcholine receptors (nAChRs) in the mesocorticolimbic reward pathway potentially linking upregulation to increased drug sensitivity. In the ventral tegmental area (VTA), functional upregulation of nAChRs containing the α4 subunit (α4* nAChRs) is restricted to GABAergic neurons. To test the hypothesis that increased functional expression of α4* nAChRs in these neurons modulates nicotine reward behaviors, we engineered a Cre recombinase-dependent gene expression system to selectively express α4 nAChR subunits harboring a "gain-of-function" mutation [a leucine mutated to a serine residue at the 9' position (Leu9'Ser)] in VTA GABAergic neurons of adult mice. In mice expressing Leu9'Ser α4 nAChR subunits in VTA GABAergic neurons (Gad2(VTA):Leu9'Ser mice), subreward threshold doses of nicotine were sufficient to selectively activate VTA GABAergic neurons and elicit acute hypolocomotion, with subsequent nicotine exposures eliciting tolerance to this effect, compared to control animals. In the conditioned place preference procedure, nicotine was sufficient to condition a significant place preference in Gad2(VTA):Leu9'Ser mice at low nicotine doses that failed to condition control animals. Together, these data indicate that functional upregulation of α4* nAChRs in VTA GABAergic neurons confers increased sensitivity to nicotine reward and points to nAChR subtypes specifically expressed in GABAergic VTA neurons as molecular targets for smoking cessation therapeutics.

  1. Effects of User Puff Topography, Device Voltage, and Liquid Nicotine Concentration on Electronic Cigarette Nicotine Yield: Measurements and Model Predictions

    PubMed Central

    Talih, Soha; Balhas, Zainab; Eissenberg, Thomas; Salman, Rola; Karaoghlanian, Nareg; El Hellani, Ahmad; Baalbaki, Rima; Saliba, Najat

    2015-01-01

    Introduction: Some electronic cigarette (ECIG) users attain tobacco cigarette–like plasma nicotine concentrations while others do not. Understanding the factors that influence ECIG aerosol nicotine delivery is relevant to regulation, including product labeling and abuse liability. These factors may include user puff topography, ECIG liquid composition, and ECIG design features. This study addresses how these factors can influence ECIG nicotine yield. Methods: Aerosols were machine generated with 1 type of ECIG cartridge (V4L CoolCart) using 5 distinct puff profiles representing a tobacco cigarette smoker (2-s puff duration, 33-ml/s puff velocity), a slow average ECIG user (4 s, 17 ml/s), a fast average user (4 s, 33 ml/s), a slow extreme user (8 s, 17 ml/s), and a fast extreme user (8 s, 33 ml/s). Output voltage (3.3–5.2 V or 3.0–7.5 W) and e-liquid nicotine concentration (18–36 mg/ml labeled concentration) were varied. A theoretical model was also developed to simulate the ECIG aerosol production process and to provide insight into the empirical observations. Results: Nicotine yields from 15 puffs varied by more than 50-fold across conditions. Experienced ECIG user profiles (longer puffs) resulted in higher nicotine yields relative to the tobacco smoker (shorter puffs). Puff velocity had no effect on nicotine yield. Higher nicotine concentration and higher voltages resulted in higher nicotine yields. These results were predicted well by the theoretical model (R 2 = 0.99). Conclusions: Depending on puff conditions and product features, 15 puffs from an ECIG can provide far less or far more nicotine than a single tobacco cigarette. ECIG emissions can be predicted using physical principles, with knowledge of puff topography and a few ECIG device design parameters. PMID:25187061

  2. Permissive nicotine regulation as a complement to traditional tobacco control

    PubMed Central

    Sumner, Walton

    2005-01-01

    Background Cigarette smoking takes a staggering toll on human health and attracts considerable public health attention, yet real solutions seem distant. The 2004 Family Smoking Prevention and Tobacco Control Act (US Senate bill S2461) would have given the US Food and Drug Administration limited authority to regulate cigarettes to "protect the public health." However, such legislation is unlikely to substantially reduce smoking or related deaths. Discussion The past 500 years of tobacco control efforts demonstrate that nicotine prohibition is a practical impossibility for numerous reasons, state revenue being one of the most ominous. The FDA already has regulatory authority over pharmaceutical grade nicotine products, and requires pharmacists to dispense the most addictive of these only with prescriptions. Meanwhile, every corner store can sell far more addictive and dangerous cigarettes to any adult. The FDA could immediately increase competition between cigarettes and clean nicotine products by approving available nicotine products for over-the-counter sales to adults. Similarly permissive regulation of cigarettes and addictive nicotine products will reduce tobacco use and improve smokers' health, but increase nicotine use in the population. Fortunately, restricted youth access and accurate labeling of nicotine's absolute risks will dissuade many non-smokers from experimenting with it, while accurate depiction of its risks relative to cigarette smoking will encourage many smokers to switch. The FDA could take a series of small steps that might ultimately replace a large proportion of cigarette smoking with equally addictive nicotine products, without risking serious public health setbacks. Vaccine, methadone, and injury prevention policies establish relevant public health precedents. Summary Cigarettes, or an equally addictive alternative, will be a permanent and common product in most societies. Regulations restricting only the safest addictive nicotine products

  3. UGT2B10 genotype influences nicotine glucuronidation, oxidation and consumption

    PubMed Central

    Berg, Jeannette Zinggeler; von Weymarn, Linda; Thompson, Elizabeth A.; Wickham, Katherine M.; Weisensel, Natalie A.; Hatsukami, Dorothy K.; Murphy, Sharon E.

