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Sample records for 4-mg nicotine lozenge

  1. Nicotine Lozenges

    MedlinePlus

    ... other nicotine smoking cessation aid, such as the nicotine patch, gum, inhaler, or nasal spray.tell your doctor and pharmacist what other prescription and nonprescription medications, ... non-nicotine smoking cessation aids, such as bupropion (Wellbutrin) or ...

  2. 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.

  3. Pharmacokinetics, safety and efficacy from randomized controlled trials of 1 and 2 mg nicotine bitartrate lozenges (Nicotinell®)

    PubMed Central

    Dautzenberg, Bertrand; Nides, Mitchell; Kienzler, Jean-Luc; Callens, Anne

    2007-01-01

    Background The use of nicotine replacement therapy (NRT) can almost double the chances of success for smokers to quit. Nevertheless, there is still a considerable number of cessation attempts that are made without any treatment. This novel oral formulation, (lozenge containing nicotine bitartrate dihydrate) has been developed to enlarge the offer for efficient smoking cessation drug therapies, assuming that increasing treatment options will bring more smokers to find the support they personally need to stop smoking. Methods Three pharmacokinetic (PK), one safety and two efficacy studies were carried out with Nicotinell lozenges. PK trials were: (1) a single-dose, three-way crossover study comparing 1 and 2 mg lozenges with 2 mg nicotine gum; (2) a multiple-dose, two-way crossover study comparing 1 mg lozenge with 2 mg gum; (3) a multiple-dose, three-way crossover study comparing 1 and 2 mg lozenges with 4 mg gum. Safety trial: (4) a single dose study to assess the safety of swallowing up to 12 lozenges containing 1 mg nicotine. Efficacy trials: two efficacy studies in (5) France and (6) the USA, including more than 900 smokers followed-up for up to one year, conducted with the 1 mg lozenge. Results The results of the individual PK trials showed that the 1 mg Nicotinell lozenge is bioequivalent to 2 mg polacrilex gum, as demonstrated by similar blood PK parameters (tmax, Cmax, AUC). The 2 mg lozenge was found to deliver quantities of nicotine that were intermediate between those delivered by 2 and 4 mg polacrilex gum. The short-term efficacy of the 1 mg lozenge in comparison with placebo was also demonstrated with significantly more subjects continuously abstinent from smoking with active lozenges on week 6 in two different populations: moderate to heavy smokers (FTND between 4 and 7) OR = 1.72 [95% CI: 1.05–2.80]; heavy to very heavy smokers (FTND 6 and over) OR = 2.87 [95% CI: 1.18–6.97]. Nicotinell lozenges were found to be safe with mainly mild and

  4. 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

  5. Zinc ion availability--the determinant of efficacy in zinc lozenge treatment of common colds.

    PubMed

    Eby, G A

    1997-10-01

    This is a re-analysis of reports from 1984 to 1992 of double-blind, placebo-controlled, clinical trials of zinc lozenges in the treatment of common colds. This re-analysis was performed to test the hypothesis that major variations in daily zinc ion availability (ZIA) between chemically different lozenge formulations caused differing results in these clinical trials. Solution chemistry computations determined the bioavailability of Zn2+ ions at physiological pH from the lozenges used in these clinical trails. ZIA was derived from Fick's laws of diffusion in a bio-electric field. Lozenges that released Zn2+ ions at physiological pH (positive ZIAs) shortened colds. Lozenges that released negatively charged zinc species at physiological pH (negative ZIAs) lengthened colds. Lozenges having a zero ZIA had no effect on common colds. Lozenges with ZIA = 100 shortened colds by 7 days while ZIA = -55 lozenges lengthened colds by 4.4 days. A linear dose-response relationship exists between ZIAs of zinc lozenges and changes in duration of common colds. It is concluded that: prospective efficacy of zinc lozenges can be predicted based upon readily determined ZIA factors and ZIAs; chemically different zinc lozenge formulations having greatly different ZIAs resulted in greatly differing results in clinical trials; mast cell granule-derived Zn2+ ions are the foundation of the primary immune system; and high ZIA zinc acetate lozenges are beneficial for common colds.

  6. 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.

  7. 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.

  8. 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.

  9. Amylmetacresol/2,4-dichlorobenzyl alcohol, hexylresorcinol, or carrageenan lozenges as active treatments for sore throat

    PubMed Central

    Morokutti-Kurz, Martina; Graf, Christine; Prieschl-Grassauer, Eva

    2017-01-01

    Up to 80% of sore throats are caused by viruses. Several over the counter products are available which provide symptomatic, not causal relief. For such lozenges, containing the antiseptics and local anesthetics amylmetacresol (AMC) and 2,4-dichlorobenzyl alcohol (DCBA) or hexylresorcinol (HR), recently an additional virucidal effect was published. Therefore, we tested a set of Strepsils® lozenges, containing either HR (Max [#2]) or AMC/DCBA (Original [#3], Extra Strong [#4], Warm [#5], Orange and Vitamin C [#6], Sugar free Lemon [#7], Children/Strawberry [#8] and Soothing Honey and Lemon [#9]) for their antiviral efficiency against representatives of respiratory viruses known to cause sore throat: human rhinovirus (HRV) 1a, HRV8, influenza virus A H1N1n, Coxsackievirus A10, and human coronavirus (hCoV) OC43. The lozenges were tested head to head with Coldamaris® lozenges (#1), which contain the patented antiviral iota-carrageenan. None of the tested AMC/DCBA or HR containing lozenges shows any antiviral effectiveness against HRV8 at the tested concentrations, whereas all are moderately active against HRV1a. Only lozenge #5 shows any activity against hCoV OC43 and Coxsackievirus A10 at the tested concentrations. Similarly, only lozenge #3 is moderately active against influenza A H1N1n virus. The data indicates that neither the isolated effect of the active ingredients nor the pH but rather one or more of the excipients of the specific formulations are responsible for the antiviral effect of some of the AMC/DCBA or HR containing lozenges. In contrast, carrageenan-containing lozenges are highly active against all viruses tested. In another experiment, we showed that binding and inactivation of virus particles by iota-carrageenan are fast and highly effective. During the residence time of the lozenge in the mouth, the viral titer is reduced by 85% and 91% for influenza A virus and hCoV OC43, respectively. Carrageenan-containing lozenges are, therefore, suitable as

  10. [Smoking cessation with nicotine replacement therapy (NRT) - a scientific update].

    PubMed

    Mulzer, Karl-Heinz; Lichtenschopf, Alfred; Homeier, Irmgard; Groman, Ernest

    2009-01-01

    Nicotine replacement therapy (NRT) is available in various application forms for the treatment of tobacco addiction. All forms underwent a comprehensive clinical study program (approx. 132 trial) to research on efficacy, safety and influence of environmental conditions. Nicotine gum, patch, nasal spray, microtab, lozenge and inhaler are recommended based on evidence criteria (OR 1.5 to 3.6, variation based on usage conditions and application form. NRT forms are OTC medicines (Exception: Nicotine nasal spray). The quality and the certainty of the nicotine replacement therapy will be enhanced by reflecting considerations concerning the indication, correlation of single NRT form to the appropriate user as well as the right dosage and compliance matters.