    2010-01-01

    Background Tobacco exposure is routinely assessed by quantifying nicotine metabolites in plasma or urine. On average, 80% of nicotine undergoes C-oxidation to cotinine. However, interindividual variation in nicotine glucuronidation is substantial and glucuronidation accounts for from 0 to 40% of total nicotine metabolism. We report here the effect of a polymorphism in a UDP-glucuronsyl transferase, UGT2B10, on nicotine metabolism and consumption. Methods Nicotine, cotinine, their N-glucuronide conjugates, and total trans-3'-hydroxycotinine were quantified in the urine (n=327) and plasma (n =115) of smokers. Urinary nicotine N-oxide was quantified in 105 smokers. Nicotine equivalents, the sum of nicotine and all major metabolites, were calculated for each smoker. The relationship of the UGT2B10 Asp67Tyr allele to nicotine equivalents, N-glucuronidation, and C-oxidation was determined. Results Individuals heterozygous for the Asp67Tyr allele excreted less nicotine or cotinine as their glucuronide conjugates than wild-type, resulting in a 60% lower ratio of cotinine glucuronide:cotinine, a 50% lower ratio of nicotine glucuronide:nicotine and increased cotinine and trans-3'-hydroxycotinine. Nicotine equivalents, a robust biomarker of nicotine intake, were lower among Asp67Tyr heterozygotes compared to individuals without this allele; 58.2 nmol/ml (95% CI, 48.9 – 68.2) versus 69.2 nmol/ml (95% CI, 64.3 – 74.5). Conclusions Individuals heterozygous for UGT2B10 Asp67Tyr consume less nicotine than do wild type smokers. This striking observation suggests that variations in nicotine N-glucuronidation, as reported for nicotine C-oxidation, may influence smoking behavior. Impact UGT2B10 genotype influences nicotine metabolism and should be taken into account when characterizing the role of nicotine metabolism on smoking. PMID:20501767

  4. Biogenic amines--a possible source for nicotine in mushrooms? A discussion of published literature data.

    PubMed

    Schindler, B K; Bruns, S; Lach, G

    2015-03-15

    Mushrooms have, repeatedly, been shown to contain nicotine. Speculation about the source of contamination has been widespread, however the source of nicotine remains unknown. Previous studies indicate that putrescine, an intermediate in nicotine biosynthesis, can be formed in mushrooms, which might be metabolised to form nicotine. Thus, endogenous formation may be a possible cause for elevated nicotine levels in mushrooms. We present evidence from the literature that may support this hypothesis.

  5. A key role for the N/OFQ-NOP receptor system in modulating nicotine taking in a model of nicotine and alcohol co-administration

    PubMed Central

    Cippitelli, Andrea; Schoch, Jennifer; Debevec, Ginamarie; Brunori, Gloria; Zaveri, Nurulain T.; Toll, Lawrence

    2016-01-01

    Alcohol and nicotine are often co-abused. Although the N/OFQ-NOP receptor system is considered a potential target for development of drug abuse pharmacotherapies, especially for alcoholism, little is known about the role of this system in nicotine dependence. Furthermore, the effect of prior history of nicotine dependence on subsequent nicotine and alcohol taking is understudied. Using an operant co-administration paradigm, in which rats concurrently self-administer nicotine and alcohol, we found that nicotine dependent rats increased nicotine self-administration over time as compared to non-dependent animals, while patterns of alcohol lever pressing did not change between groups. Pretreatment with the potent NOP receptor agonist AT-202 (0.3–3 mg/kg) increased nicotine lever pressing of both dependent and non-dependent groups, whereas the selective antagonist SB612111 (1–10 mg/kg) elicited a clear reduction of nicotine responses, in both dependent and non-dependent rats. In parallel, AT-202 only produced minor changes on alcohol responses and SB612111 reduced alcohol taking at a dose that also reduced locomotor behavior. Results indicate that a history of nicotine dependence affects subsequent nicotine- but not alcohol-maintained responding, and that NOP receptor antagonism, rather than agonism, blocks nicotine self-administration, which strongly suggests a critical role for the endogenous N/OFQ in the modulation of nicotine reinforcement processes. PMID:27199205

  6. SOLID SOLUTION EFFECTS ON THE THERMAL PROPERTIES IN THE MgAl2O4-MgGa2O4

    SciTech Connect

    O'Hara, Kelley; Smith, Jeffrey D; Sander, Todd P.; Hemrick, James Gordon

    2013-01-01

    Solid solution eects on thermal conductivity within the MgO-Al2O3-Ga2O3 system were studied. Samples with systematically varied additions of MgGa2O4 to MgAl2O4 were prepared and the laser ash technique was used to determine thermal diusivity at temperatures between 200C and 1300C. Heat capacity as a function of temperature from room temperature to 800C was also determined using dierential scanning calorimetry. Solid solution in the MgAl2O4-MgGa2O4 system decreases the thermal conductivity up to 1000C. At 200C thermal conductivity decreased 24% with a 5 mol% addition of MgGa2O4 to the system. At 1000C the thermal conductivity decreased 13% with a 5 mol% addition. Steady state calculations showed a 12.5% decrease in heat ux with 5 mol% MgGa2O4 considered across a 12 inch thickness.

  7. Cholinergic transmission during nicotine withdrawal is influenced by age and pre-exposure to nicotine: implications for teenage smoking.

    PubMed

    Carcoba, Luis M; Orfila, James E; Natividad, Luis A; Torres, Oscar V; Pipkin, Joseph A; Ferree, Patrick L; Castañeda, Eddie; Moss, Donald E; O'Dell, Laura E

    2014-01-01

    Adolescence is a unique period of development characterized by enhanced tobacco use and long-term vulnerability to neurochemical changes produced by adolescent nicotine exposure. In order to understand the underlying mechanisms that contribute to developmental differences in tobacco use, this study compared changes in cholinergic transmission during nicotine exposure and withdrawal in naïve adult rats compared to (1) adolescent rats and (2) adult rats that were pre-exposed to nicotine during adolescence. The first study compared extracellular levels of acetylcholine (ACh) in the nucleus accumbens (NAc) during nicotine exposure and precipitated withdrawal using microdialysis procedures. Adolescent (postnatal day, PND, 28-42) and adult rats (PND60-74) were prepared with osmotic pumps that delivered nicotine for 14 days (adolescents 4.7 mg/kg/day; adults 3.2 mg/kg/day; expressed as base). Another group of adults was exposed to nicotine during adolescence and then again in adulthood (pre-exposed adults) using similar methods. Control rats received a sham surgery. Following 13 days of nicotine exposure, the rats were implanted with microdialysis probes in the NAc. The following day, dialysis samples were collected during baseline and following systemic administration of the nicotinic receptor antagonist mecamylamine (1.5 and 3.0 mg/kg, i.p.) to precipitate withdrawal. A second study compared various metabolic differences in cholinergic transmission using the same treatment procedures as the first study. Following 14 days of nicotine exposure, the NAc was dissected and acetylcholinesterase (AChE) activity was compared across groups. In order to examine potential group differences in nicotine metabolism, blood plasma levels of cotinine (a nicotine metabolite) were also compared following 14 days of nicotine exposure. The results from the first study revealed that nicotine exposure increased baseline ACh levels to a greater extent in adolescent versus adult rats. During

  8. Cholinergic transmission during nicotine withdrawal is influenced by age and pre-exposure to nicotine: implications for teenage smoking.

    PubMed

    Carcoba, Luis M; Orfila, James E; Natividad, Luis A; Torres, Oscar V; Pipkin, Joseph A; Ferree, Patrick L; Castañeda, Eddie; Moss, Donald E; O'Dell, Laura E

    2014-01-01

    Adolescence is a unique period of development characterized by enhanced tobacco use and long-term vulnerability to neurochemical changes produced by adolescent nicotine exposure. In order to understand the underlying mechanisms that contribute to developmental differences in tobacco use, this study compared changes in cholinergic transmission during nicotine exposure and withdrawal in naïve adult rats compared to (1) adolescent rats and (2) adult rats that were pre-exposed to nicotine during adolescence. The first study compared extracellular levels of acetylcholine (ACh) in the nucleus accumbens (NAc) during nicotine exposure and precipitated withdrawal using microdialysis procedures. Adolescent (postnatal day, PND, 28-42) and adult rats (PND60-74) were prepared with osmotic pumps that delivered nicotine for 14 days (adolescents 4.7 mg/kg/day; adults 3.2 mg/kg/day; expressed as base). Another group of adults was exposed to nicotine during adolescence and then again in adulthood (pre-exposed adults) using similar methods. Control rats received a sham surgery. Following 13 days of nicotine exposure, the rats were implanted with microdialysis probes in the NAc. The following day, dialysis samples were collected during baseline and following systemic administration of the nicotinic receptor antagonist mecamylamine (1.5 and 3.0 mg/kg, i.p.) to precipitate withdrawal. A second study compared various metabolic differences in cholinergic transmission using the same treatment procedures as the first study. Following 14 days of nicotine exposure, the NAc was dissected and acetylcholinesterase (AChE) activity was compared across groups. In order to examine potential group differences in nicotine metabolism, blood plasma levels of cotinine (a nicotine metabolite) were also compared following 14 days of nicotine exposure. The results from the first study revealed that nicotine exposure increased baseline ACh levels to a greater extent in adolescent versus adult rats. During