  11. Differential discriminative-stimulus effects of cigarette smoke condensate and nicotine in nicotine-discriminating rats.

    PubMed

    Lee, Jun-Yeob; Choi, Mee Jung; Choe, Eun Sang; Lee, Young-Ju; Seo, Joung-Wook; Yoon, Seong Shoon

    2016-06-01

    Although it is widely accepted that nicotine plays a key role in tobacco dependence, nicotine alone cannot account for all of the pharmacological effects associated with cigarette smoke found in preclinical models. Thus, the present study aimed to determine the differential effects of the interoceptive cues of nicotine alone versus those of cigarette smoke condensate (CSC) in nicotine-trained rats. First, the rats were trained to discriminate nicotine (0.4mg/kg, subcutaneous [s.c.]) from saline in a two-lever drug discrimination paradigm. Then, to clarify the different neuropharmacological mechanisms underlying the discriminative-stimulus effects in the nicotine and CSC in nicotine-trained rats, either the α4β2 nicotinic acetylcholine receptor (nAChR) antagonist dihydro-β-erythroidine (DHβE; 0.3-1.0mg/kg, s.c.) or the α7 nAChR antagonist methyllycaconitine citrate (MLA; 5-10mg/kg, intraperitoneal [i.p.]) was administered prior to the injection of either nicotine or CSC. Separate set of experiments was performed to compare the duration of action of the discriminative-stimulus effects of CSC and nicotine. CSC exhibited a dose-dependent nicotine generalization, and interestingly, 1.0mg/kg of DHβE antagonized the discriminative effects of nicotine (0.4mg/kg) but not CSC (0.4mg/kg nicotine content). However, pretreatment with MLA had no effect. In the time-course study, CSC had a relatively longer half-life in terms of the discriminative-stimulus effects compared with nicotine alone. Taken together, the present findings indicate that CSC has a distinct influence on interoceptive effects relative to nicotine alone and that these differential effects might be mediated, at least in part, by the α4β2, but not the α7, nAChR.

  12. Absorption of Bupivacaine after Administration of a Lozenge as Topical Treatment for Pain from Oral Mucositis.

    PubMed

    Mogensen, Stine; Sverrisdóttir, Eva; Sveinsdóttir, Kolbrún; Treldal, Charlotte; Jensen, Kenneth; Jensen, Anders Bonde; Kristensen, Claus Andrup; Jacobsen, Jette; Kreilgaard, Mads; Petersen, Janne; Andersen, Ove

    2017-01-01

    The aim was to investigate systemic exposure after administration of a novel bupivacaine lozenge in healthy individuals with normal mucosa and in head and neck cancer (HNC) patients with oral mucositis. A lozenge containing 5, 10, 25 and 50 mg bupivacaine, respectively, was administered as single dose to 10 healthy individuals, and a lozenge containing 25 mg bupivacaine was administered as single dose to 10 HNC patients with oral mucositis and as multiple doses to five patients with HNC. Blood samples were collected for 6 hr from the healthy individuals and 3 hr from the patients with HNC, respectively, after administration. The plasma concentration-time profiles of bupivacaine were fitted to pharmacokinetic models using nonlinear mixed-effects modelling, evaluating demographics and health status as covariates. The population pharmacokinetics (PK) of bupivacaine lozenge was best described by a two-compartment distribution model with absorption transit compartments. All the observed plasma concentrations were well below the bupivacaine concentrations (2000-2250 ng/ml) which have caused toxic symptoms. The PK model suggested that relative bioavailability was two times higher in HNC patients with oral mucositis grade 1-2 and three times higher in HNC patients with oral mucositis grade 3-4 than in the healthy individuals. Simulations showed that the plasma concentrations would be below the toxic limit after repeated dosing every second hour with 25 mg bupivacaine for five days. The 25-mg bupivacaine lozenges were safe without systemic toxic levels of bupivacaine or risk of side effects. Based on PK simulations of repeated doses of 25 mg every two hours for 16 hr a day, the lozenges can be administered with minimum risk of exceeding the toxic limit.

  13. Nicotine and tobacco

    MedlinePlus

    Withdrawal from nicotine; Smoking - nicotine addiction and withdrawal; Smokeless tobacco - nicotine addiction; Cigar smoking; Pipe smoking; Smokeless snuff; Tobacco use; Chewing tobacco; Nicotine addiction and tobacco

  14. The Effects of Nicotine on the Human Electroretinogram

    PubMed Central

    Reid, Jamie C.; Hartmann, E. Eugenie; Keyser, Kent T.

    2011-01-01

    Purpose. To examine the effects of nicotine on responses from the human retina measured electrophysiologically. Methods. Electroretinogram (ERG) responses were obtained from ten healthy, visually normal adults who were nonsmokers. Nicotine (2 and 4 mg) and a placebo were administered in the form of gum 30 minutes before testing in two separate experiments. ERG responses were collected and analyzed using a full-field ERG system. Responses were recorded from one eye of each subject using a bipolar contact-lens electrode. Intensity–response curves were obtained under both dark- and light-adapted conditions. In experiment 1, both dark- and light-adapted tests were completed sequentially. In experiment 2, only light-adapted testing was performed. Intensity–response functions were analyzed using the Naka–Rushton equation. Results. In experiment 1, compared with placebo, dark-adapted b-wave amplitude responses decreased significantly after chewing gum containing both 2 and 4 mg of nicotine. Under light-adapted conditions, the peak b-wave amplitude was significantly decreased after chewing gum containing 4 mg of nicotine. In experiment 2, light-adapted b-wave amplitudes were increased after 4 mg nicotine. Oscillatory potentials were measured but no significant effects under nicotine were observed. Conclusions. To the knowledge of the authors, this is the first demonstration that nicotine by itself affects responses in the human retina. These data support reports of the expression of nicotinic acetylcholine receptors in rabbit and nonhuman primate retina. PMID:22064991

  15. 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.

  16. 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.