  9. Nicotine effects and the endogenous opioid system.

    PubMed

    Kishioka, Shiroh; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro

    2014-01-01

    Nicotine (NIC) is an exogenous ligand of the nicotinic acetylcholine receptor (nAChR), and it influences various functions in the central nervous system. Systemic administration of NIC elicits the release of endogenous opioids (endorphins, enkephalins, and dynorphins) in the supraspinal cord. Additionally, systemic NIC administration induces the release of methionine-enkephalin in the spinal dorsal horn. NIC has acute neurophysiological actions, including antinociceptive effects, and the ability to activate the hypothalamic-pituitary-adrenal (HPA) axis. The endogenous opioid system participates in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception is mediated by α4β2 and α7 nAChRs, while NIC-induced HPA axis activation is mediated by α4β2, not α7, suggesting that the effects of NIC on the endogenous opioid system are mediated by α7, not α4β2. NIC has substantial physical dependence liability. The opioid-receptor antagonist naloxone (NLX) elicits NIC withdrawal after repeated NIC administration, and NLX-induced NIC withdrawal is inhibited by concomitant administration of an opioid-receptor antagonist. NLX-induced NIC withdrawal is also inhibited by concomitant administration of an α7 antagonist, but not an α4β2 antagonist. Taken together, these findings suggest that NIC-induced antinociception and the development of physical dependence are mediated by the endogenous opioid system, via the α7 nAChR.

  10. Nicotine effects and the endogenous opioid system.

    PubMed

    Kishioka, Shiroh; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro

    2014-01-01

    Nicotine (NIC) is an exogenous ligand of the nicotinic acetylcholine receptor (nAChR), and it influences various functions in the central nervous system. Systemic administration of NIC elicits the release of endogenous opioids (endorphins, enkephalins, and dynorphins) in the supraspinal cord. Additionally, systemic NIC administration induces the release of methionine-enkephalin in the spinal dorsal horn. NIC has acute neurophysiological actions, including antinociceptive effects, and the ability to activate the hypothalamic-pituitary-adrenal (HPA) axis. The endogenous opioid system participates in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception is mediated by α4β2 and α7 nAChRs, while NIC-induced HPA axis activation is mediated by α4β2, not α7, suggesting that the effects of NIC on the endogenous opioid system are mediated by α7, not α4β2. NIC has substantial physical dependence liability. The opioid-receptor antagonist naloxone (NLX) elicits NIC withdrawal after repeated NIC administration, and NLX-induced NIC withdrawal is inhibited by concomitant administration of an opioid-receptor antagonist. NLX-induced NIC withdrawal is also inhibited by concomitant administration of an α7 antagonist, but not an α4β2 antagonist. Taken together, these findings suggest that NIC-induced antinociception and the development of physical dependence are mediated by the endogenous opioid system, via the α7 nAChR. PMID:24882143

  11. Neurocircuitry of the nicotinic cholinergic system

    PubMed Central

    Bertrand, Daniel

    2010-01-01

    Continuing to discover how the brain works is one of the great challenges ahead of us. Although understanding the brain anatomy and its functional organization provided a first and indispensable foundation, it became clear that a static view was insufficient. To understand the complexity of neuronal communication, it is necessary to examine the chemical nature of the neurotransmission and, using the example of the acetylcholine receptors, follow the different layers of networks that can be distinguished. The natural alkaloid nicotine contained in tobacco leaves acts as an agonist with a subclass of acetylcholine receptors, and provides an interesting tool to approach brain functions. Analysis of the nicotinic acetylcholine receptors, which are ligand gated channels, revealed that these receptors are expressed at different critical locations on the neurons including the synaptic boutons, neurites, cell bodies, and even on the axons. These receptors can modulate the activity at the microcircuit synaptic level, in the cell processing of information, and, by acting on the velocity of action potential, the synchrony of communication between brain areas. These actions at multiple levels of brain organization provide an example of the complexity of brain neurocircuitry and an illustration of the relevance of this knowledge for psychiatry. PMID:21319492

  12. Magnesium influence on nicotine pharmacodependence and smoking.

    PubMed

    Nechifor, Mihai; Chelarescu, Dan; Mândreci, Ioan; Cartas, Nicoleta

    2004-09-01

    We followed the magnesium effect (Magne B(6)R, Sanofi-Synthelabo) with internal administration in 53 adult neurotic smoking patients (more than 10 cigarettes/day) of both genders admitted into psychiatric hospital. The nicotine dependence was assessed by the Fagerstrom test, initially and after 28 days of magnesium intake. Plasmatic magnesium level was determined before any therapy and at 28 days. All patients received benzodiazepines during the trial. Our data show that patients that received magnesium therapy showed a significant decrease in the number of cigarettes smoked and Fagerstrom test after 4 weeks [Fagerstrom score 7.93 +/- 0.17 before magnesium therapy versus 6.78 +/- 0.18 (P < 0.05) after 28 days of magnesium therapy]. In the group of smokers who did not receive magnesium, the Fagerstrom score did not change significantly [Fagerstrom score 7.48 +/- 0.22 initial versus 7.24 +/- 0.19 after 28 days]. Magnesium supplementation raised plasmatic levels (17.2 +/- 1.2 mg/L before versus 26.1 +/- 1.6 mg/L after 28 days of magnesium intake, P < 0.01). The results suggest that this cation might be a useful adjuvant in treatment of nicotine pharmacodependence.

  13. Nicotine receptors mediating sensorimotor gating and its enhancement by systemic nicotine.

    PubMed

    Pinnock, Farena; Bosch, Daniel; Brown, Tyler; Simons, Nadine; Yeomans, John R; DeOliveira, Cleusa; Schmid, Susanne

    2015-01-01

    Prepulse inhibition (PPI) of startle occurs when intensity stimuli precede stronger startle-inducing stimuli by 10-1000 ms. PPI deficits are found in individuals with schizophrenia and other psychiatric disorders, and they correlate with other cognitive impairments. Animal research and clinical studies have demonstrated that both PPI and cognitive function can be enhanced by nicotine. PPI has been shown to be mediated, at least in part, by mesopontine cholinergic neurons that project to pontine startle neurons and activate muscarinic and potentially nicotine receptors (nAChRs). The subtypes and anatomical location of nAChRs involved in mediating and modulating PPI remain unresolved. We tested the hypothesis that nAChRs that are expressed by pontine startle neurons contribute to PPI. We also explored whether or not these pontine receptors are responsible for the nicotine enhancement of PPI. While systemic administration of nAChR antagonists had limited effects on PPI, PnC microinfusions of the non-α7nAChR preferring antagonist TMPH, but not of the α7nAChR antagonist MLA, into the PnC significantly reduced PPI. Electrophysiological recordings from startle-mediating PnC neurons confirmed that nicotine affects excitability of PnC neurons, which could be antagonized by TMPH, but not by MLA, indicating the expression of non-α7nAChR. In contrast, systemic nicotine enhancement of PPI was only reversed by systemic MLA and not by TMPH or local microinfusions of MLA into the PnC. In summary, our data indicate that non-α7nAChRs in the PnC contribute to PPI at stimulus intervals of 100 ms or less, whereas activation of α7nAChRs in other brain areas is responsible for the systemic nicotine enhancement of PPI. This is important knowledge for the correct interpretation of behavioral, preclinical, and clinical data as well as for developing drugs for the amelioration of PPI deficits and the enhancement of cognitive function.

  14. Nicotine nasal spray and vapor inhaler: abuse liability assessment.

    PubMed

    Schuh, K J; Schuh, L M; Henningfield, J E; Stitzer, M L

    1997-04-01

    Acute subjective and physiological effects were examined to provide information relevant to abuse liability of new nicotine delivery systems. Subjects (n = 12) were overnight-deprived smokers who received 0, 4, 8 and 16 active puffs from nicotine-containing cigarettes (0.1 mg per puff), 0, 1, 2 or 4 nasal sprays (0.5 mg nicotine per spray) and 0, 30, 60 and 120 vapor inhalations (estimated 0.013 mg nicotine per inhalation) in a within-subject single blinded design. While smokers clearly liked cigarette puffs, there was much less evidence of liking produced by either nasal spray or vapor inhaler; only modest elevations on a measure of good drug effects were observed. The novel delivery products engendered unpleasant effects of burning throat and nose, watery eyes, runny nose, coughing and sneezing that might be expected to limit abuse liability. Nicotine plasma level and heart rate increase was dose-related for cigarettes and nasal spray but not for vapor inhaler, indicating limited nicotine delivery with the latter device. Overall, results are consistent with the conclusion that the nicotine nasal spray and vapor inhaler are of substantially lower abuse liability than cigarettes in experienced cigarette smokers receiving initial exposure to these products. PMID:9160851

  15. Schizophrenia and the alpha7 nicotinic acetylcholine receptor.

    PubMed

    Martin, Laura F; Freedman, Robert

    2007-01-01

    In addition to the devastating symptoms of psychosis, many people with schizophrenia also suffer from cognitive impairment. These cognitive symptoms lead to marked dysfunction and can impact employability, treatment adherence, and social skills. Deficits in P50 auditory gating are associated with attentional impairment and may contribute to cognitive symptoms and perceptual disturbances. This nicotinic cholinergic-mediated inhibitory process represents a potential new target for therapeutic intervention in schizophrenia. This chapter will review evidence implicating the nicotinic cholinergic, and specifically, the alpha7 nicotinic receptor system in the pathology of schizophrenia. Impaired auditory sensory gating has been linked to the alpha7 nicotinic receptor gene on the chromosome 15q14 locus. A majority of persons with schizophrenia are heavy smokers. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. The alpha7 nicotinic agonist 3-(2,4 dimethoxy)benzylidene-anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and a new study in persons with schizophrenia has found that DMXBA enhances both P50 auditory gating and cognition. alpha7 Nicotinic acetylcholine receptor agonists appear to be viable candidates for the treatment of cognitive disturbances in schizophrenia.