  17. Nicotine Elicits Convulsive Seizures by Activating Amygdalar Neurons

    PubMed Central

    Iha, Higor A.; Kunisawa, Naofumi; Shimizu, Saki; Tokudome, Kentaro; Mukai, Takahiro; Kinboshi, Masato; Ikeda, Akio; Ito, Hidefumi; Serikawa, Tadao; Ohno, Yukihiro

    2017-01-01

    Nicotinic acetylcholine (nACh) receptors are implicated in the pathogenesis of epileptic disorders; however, the mechanisms of nACh receptors in seizure generation remain unknown. Here, we performed behavioral and immunohistochemical studies in mice and rats to clarify the mechanisms underlying nicotine-induced seizures. Treatment of animals with nicotine (1–4 mg/kg, i.p.) produced motor excitement in a dose-dependent manner and elicited convulsive seizures at 3 and 4 mg/kg. The nicotine-induced seizures were abolished by a subtype non-selective nACh antagonist, mecamylamine (MEC). An α7 nACh antagonist, methyllycaconitine, also significantly inhibited nicotine-induced seizures whereas an α4β2 nACh antagonist, dihydro-β-erythroidine, affected only weakly. Topographical analysis of Fos protein expression, a biological marker of neural excitation, revealed that a convulsive dose (4 mg/kg) of nicotine region-specifically activated neurons in the piriform cortex, amygdala, medial habenula, paratenial thalamus, anterior hypothalamus and solitary nucleus among 48 brain regions examined, and this was also suppressed by MEC. In addition, electric lesioning of the amygdala, but not the piriform cortex, medial habenula and thalamus, specifically inhibited nicotine-induced seizures. Furthermore, microinjection of nicotine (100 and 300 μg/side) into the amygdala elicited convulsive seizures in a dose-related manner. The present results suggest that nicotine elicits convulsive seizures by activating amygdalar neurons mainly via α7 nACh receptors. PMID:28232801

  18. Acquisition of nicotine discrimination and discriminative stimulus effects of nicotine in rats chronically exposed to caffeine.

    PubMed

    Gasior, M; Shoaib, M; Yasar, S; Jaszyna, M; Goldberg, S R

    1999-03-01

    Caffeine and nicotine are the main psychoactive ingredients of coffee and tobacco, with a high frequency of concurrent use in humans. This study examined the effects of chronic caffeine exposure on 1) rates of acquisition of a nicotine discrimination (0.1 or 0.4 mg/kg, s.c., training doses) and 2) the pharmacological characteristics of the established nicotine discrimination in male Sprague-Dawley rats. Once rats learned to lever-press reliably under a fixed ratio of 10 schedule for food pellets, they were randomly divided into two groups; 12 animals were maintained continuously on caffeine added to the drinking water (3 mg/ml) and another 12 control rats continued to drink tap water. In each group of water- and caffeine-drinking rats, there were six rats trained to discriminate 0.1 mg/kg of nicotine from saline and six rats trained to discriminate 0.4 mg/kg of nicotine from saline. Regardless of the training dose of nicotine, both water- and caffeine-drinking groups required a comparable number of training sessions to attain reliable stimulus control, although there was a trend for a slower acquisition in the caffeine-drinking group trained with 0.1 mg/kg of nicotine. Tests for generalization to different doses of nicotine revealed no significant differences in potency of nicotine between water- and caffeine-drinking groups. The nicotinic-receptor antagonist mecamylamine blocked the discriminative effects of 0.1 and 0.4 mg/kg nicotine with comparable potency and efficacy in water- and caffeine-drinking groups. There was a dose-related generalization to both the 0.1 and 0.4 mg/kg nicotine cue (maximum average of 51-83%) in water-drinking rats after i.p. treatment with d-amphetamine, cocaine, the selective dopamine uptake inhibitor GBR-12909, apomorphine, and the selective dopamine D1 receptor agonist SKF-82958, but not in caffeine-drinking rats (0-22%). There was no generalization to the nicotine cues after i.p. treatment with caffeine or the selective D2 (NPA) and

  19. Lozenge directly activates argos and klumpfuss to regulate programmed cell death.

    PubMed

    Wildonger, Jill; Sosinsky, Alona; Honig, Barry; Mann, Richard S

    2005-05-01

    We show that reducing the activity of the Drosophila Runx protein Lozenge (Lz) during pupal development causes a decrease in cell death in the eye. We identified Lz-binding sites in introns of argos (aos) and klumpfuss (klu) and demonstrate that these genes are directly activated targets of Lz. Loss of either aos or klu reduces cell death, suggesting that Lz promotes apoptosis at least in part by regulating aos and klu. These results provide novel insights into the control of programmed cell death (PCD) by Lz during Drosophila eye development.

  20. Nicotine Gum

    MedlinePlus

    ... gum is used to help people stop smoking cigarettes. Nicotine chewing gum should be used together with ... by your doctor.If you smoke your first cigarette more than 30 minutes after waking up, use ...

  1. Nicotine enhancement and reinforcer devaluation: Interaction with opioid receptors.

    PubMed

    Kirshenbaum, Ari P; Suhaka, Jesse A; Phillips, Jessie L; Voltolini de Souza Pinto, Maiary

    In rats, nicotine enhances responding maintained by non-pharmacological reinforcers, and discontinuation of nicotine devalues those same reinforcers. The goal of this study was to assess the interaction of nicotine and opioid receptors and to evaluate the degree to which nicotine enhancement and nicotine-induced devaluation are related to opioid activation. Nicotine (0.4mg/kg), or nicotine plus naloxone (0.3 or 3.0mg/kg), was delivered to rats prior to progressive ratio (PR) schedule sessions in which sucrose was used as a reinforcer. PR-schedule responding was assessed during ten daily sessions of drug delivery, and for three post-dosing days/sessions. Control groups for this investigation included a saline-only condition, and naloxone-only (0.3 or 3.0mg/kg) conditions. When administered in conjunction with nicotine, both naloxone doses attenuated nicotine enhancement of the sucrose reinforcer, and the combination of the larger dose of naloxone (3.0mg/kg) with nicotine produced significant impairments in sucrose reinforced responding. When administered alone, neither dose of naloxone (0.3 & 3.0mg/kg) significantly altered responding in comparison to saline. Furthermore, when dosing was discontinued after ten once-daily doses, all nicotine groups (nicotine-only and nicotine+naloxone combination) demonstrated significant decreases in sucrose reinforcement compared to the saline group. Although opioid antagonism attenuated reinforcement enhancement by nicotine, it did not prevent reinforcer devaluation upon discontinuation of nicotine dosing, and the higher dose of naloxone (3.0mg/kg) produced decrements upon discontinuation on its own in the absence of nicotine.

  2. Topiramate does not alter nicotine or cocaine discrimination in rats.

    PubMed

    Le Foll, Bernard; Justinova, Zuzana; Wertheim, Carrie E; Barnes, Chanel; Goldberg, Steven R

    2008-02-01

    The effects of topiramate, a potential treatment for drug dependence, were evaluated in two groups of rats trained to discriminate the administration of either 0.4 mg/kg nicotine or 10 mg/kg cocaine from that of saline, under a fixed-ratio 10 schedule of food delivery. Topiramate (1-60 mg/kg, intraperitoneal) did not produce any nicotine-like or cocaine-like discriminative effects by itself and did not produce any shift in the dose-response curves for nicotine or cocaine discrimination. Thus, the ability to discriminate the effects of nicotine or cocaine does not appear to be altered by topiramate administration. Furthermore, topiramate, given either alone or in combination with nicotine or cocaine, did not depress rates of responding. These experiments indicate that topiramate does not enhance or reduce the ability of rats to discriminate the effects of nicotine or cocaine.

  3. Capillary electrophoresis and liquid chromatography in the analysis of some quaternary ammonium salts used in lozenges as antibacterial agents.