  16. Ameliorative effect of sesame lignans on nicotine toxicity in rats.

    PubMed

    Chattopadhyay, Krishna; Mondal, Srinath; Chattopadhyay, Brajadulal; Ghosh, Santinath

    2010-11-01

    Nicotine causes oxidative and genotoxic damages in the tissues leading to several diseases. Any strategy through natural diet that prevents or slows the progression and severity of nicotine toxicity has a significant health impact. This work is designed to investigate natural antioxidants that play effective protective role against nicotine-induced toxicity. Experiments were conducted on male albino rats by injecting nicotine tartrate (3.5 mg/kg body wt./day for 15 days) subcutaneously and thereby supplementing sesame lignans (0.1 g/100g diet and 0.2 g/100g diet) orally to them. Significant (P<0.01) increase of total cholesterol, triglyceride, LDL-cholesterol, VLDL-cholesterol, decrease of HDL-cholesterol, decrease in antioxidant enzymes and increase in concentration of lipid peroxidative product has been observed in plasma due to nicotine toxicity. Significant (P<0.01) decrease of total DNA contents and highly significant (P<0.001) DNA damage of liver tissue is also observed on nicotine treatment. Sesame lignans minimizes the above mentioned effects. The nicotine-induced oxidative and genotoxic damages on the tissues can be effectively attenuated by sesame lignans supplemented diet. PMID:20804815

  17. Adverse effects of perinatal nicotine exposure on reproductive outcomes.

    PubMed

    Wong, Michael K; Barra, Nicole G; Alfaidy, Nadia; Hardy, Daniel B; Holloway, Alison C

    2015-12-01

    Nicotine exposure during pregnancy through cigarette smoking, nicotine replacement therapies or e-cigarette use continues to be a widespread public health problem, impacting both fetal and postnatal health. Yet, at this time, there remains limited data regarding the safety and efficacy in using these nicotine products during pregnancy. Notably, reports assessing the effect of nicotine exposure on postnatal health outcomes in humans, including reproductive health, are severely lacking. Our current understanding regarding the consequences of nicotine exposure during pregnancy is limited to a few animal studies, which do not comprehensively address the underlying cellular mechanisms involved. This paper aims to critically review the current knowledge from human and animal studies regarding the direct and indirect effects (e.g. obesity) of maternal nicotine exposure, regardless of its source, on reproductive outcomes in pregnancy and postnatal life. Furthermore, this review highlights several key cellular mechanisms involved in these adverse reproductive deficits including oxidative stress, inflammation, and endoplasmic reticulum (ER) stress. By understanding the interplay of the cellular mechanisms involved, further strategies could be developed to prevent the reproductive abnormalities resulting from exposure to nicotine in utero and influence informed clinical guidelines for pregnant women.

  18. Taurine treatment protects against chronic nicotine-induced oxidative changes.

    PubMed

    Sener, Göksel; Ozer Sehirli, A; Ipçi, Yeşim; Cetinel, Sule; Cikler, Esra; Gedik, Nursal; Alican, Inci

    2005-04-01

    Experiments have shown that chronic nicotine administration caused oxidative damage in various organs by increasing lipid peroxidation products and decreasing the activity of endogenous antioxidants. The aim of this study was to investigate the effects of taurine treatment on nicotine-induced oxidative changes in rat thoracic aorta and heart and to explore the possible mechanisms of action. Male Wistar albino rats (200-250 g) were injected with nicotine hydrogen bitartrate (0.6 mg/kg; i.p.) or saline for 21 days. Taurine was administered (50 mg/kg; i.p.) alone or along with nicotine injections. After decapitation, the thoracic aorta and heart tissues were excised. The aorta was used for in vitro contractility studies or stored along with the heart samples for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content. Tissue samples were also examined histologically. Serum samples were stored for the measurement of MDA, GSH and lactate dehydrogenase (LDH) activity. Chronic nicotine treatment impaired both the contraction and relaxation responses of the aortic rings to phenylephrine and acetylcholine, respectively. It increased lipid peroxidation, MPO levels and tissue collagen content of both aorta and heart samples. Taurine supplementation to nicotine-treated animals reversed the contractile dysfunction and restored the endogenous GSH levels and decreased high lipid peroxidation and MPO activities in both tissues. These data suggest that taurine supplementation effectively attenuates the oxidative damage because of chronic nicotine administration possibly by its antioxidant effects.

  19. The nicotinic cholinergic system function in the human brain.

    PubMed

    Nees, Frauke

    2015-09-01

    Research on the nicotinic cholinergic system function in the brain was previously mainly derived from animal studies, yet, research in humans is growing. Up to date, findings allow significant advances on the understanding of nicotinic cholinergic effects on human cognition, emotion and behavior using a range of functional brain imaging approaches such as pharmacological functional magnetic resonance imaging or positron emission tomography. Studies provided insights across various mechanistic psychological domains using different tasks as well as at rest in both healthy individuals and patient populations, with so far partly mixed results reporting both enhancements and decrements of neural activity related to the nicotinic cholinergic system. Moreover, studies on the relation between brain structure and the nicotinic cholinergic system add important information in this context. The present review summarizes the current status of human brain imaging studies and presents the findings within a theoretical and clinical perspective as they may be useful not only for an advancement of the understanding of basic nicotinic cholinergic-related mechanisms, but also for the development and integration of psychological and pharmacological treatment approaches. Patterns of functional neuroanatomy and neural circuitry across various cognitive and emotional domains may be used as neuropsychological markers of mental disorders such as addiction, Alzheimer's disease, Parkinson disease or schizophrenia, where nicotinic cholinergic system changes are characteristic. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

  20. Nicotine Dependence and Problem Behaviors Among Urban South African Adolescents

    PubMed Central

    Pahl, Kerstin; Brook, David W.; Morojele, Neo K.; Brook, Judith S.