    PubMed

    Taylor, R B; Toasaksiri, S; Reid, R G

    1998-01-01

    A comparison is made of the relative merits of high-performance liquid chromatography and capillary electrophoresis, both using direct UV detection, for the determination of three quaternary ammonium compounds used as the active antibacterial ingredient in lozenge formulations. While both techniques are capable of separating the compounds cetylpyridinium chloride, dequalinium chloride, and benzalkonium chlorides, the liquid chromatographic method involving ion pairing and using a 5-micron cyanopropyl stationary phase, was unable to resolve the benzalkonium chlorides from the lozenge excipients and quantitation was not possible. The capillary electrophoresis method using a 205-mm 50-micron-i.d. capillary with a running buffer of 50% vol/vol 50 mM phosphate buffer at pH 3 provided superior resolution of the three antibacterials in all lozenge formulations. This system was also capable of resolving impurities in the dequalinium chloride both in the standard and in lozenges containing this compound. On the basis of quantitative results previously published, both methods have adequate validation parameters since the relative insensitivity of capillary electrophoresis compared with liquid chromatography is not important at the concentration required to be determined following a single simple sample pretreatment.

  4. Behavioral and neuropharmacological characterization of nicotine as a conditional stimulus

    PubMed Central

    Murray, Jennifer E.; Bevins, Rick A.

    2007-01-01

    In rats, the pharmacological (interoceptive) effects of 0.4 mg/kg nicotine can serve as a conditional stimulus in a Pavlovian conditioning task. Nicotine administration is paired with intermittent access to a liquid sucrose unconditional stimulus; sucrose is withheld on saline sessions. An increase in sucrose receptacle entries (goal tracking) on nicotine sessions indicates conditioning. Rats were trained on a nicotine dose ((−)-1-Methyl-2-(3-pyridyl)pyrrolidine; 0.1, 0.2, or 0.4 mg base/kg, s.c.). Generalization was examined using 0.025, 0.05, 0.1, 0.2, and 0.4 mg/kg nicotine and saline. Some behavioral effects of nicotine have been attributed to dopamine and glutamate. Accordingly, potential blockade of the nicotine cue via the dopamine system was examined by administering (R)-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390; 0.005, 0.01, and 0.03 mg/kg), 3-Chloro-5-ethyl-N-[[(2S)-1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxy-benzamide hydrochloride (eticlopride; 0.01, 0.03, 0.1, and 0.3 mg/kg), or N-[(1-Butyl-2-pyrrolidinyl)methyl]-4-cyano-1-methoxy-2-naphthalenecarboxamide (nafadotride; 0.03, 0.1, 0.3, 1, and 3 mg/kg) before nicotine. 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP; 0.3, 1, and 3 mg/kg) and (5S,10R)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801; 0.01, 0.03, 0.1, and 0.2 mg/kg; dizocilpine) were used to examine possible glutamatergic components. Substitution tests were conducted with MPEP and nafadotride. Differential conditioned responding was acquired in the 3 groups. Conditioned responding generally decreased as the nicotine test dose moved away from the training dose; responding increased when 0.4 mg/kg trained rats were tested with 0.2 mg/kg. SCH-23390, eticlopride, nafadotride, and MPEP decreased conditioned responding on nicotine at doses that also decreased chamber activity. In contrast, MK-801 decreased goal tracking on nicotine without

  5. Behavioral and neuropharmacological characterization of nicotine as a conditional stimulus.

    PubMed

    Murray, Jennifer E; Bevins, Rick A

    2007-04-30

    In rats, the pharmacological (interoceptive) effects of 0.4 mg/kg nicotine can serve as a conditional stimulus in a Pavlovian conditioning task. Nicotine administration is paired with intermittent access to a liquid sucrose unconditional stimulus; sucrose is withheld on saline sessions. An increase in sucrose receptacle entries (goal tracking) on nicotine sessions indicates conditioning. Rats were trained on a nicotine dose ((-)-1-Methyl-2-(3-pyridyl)pyrrolidine; 0.1, 0.2, or 0.4 mg base/kg, s.c.). Generalization was examined using 0.025, 0.05, 0.1, 0.2, and 0.4 mg/kg nicotine and saline. Some behavioral effects of nicotine have been attributed to dopamine and glutamate. Accordingly, potential blockade of the nicotine cue via the dopamine system was examined by administering (R)-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390; 0.005, 0.01, and 0.03 mg/kg), 3-Chloro-5-ethyl-N-[[(2S)-1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxy-benzamide hydrochloride (eticlopride; 0.01, 0.03, 0.1, and 0.3 mg/kg), or N-[(1-Butyl-2-pyrrolidinyl)methyl]-4-cyano-1-methoxy-2-naphthalenecarboxamide (nafadotride; 0.03, 0.1, 0.3, 1, and 3 mg/kg) before nicotine. 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP; 0.3, 1, and 3 mg/kg) and (5S,10R)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801; 0.01, 0.03, 0.1, and 0.2 mg/kg; dizocilpine) were used to examine possible glutamatergic components. Substitution tests were conducted with MPEP and nafadotride. Differential conditioned responding was acquired in the 3 groups. Conditioned responding generally decreased as the nicotine test dose moved away from the training dose; responding increased when 0.4 mg/kg trained rats were tested with 0.2 mg/kg. SCH-23390, eticlopride, nafadotride, and MPEP decreased conditioned responding on nicotine at doses that also decreased chamber activity. In contrast, MK-801 decreased goal tracking on nicotine without

  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.

  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.

  8. Airborne Nicotine Concentrations in the Workplaces of Tobacco Farmers

    PubMed Central

    Yoo, Seok-Ju; Park, Sung-Jun; Kim, Byoung-Seok; Lim, Hyun-Sul; Kim, Jik-Su; Kim, In-Shik

    2014-01-01

    Objectives Nicotine is a natural alkaloid and insecticide in tobacco leaves. Green tobacco sickness (GTS) is known as a disease of acute nicotine intoxication among tobacco farmers. Until now, GTS has been recognized globally as a disease that results from nicotine absorption through the skin. However, we assumed that GTS might also result from nicotine inhalation as well as absorption. We aimed to measure the airborne nicotine concentrations in various work environments of Korean tobacco farmers. Methods We measured the nicotine concentrations in the tobacco fields, private curing barns, and joint curing barns of farmers from July to October 2010. All sampling and analyses of airborne nicotine were conducted according to the National Institute for Occupational Safety and Health manual of analytic methods. Results The airborne nicotine concentrations (geometric mean [geometric standard deviation]) in the tobacco field were 83.4 mg/m3 (1.2) in the upper region and 93.3 mg/m3 (1.2) in the lower region. In addition, the nicotine concentration by personal sampling was 150.1 mg/m3. Similarly, the nicotine concentrations in the private curing barn, workers in curing barns, the front yard of the curing barn, and in the joint curing barn were 323.7 mg/m3 (2.0), 121.0 mg/m3 (1.5), 73.7 mg/m3 (1.7), and 610.3 mg/m3 (1.0), respectively. Conclusions The nicotine concentration in the workplaces of tobacco farmers was very high. Future studies should measure the environmental concentration of nicotine that is inhaled by tobacco farmers. PMID:24921017

  9. 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.

  10. Nicotine Dependence as a Moderator of a Quitline-Based Message Framing Intervention

    PubMed Central

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

    2010-01-01

    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

  11. 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.

  12. 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.

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

    PubMed Central

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

    2013-01-01

    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

  14. Neuronal nicotinic receptor ligands modulate chronic nicotine-induced ethanol consumption in C57BL/6J mice.

    PubMed

    Sajja, Ravi K; Rahman, Shafiqur

    2012-07-01

    Alcohol and nicotine are commonly abused drugs in humans and evidence suggests that neuronal nicotinic acetylcholine receptors (nAChRs) in the midbrain dopamine system are common targets for the neurobehavioral interactions between alcohol (ethanol) and nicotine. The present study examined the efficacy of nAChR ligands with different pharmacological profiles such as cytisine, lobeline and dihydro-β-erythroidine (DHβE) to modulate chronic nicotine-induced increase in ethanol intake by C57BL/6J mice, using a two-bottle choice procedure. After establishment of baseline ethanol preference (10%, v/v), animals received daily subcutaneous injections of saline, nicotine (0.4 mg/kg) or different doses of cytisine, lobeline or DHβE 15 min prior to nicotine, for 10 days. Ethanol and water were presented immediately after the last (saline or nicotine) injection and fluid levels were monitored for post 1 h and 2 h treatment. Compared to control, nicotine injection significantly increased mean ethanol intake over 10 days, at both post 1 h and 2 h. Pretreatment with cytisine (0.5, 1.5 or 3.0 mg/kg) or lobeline (4.0 or 10.0 mg/kg) significantly reduced nicotine-induced increase in ethanol intake post 1 h and 2 h, without affecting water consumption. DHβE (0.5 or 2.0 mg/kg) failed to suppress nicotine-induced ethanol intake across 2 h post injection. These results indicate that nAChRmediated signaling is critical in regulating nicotine-induced ethanol drinking behaviors.

  15. Periadolescent nicotine exposure causes heterologous sensitization to cocaine reinforcement.

    PubMed

    McMillen, Brian A; Davis, Barbara J; Williams, Helen L; Soderstrom, Ken

    2005-02-21

    There is increasing concern that abuse of tobacco during periadolescence increases the potential for later abuse of other drugs. To test this hypothesis, Sprague-Dawley rats received once-daily injections of either water or 0.4 mg/kg nicotine from postnatal day 35 through 44. Beginning on postnatal day 80, animals were tested in a 12-day cocaine-induced conditioned place preference (CPP) paradigm. Prior nicotine treatment enhanced the dose-response to cocaine. CPP training with 3.0 mg/kg i.p. cocaine increased time in drug-paired chambers by 50% in control rats and 94% in nicotine-exposed animals. Thus, periadolescent nicotine exposure produced long-term sensitization to an indirect-acting dopamine agonist.

  16. Nicotine replacement therapy

    MedlinePlus

    ... takes for the patch to work. The inhaler satisfies oral urges. Most of the nicotine vapor does ... spray provides a quick dose of nicotine to satisfy a craving you are unable to ignore. Levels ...

  17. The Effects of the Nicotine Patch vs. Varenicline vs. Combination Nicotine Replacement Therapy on Smoking Cessation at 26 Weeks: A Randomized Controlled Trial

    PubMed Central

    Baker, Timothy B.; Piper, Megan E.; Stein, James H.; Smith, Stevens S.; Bolt, Daniel M.; Fraser, David L.; Fiore, Michael C.

    2016-01-01

    Importance Smoking cessation medications are routinely used in healthcare; it is vital to identify medications that most effectively treat this leading cause of preventable mortality. Objective Compare the efficacies of varenicline, combination nicotine replacement (C-NRT), and the nicotine patch on 26-week quit rates. Design, Setting, Participants 3-group randomized clinical trial occurring from 5/22/2012 – 11/18/2015, using the intention-to-treat principle. Among 1086 smokers who were randomized (52% women, 67% White, mean age 48 years, mean of 17 cigarettes smoked/day), 917 (84%) provided 12 month follow-up data. Recruitment was in the Madison WI and Milwaukee WI communities and 65.5% of smokers offered the study (2687/4102) refused participation prior to randomization. Interventions Three open-label smoking cessation pharmacotherapies for 12 weeks: 1) nicotine patch only (n=241); 2) varenicline only (including 1 pre-quit week; n=424); and 3) C-NRT (nicotine patch + nicotine lozenge; n=421). 6 counseling sessions were offered. Main Outcomes and Measurements Primary outcome was carbon monoxide confirmed self-reported 7-day point-prevalence abstinence at 26 weeks. Secondary outcomes were carbon monoxide confirmed self-reported initial abstinence, prolonged abstinence at 26 weeks, and point prevalence abstinence at Weeks 1, 4, and 52. Results Treatments did not differ on any abstinence outcome measure at 26 or 52 Weeks, including point-prevalence abstinence at 26 Weeks (nicotine patch: 22.8% [55/241]; varenicline: 23.6% [100/424]; and C-NRT: 26.8% [113/421] or 52 weeks (nicotine patch: 20.8% [50/214]; varenicline: 19.1% [81/424]; and C-NRT: 20.2% [85/421]). At 26 weeks the risk differences for abstinence were: patch versus varenicline (−0.76, 95% CI: −7.4 to 5.9), patch versus C-NRT (−4.0, 95%CI: −10.8 to 2.8), and varenicline versus C-NRT (−3.3, 95% CI: −9.1 to 2.6). All medications were well tolerated, but varenicline produced greater adverse event

  18. 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.

  19. Effects of baclofen on conditioned rewarding and discriminative stimulus effects of nicotine in rats.

    PubMed

    Le Foll, Bernard; Wertheim, Carrie E; Goldberg, Steven R

    2008-10-10

    Neurochemical studies suggest that baclofen, an agonist at GABA(B) receptors, may be useful for treatment of nicotine dependence. However, its ability to selectively reduce nicotine's abuse-related behavioral effects remains in question. We assessed effects of baclofen doses ranging from 0.1 to 3mg/kg on nicotine-induced conditioned place preferences (CPPs), nicotine discrimination, locomotor activity and food-reinforced behavior in male Sprague-Dawley rats. The high dose of baclofen (3mg/kg) totally eliminated food-reinforced responding and significantly decreased locomotor activity. Lower doses of baclofen did not have nicotine-like discriminative effects in rats trained to discriminate 0.4mg/kg nicotine from saline under a fixed-ratio 10 schedule of food delivery. Lower doses of baclofen also did not reduce discriminative stimulus effects of the training dose of nicotine and did not significantly shift the dose-response curve for nicotine discrimination. Rats treated with the high 3mg/kg dose of baclofen did not express nicotine-induced CPP. These experiments, along with previous reports that baclofen can reduce intravenous nicotine self-administration behavior, confirm the potential utility of baclofen as a tool for smoking cessation.