    2010-01-01

    Tobacco use and its concomitant, nicotine dependence, are increasing in African countries and other parts of the developing world. However, little research has assessed nicotine dependence in South Africa or other parts of the African continent. Previous research has found that adolescent problem behaviors, including tobacco use, tend to cluster. This study examined the relationship between nicotine dependence and adolescent problem behaviors in an ethnically diverse sample of urban South African adolescents. A community sample (N = 731) consisting of “Black,” “White,” “Coloured,” and “Indian” youths aged 12–17 years was drawn from the Johannesburg metropolitan area. Structured interviews were administered by trained interviewers. Nicotine dependence was assessed by the Fagerström Test of Nicotine Dependence. Logistic regression analyses showed that higher levels of nicotine dependence significantly predicted elevated levels of violent behavior, deviant behavior, marijuana and other illegal drug use, binge drinking, early sexual intercourse, multiple sexual partners, and inconsistent condom use, despite control on the adolescents’ demographic characteristics, peer smoking, conflict with parents, peer deviance, and the availability of legal and illegal substances. These relationships were robust across ethnicity and gender. The findings indicate the need for policy makers and prevention and intervention programs in South Africa to consider adolescent nicotine dependence in conjunction with comorbid problem behaviors, including other substance use, sexual risk behaviors, and deviant behaviors. PMID:20099015

  1. SENSORY REINFORCEMENT ENHANCING EFFECTS OF NICOTINE VIA SMOKING

    PubMed Central

    Perkins, Kenneth A.; Karelitz, Joshua L.

    2014-01-01

    As in animal research, acute nicotine in humans enhances reinforcement from rewards unrelated to nicotine intake, but this effect may be specific to rewards from stimuli that are “sensory” in nature. We assessed acute effects of nicotine via smoking on responding for music or video (“sensory”) rewards, for monetary (“non-sensory”) reward, or for no reward (control), to gauge the generalizability of nicotine’s reinforcement enhancing effects. Using a fully within-subjects design, dependent smokers (N=20) participated in three similar experimental sessions, each following overnight abstinence (verified by CO<10 ppm) and varying only in the smoking condition. Sessions involved no smoking or smoking denicotinized (0.05 mg) or nicotine (0.6 mg) QuestR brand cigarettes in controlled fashion prior to responding on a simple operant computer task for each reward separately, using a progressive ratio schedule. The reinforcing effects of music and video rewards, but not money, were significantly greater due to the nicotine versus denicotinized cigarette (i.e. nicotine per se), while there were no differences between the denicotinized cigarette versus no smoking (i.e. smoking behavior per se), except for no reward. These effects were not influenced by withdrawal relief from either cigarette. Results that generalize from an auditory to a visual reward confirm that acute nicotine intake per se enhances the reinforcing value of sensory rewards, but its effects on the value of other (perhaps non-sensory) types of rewards may be more modest. PMID:25180451

  2. Impact of Tobacco Smoke and Nicotine Exposure on Lung Development.

    PubMed

    Gibbs, Kevin; Collaco, Joseph M; McGrath-Morrow, Sharon A

    2016-02-01

    Tobacco smoke and nicotine exposure during prenatal and postnatal life can impair lung development, alter the immune response to viral infections, and increase the prevalence of wheezing during childhood. The following review examines recent discoveries in the fields of lung development and tobacco and nicotine exposure, emphasizing studies published within the last 5 years. In utero tobacco and nicotine exposure remains common, occurring in approximately 10% of pregnancies within the United States. Exposed neonates are at increased risk for diminished lung function, altered central and peripheral respiratory chemoreception, and increased asthma symptoms throughout childhood. Recently, genomic and epigenetic risk factors, such as alterations in DNA methylation, have been identified that may influence the risk for long-term disease. This review examines the impact of prenatal tobacco and nicotine exposure on lung development with a particular focus on nicotinic acetylcholine receptors. In addition, this review examines the role of prenatal and postnatal tobacco smoke and nicotine exposure and its association with augmenting infection risk, skewing the immune response toward a T-helper type 2 bias and increasing risk for developing an allergic phenotype and asthmalike symptoms during childhood. Finally, this review outlines the respiratory morbidities associated with childhood secondhand smoke and nicotine exposure and examines genetic and epigenetic modifiers that may influence respiratory health in infants and children exposed to in utero or postnatal tobacco smoke.