  20. The Impact of Smoking Very Low Nicotine Content Cigarettes on Alcohol Use

    PubMed Central

    Dermody, Sarah S.; Tidey, Jennifer W.; Denlinger, Rachel L.; Pacek, Lauren R.; al’Absi, Mustafa; Drobes, David J.; Hatsukami, Dorothy K.; Vandrey, Ryan; Donny, Eric C.

    2017-01-01

    Background Reducing the nicotine content in cigarettes could improve public health by reducing smoking and toxicant exposure, but may also have unintended consequences on alcohol use. The primary objective of this study was to examine the effect of reducing the nicotine content in cigarettes on alcohol outcomes. The secondary aim was to examine whether the effects of these cigarettes on alcohol outcomes were mediated by changes in nicotine exposure, smoking behavior, or withdrawal. Methods Between June 2013 and July 2014, we conducted a 7-arm, double-blind, randomized clinical trial at 10 U.S.-based sites. Daily smokers not currently interested in quitting (n = 839) were assigned to equally sized groups to smoke for 6 weeks cigarettes containing either normal nicotine content (NNC; 15.8 mg/g, 9 mg tar), moderate nicotine content (5.2 mg/g nicotine, 9 mg tar), or very low nicotine content (VLNC; 0.4 to 2.4 mg/g, 9 to 13 mg tar). This investigation focused on a subsample of current drinkers (n = 403). Each reduced nicotine content cigarette condition was compared to the NNC control condition with respect to trajectories over the 6-week period of average daily alcohol use and occurrence of binge drinking. Moderating variables were considered. Mediation analyses tested potential explanatory processes including changes in nicotine exposure, cigarettes per day, and withdrawal. Results Over time, reduced nicotine exposure and smoking rate mediated effects of VLNC cigarette use on reduced alcohol use. There was no evidence of compensatory drinking in response to nicotine reduction or nicotine withdrawal, even among subgroups expected to be at greater risk (e.g., relatively heavier drinkers, highly nicotine-dependent individuals). Conclusions The findings suggest that compensatory drinking is unlikely to occur in response to switching to VLNC cigarettes. In contrast, reducing the nicotine content of cigarettes may reduce alcohol use (clinicalTrials.gov number, NCT01681875

  1. Presence of Lactobacillus reuteri in saliva coincide with higher salivary IgA in young adults after intake of probiotic lozenges.

    PubMed

    Braathen, G; Ingildsen, V; Twetman, S; Ericson, D; Jørgensen, M R

    2017-02-07

    The aim of this study was to compare the concentration of salivary immunoglobulin A (IgA) and the selected interleukins (IL)-1β, IL-6, IL-8 and IL-10 in young individuals with presence and non-presence of Lactobacillus reuteri in saliva after a three-week intervention with probiotic lozenges. The study group consisted of 47 healthy individuals aged 18-32 years with no clinical signs of oral inflammation. In a randomised, double-blind, placebo-controlled, cross-over trial participants ingested two lozenges per day containing two strains of the probiotic bacterium L. reuteri or placebo lozenges. The intervention and wash-out periods were three weeks. Stimulated and unstimulated whole saliva was collected at baseline and immediately after termination of the intervention periods. The samples were analysed for total protein, salivary IgA and selected cytokines. In this extended analysis, data were collected by analysing baseline and follow-up saliva samples related to ingestion of the probiotic lozenges for the presence of L. reuteri through DNA-extraction, PCR-amplification and gel-electrophoresis. At baseline, 27% of the individuals displayed presence of L. reuteri and 42% were positive immediately after the three-week probiotic intervention. Individuals with presence of L. reuteri in saliva had significantly higher (P<0.05) concentrations of salivary IgA and %IgA/protein at the termination of the probiotic intake compared with non-presence. No differences in the cytokine levels were observed. In conclusion, detectable levels of L. reuteri in saliva coincided with higher concentrations of salivary IgA and %IgA/protein in stimulated whole saliva after the three-week daily intake of probiotic lozenges. Our findings suggest that monitoring the presence of probiotic candidates in the oral environment is important to interpret and understand their possible immune-modulating role in maintaining oral health.

  2. 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.

  3. 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.

  4. Electronic Nicotine Delivery Systems.

    PubMed

    Walley, Susan C; Jenssen, Brian P

    2015-11-01

    Electronic nicotine delivery systems (ENDS) are rapidly growing in popularity among youth. ENDS are handheld devices that produce an aerosolized mixture from a solution typically containing concentrated nicotine, flavoring chemicals, and propylene glycol to be inhaled by the user. ENDS are marketed under a variety of names, most commonly electronic cigarettes and e-cigarettes. In 2014, more youth reported using ENDS than any other tobacco product. ENDS pose health risks to both users and nonusers. Nicotine, the major psychoactive ingredient in ENDS solutions, is both highly addictive and toxic. In addition to nicotine, other toxicants, carcinogens, and metal particles have been detected in solutions and aerosols of ENDS. Nonusers are involuntarily exposed to the emissions of these devices with secondhand and thirdhand aerosol. The concentrated and often flavored nicotine in ENDS solutions poses a poisoning risk for young children. Reports of acute nicotine toxicity from US poison control centers have been increasing, with at least 1 child death reported from unintentional exposure to a nicotine-containing ENDS solution. With flavors, design, and marketing that appeal to youth, ENDS threaten to renormalize and glamorize nicotine and tobacco product use. There is a critical need for ENDS regulation, legislative action, and counter promotion to protect youth. ENDS have the potential to addict a new generation of youth to nicotine and reverse more than 50 years of progress in tobacco control.

  5. Nicotine enhances the reconsolidation of novel object recognition memory in rats.

    PubMed

    Tian, Shaowen; Pan, Si; You, Yong

    2015-02-01

    There is increasing evidence that nicotine is involved in learning and memory. However, there are only few studies that have evaluated the relationship between nicotine and memory reconsolidation. In this study, we investigated the effects of nicotine on the reconsolidation of novel object recognition memory in rats. Behavior procedure involved four training phases: habituation (Days 1 and 2), sample (Day 3), reactivation (Day 4) and test (Day 6). Rats were injected with saline or nicotine (0.1, 0.2 and 0.4 mg/kg) immediately or 6h after reactivation. The discrimination index was used to assess memory performance and calculated as the difference in time exploring on the novel and familiar objects. Results showed that nicotine administration immediately but not 6 h after reactivation significantly enhanced memory performance of rats. Further results showed that the enhancing effect of nicotine on memory performance was dependent on memory reactivation, and was not attributed to the changes of the nonspecific responses (locomotor activity and anxiety level) 48 h after nicotine administration. The results suggest that post-reactivation nicotine administration enhances the reconsolidation of novel object recognition memory. Our present finding extends previous research on the nicotinic effects on learning and memory.

  6. Pharmacologic Antagonism of Ghrelin Receptors Attenuates Development of Nicotine Induced Locomotor Sensitization in Rats

    PubMed Central

    Wellman, Paul J.; Clifford, P. Shane; Rodriguez, Juan; Hughes, Samuel; Eitan, Shoshana; Brunel, Luc; Fehrentz, Jean-Alain; Martinez, Jean

    2011-01-01

    Aims Ghrelin (GHR) is an orexigenic gut peptide that interacts with ghrelin receptors (GHR-Rs) to modulate brain reinforcement circuits. Systemic GHR infusions augment cocaine stimulated locomotion and conditioned place preference (CPP) in rats, whereas genetic or pharmacological ablation of GHR-Rs has been shown to attenuate the acute locomotor-enhancing effects of nicotine, cocaine, amphetamine and alcohol and to blunt the CPP induced by food, alcohol, amphetamine and cocaine in mice. The stimulant nicotine can induce CPP and like amphetamine and cocaine, repeated administration of nicotine induces locomotor sensitization in rats. A key issue is whether pharmacological antagonism of GHR-Rs would similarly attenuate nicotine-induced locomotor sensitization. Method To examine the role of GHR-Rs in the behavioral sensitizing effects of nicotine, adult male rats were injected with either 0, 3 or 6 mg/kg of the GHR-R receptor antagonist JMV 2959 (i.p.) and 20 minutes later with either vehicle or 0.4 mg/kg nicotine hydrogen tartrate (s.c.) on each of 7 consecutive days. Results Rats treated with nicotine alone showed robust locomotor sensitization, whereas rats pretreated with JMV 2959 showed significantly attenuated nicotine-induced hyperlocomotion. Conclusions These results suggest that GHR-R activity is required for the induction of locomotor sensitization to nicotine and complement an emerging literature implicating central GHR systems in drug reward/reinforcement. PMID:21903141

  7. Context modulates effects of nicotine abstinence on human cooperative responding.

    PubMed

    Spiga, R; Day, J D; Schmitz, J M; Broitman, M; Elk, R; Caperton-Brown, H

    1998-11-01

    The effects of ad libitum smoking, abstinence, and 0-, 2-, and 4-mg nicotine gum on human cooperative responding were examined. Participants were provided the opportunity to respond cooperatively or independently to episodes initiated by a computer-simulated other person. Participants could also initiate episodes that ostensibly provided the other person the opportunity to respond cooperatively or independently of the participant. Working cooperatively added points to both the participant's and other person's counters. Working independently added points only to the participant's counter. Results demonstrated that abstinence decreased cooperative responses during episodes initiated by the computer-stimulated other person. Relative to abstinence and placebo gum conditions, ad libitum smoking and administration of 2- and 4-mg nicotine gum increased these cooperative responses. No gender differences were observed. The number of cooperative episodes initiated by the participants was not affected significantly by the smoking or gum conditions. Nicotine increased reports of vigor and decreased abstinence-engendered reports of depression, anger, confusion, and tension. The difference in the effects of nicotine abstinence on the 2 classes of cooperative responding demonstrates that the social contingency mediates the behavioral effects of abstinence.

  8. Treatment of nicotine dependence.

    PubMed

    Haxby, D G

    1995-02-01

    Drug and nondrug interventions used in treating nicotine dependence are reviewed. Tobacco use is the leading preventable cause of death in the United States. Risks of smoking-related disease and death decline sharply when smokers quit, but 26% of Americans continue to smoke. Most smokers find it extremely difficult to quit smoking because of their nicotine addiction. Nonpharmacologic interventions used to promote smoking cessation include behavioral therapy, setting a specific date for quitting, receiving advice to quit from a health care professional, follow-up visits to review progress, self-help approaches, group counseling, filtration devices, hypnosis, and acupuncture. The efficacy of these approaches ranges from substantial to almost nil. The only pharmacologic agent with FDA-approved labeling for use in smoking-cessation therapy is nicotine. When used in conjunction with appropriate nonpharmacologic interventions, nicotine-replacement therapy roughly doubles the rate of quitting obtained with placebo. Nicotine-replacement therapies consist of nicotine transdermal (patch) systems and nicotine chewing gum. The nicotine patch is the first-line replacement therapy because it is effective when accompanied by only minimal (as opposed to more intensive) nonpharmacologic interventions and because it is easier to use and comply with than gum. Clonidine, antidepressants, and buspirone require further study to determine what role, if any, they should play in the treatment of nicotine dependence. The stages of smoking cessation are precontemplation, contemplation, action, and maintenance; interventions are selected on the basis of the stage the smoker is in. Nicotine dependence is difficult to treat, but there are aids that boost a smoker's chances of quitting. Nicotine patches and chewing gum offer the most effective pharmacologic options, especially when combined with behavioral interventions and counseling.

  9. Decreasing nicotinic receptor activity and the spatial learning impairment caused by the NMDA glutamate antagonist dizocilpine in rats

    PubMed Central

    Burke, Dennis A.; Heshmati, Pooneh; Kholdebarin, Ehsan; Levin, Edward D.

    2014-01-01

    Nicotinic systems have been shown by a variety of studies to be involved in cognitive function. Nicotinic receptors have an inherent property to become desensitized after activation. The relative role of nicotinic receptor activation vs. net receptor inactivation by desensitization in the cognitive effects of nicotinic drugs remains to be fully understood. In these studies, we tested the effects of the α7 nicotinic receptor antagonist methyllycaconitine (MLA), the α4β2 nicotinic receptor antagonist dihydro-β-erythroidine (DHβE), the nonspecific nicotinic channel blocker mecamylamine and the α4β2 nicotinic receptor desensitizing agent sazetidine-A on learning in a repeated acquisition test. Adult female Sprague-Dawley rats were trained on a repeated acquisition learning procedure in an 8-arm radial maze. MLA (1–4 mg/kg), DHβE (1–4 mg/kg), mecamylamine (0.125–0.5 mg/kg) or sazetidine-A (1 and 3 mg/kg) were administered in four different studies either alone or together with the NMDA glutamate antagonist dizocilpine (0.05 and 0.10 mg/kg). MLA significantly counteracted the learning impairment caused by dizocilpine. The overall choice accuracy impairment caused by dizocilpine was significantly attenuated by co-administration of DHβE. Low doses of the non-specific nicotinic antagonist mecamylamine also reduced dizocilpine-induced repeated acquisition impairment. Sazetidine-A reversed the accuracy impairment caused by dizocilpine. These studies provide evidence that a net decrease in nicotinic receptor activity can improve learning by attenuating learning impairment induced by NMDA glutamate blockade. This adds to evidence in cognitive tests that nicotinic antagonists can improve cognitive function. Further research characterizing the efficacy and mechanisms underlying nicotinic antagonist and desensitization induced cognitive improvement is warranted. PMID:25064338

  10. Diminished conditioned responding to the nicotine stimulus by antidepressant drugs with differing specificity for the serotonin and norepinephrine transporter.