  3. Direct action and modulating effect of (+)- and (-)-nicotine on ion channels expressed in trigeminal sensory neurons.

    PubMed

    Schreiner, Benjamin S P; Lehmann, Ramona; Thiel, Ulrike; Ziemba, Paul M; Beltrán, Leopoldo R; Sherkheli, Muhammad A; Jeanbourquin, Philippe; Hugi, Alain; Werner, Markus; Gisselmann, Günter; Hatt, Hanns

    2014-04-01

    Nicotine sensory perception is generally thought to be mediated by nicotinic acetylcholine (nACh) receptors. However, recent data strongly support the idea that other receptors (e.g., transient receptor potential A1 channel, TRPA1) and other pathways contribute to the detection mechanisms underlying the olfactory and trigeminal cell response to nicotine flavor. This is in accordance with the reported ability of humans to discriminate between (+)- and (-)- nicotine enantiomers. To get a more detailed understanding of the molecular and cellular basis underlying the sensory perception of nicotine, we studied the activity of (+)- and (-)-nicotine on cultured murine trigeminal sensory neurons and on a range of heterologously expressed receptors. The human TRPA1 channel is activated by (-)-nicotine. In this work, we show that (+)-nicotine is also an activator of this channel. Pharmacological experiments using nicotinic acetylcholine receptors and transient receptor potential blockers revealed that trigeminal neurons express one or more unidentified receptors that are sensitive to (+)- and/or (-)-nicotine. Results also indicate that the presence of extracellular calcium ions is required to elicit trigeminal neuron responses to (+)- and (-)-nicotine. Results also show that both (+)-nicotine and (-)-nicotine can block 5-hydroxytryptamine type 3 (5-HT3) receptor-mediated responses in recombinant expression systems and in cultured trigeminal neurons expressing 5-HT3 receptors. Our investigations broaden the spectra of receptors that are targets for nicotine enantiomers and give new insights into the physiological role of nicotine. PMID:24512725

  4. Functional interaction between Lypd6 and nicotinic acetylcholine receptors.

    PubMed

    Arvaniti, Maria; Jensen, Majbrit M; Soni, Neeraj; Wang, Hong; Klein, Anders B; Thiriet, Nathalie; Pinborg, Lars H; Muldoon, Pretal P; Wienecke, Jacob; Imad Damaj, M; Kohlmeier, Kristi A; Gondré-Lewis, Marjorie C; Mikkelsen, Jens D; Thomsen, Morten S

    2016-09-01

    Nicotinic acetylcholine receptors (nAChRs) affect multiple physiological functions in the brain and their functions are modulated by regulatory proteins of the Lynx family. Here, we report for the first time a direct interaction of the Lynx protein LY6/PLAUR domain-containing 6 (Lypd6) with nAChRs in human brain extracts, identifying Lypd6 as a novel regulator of nAChR function. Using protein cross-linking and affinity purification from human temporal cortical extracts, we demonstrate that Lypd6 is a synaptically enriched membrane-bound protein that binds to multiple nAChR subtypes in the human brain. Additionally, soluble recombinant Lypd6 protein attenuates nicotine-induced hippocampal inward currents in rat brain slices and decreases nicotine-induced extracellular signal-regulated kinase phosphorylation in PC12 cells, suggesting that binding of Lypd6 is sufficient to inhibit nAChR-mediated intracellular signaling. We further show that perinatal nicotine exposure in rats (4 mg/kg/day through minipumps to dams from embryonic day 7 to post-natal day 21) significantly increases Lypd6 protein levels in the hippocampus in adulthood, which did not occur after exposure to nicotine in adulthood only. Our findings suggest that Lypd6 is a versatile inhibitor of cholinergic signaling in the brain, and that Lypd6 is dysregulated by nicotine exposure during early development. Regulatory proteins of the Lynx family modulate the function of nicotinic receptors (nAChRs). We report for the first time that the Lynx protein Lypd6 binds to nAChRs in human brain extracts, and that recombinant Lypd6 decreases nicotine-induced ERK phosphorylation and attenuates nicotine-induced hippocampal inward currents. Our findings suggest that Lypd6 is a versatile inhibitor of cholinergic signaling in the brain. PMID:27344019

  5. The effects of extrinsic context on nicotine discrimination.

    PubMed

    Duka, T; Seiss, E; Tasker, R

    2002-02-01

    There is evidence from memory studies that context acquired in parallel with the encoded material will facilitate retrieval. However, relatively little is known of how context affects drug discrimination behaviour in humans. The present study employs conventional drug discrimination procedures to investigate the effects of music, as an external cue, on nicotine drug discrimination. Subjects were trained to discriminate a low dose of nicotine (1 mg) from placebo while listening to two different types of music [elated (EL) and depressant (DE): thought to induce happy and sad mood respectively]. Half of the subjects received EL music with nicotine and DE with placebo and the other half vice versa. At the end of training, subjects who reached the criterion (80% of trials identified correctly) entered the generalization phase and were required to discriminate different doses of nicotine