    PubMed

    Dion, Amanda M; Sanderson, Scott C; Murrin, L Charles; Bevins, Rick A

    2012-01-01

    People diagnosed with depression also tend to have a co-morbid nicotine addiction. Thus, there is interest in whether medications used to treat depression alter the effects of nicotine. This study assessed whether the antidepressant drugs citalopram, imipramine, and reboxetine, with differing specificity for the serotonin and norepinephrine transporter, altered responding controlled by the conditional stimulus (CS) effects of nicotine. Rats received intermixed 20-min nicotine (0.4 mg base/kg, SC) and saline sessions. On nicotine sessions, rats had intermittent access to sucrose; no sucrose was available on saline sessions. After discrimination performance stabilized and a nicotine generalization curve (0.025-0.4 mg/kg) was established, the antidepressant drugs were assessed. In these tests, rats were pretreated with citalopram (1-17 mg/kg), imipramine (1-17 mg/kg), or reboxetine (1-30 mg/kg) before the training dose of nicotine and placement in a chamber for a 4-min extinction test. At the higher doses, all three antidepressant drugs blocked responding evoked by the nicotine CS and decreased nicotine-induced hyperactivity. When these higher doses of citalopram, imipramine, and reboxetine were tested alone (no nicotine), they decreased chamber activity and/or dipper entries. Nevertheless, all three drugs produced partial or complete blockade of the CS effects of nicotine at doses that produced no effect on dipper entries or chamber entries. This finding suggests that both neurotransmitters play a role in the CS effects of nicotine and that modifications in these systems by antidepressants may be clinically relevant.

  11. 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…

  12. Determination of the quaternary ammonium compounds dequalinium and cetylpyridinium chlorides in candy-based lozenges by high-performance liquid chromatography.

    PubMed

    Taylor, R B; Toasaksiri, S; Reid, R G; Wood, D

    1997-09-01

    The retention behavior of the quaternary ammonium compounds benzalkonium chloride, cetylpyridinium chloride and dequalinium chloride on a 100 x 4.6 mm id cyanopropyl stationary phase column is reported as a function of organic modifier and ionic hydrophobic mobile phase additive concentrations. Optimum liquid chromatographic mobile phases using different mobile phase additives are reported which are suitable for the determination of cetylpyridinium chloride and dequalinium chloride in a variety of candy-based lozenge formulations. The quantitative aspects of assays based on the separation of active ingredients and formulation excipients were established. The generality of application of the assay methods was evaluated by determining the quaternary ammonium content of different lozenges and comparing the values obtained with the stated dose.

  13. Nicotine vapor inhalation escalates nicotine self-administration.

    PubMed

    Gilpin, Nicholas W; Whitaker, Annie M; Baynes, Brittni; Abdel, Abdelrahim Y; Weil, Madelyn T; George, Olivier

    2014-07-01

    Humans escalate their cigarette smoking over time, and a major obstacle in the field of pre-clinical nicotine addiction research has been the inability to produce escalated nicotine self-administration in rats. In experiment 1, male Wistar rats were trained to respond for nicotine in 2-hour operant sessions, then exposed to chronic intermittent (12 hours/day) nicotine vapor and repeatedly tested for nicotine self-administration at 8-12 hours of withdrawal. Rats were tested intermittently on days 1, 3 and 5 of the vapor exposure procedure, then tested with nicotine vapor exposure on 6-15 consecutive days. Rats exhibited transient increases in operant nicotine responding during intermittent testing, regardless of vapor condition, and this responding returned to baseline levels upon resumption of consecutive-days testing (i.e. nicotine deprivation effect). Nicotine vapor-exposed rats then escalated nicotine self-administration relative to both their own baseline (∼200% increase) and non-dependent controls (∼3× higher). In experiment 2, rats were exposed or not exposed to chronic intermittent nicotine vapor, then tested for spontaneous and precipitated somatic signs of nicotine withdrawal. Eight hours following removal from nicotine vapor, rats exhibited robust mecamylamine-precipitated somatic signs of withdrawal. There was a strong correlation between nicotine flow rate and air-nicotine concentration, and the air-nicotine concentrations used in experiments 1 and 2 resemble concentrations experienced by human smokers. Collectively, these results suggest that chronic intermittent nicotine vapor inhalation produces somatic and motivational signs of nicotine dependence, the latter of which is evidenced by escalation of nicotine self-administration.

  14. Effect of a novel neurotensin analog, NT69L, on nicotine-induced alterations in monoamine levels in rat brain.

    PubMed

    Liang, Yanqi; Boules, Mona; Shaw, Amanda M; Williams, Katrina; Fredrickson, Paul; Richelson, Elliott

    2008-09-22

    NT69L, is a novel neurotensin (8-13) analog that participates in the modulation of the dopaminergic pathways implicated in addiction to psychostimulants. NT69L blocks nicotine-induced hyperactivity as well as the initiation and expression of sensitization in rats. Recent evidence suggests that stimulation of mesocorticolimbic dopamine system, with influences from the other monoamine systems, e.g. norepinephrine and serotonin, is involved in nicotine's reinforcing properties. The aim of the present study was to investigate the effect of pretreatment with NT69L on nicotine-induced changes in monoamine levels in the rat brain using in vivo microdialysis. Acute or chronic (0.4 mg/kg, sc, once daily for 2 weeks) administration of nicotine elicited increases in extracellular levels of dopamine, dopamine metabolites, norepinephrine, or serotonin in medial prefrontal cortex, nucleus accumbens shell, and core of rats. Pretreatment with NT69L (1 mg/kg, intraperitoneally, ip) administered 40 min before nicotine injection significantly attenuated the acute nicotine-evoked increases in norepinephrine levels in medial prefrontal cortex, dopamine and serotonin in nucleus accumbens shell. After chronic nicotine administration, pretreatment of NT69L markedly reversed the increase in dopamine levels in the nucleus accumbens core. NT69L's attenuation of some of the biochemical effects of acute and chronic nicotine is consistent with this peptide's attenuation of nicotine-induced behavioral effects. These data further support a role for NT69L or other neurotensin receptor agonists to treat nicotine addiction.

  15. Multi-Sensor Approach for the Monitoring of Halitosis Treatment via Lactobacillus brevis (CD2)-Containing Lozenges--A Randomized, Double-Blind Placebo-Controlled Clinical Trial.

    PubMed

    Marchetti, Enrico; Tecco, Simona; Santonico, Marco; Vernile, Chiara; Ciciarelli, Daniele; Tarantino, Ester; Marzo, Giuseppe; Pennazza, Giorgio

    2015-08-10

    The aim of this randomized clinical trial was to evaluate whether a recently described multi-sensor approach called BIONOTE(®) is accurate enough to verify the efficacy of treatment of patients with halitosis. A treatment with Lactobacillus brevis (CD2)-containing lozenges, compared with placebo was tested. The BIONOTE(®) was compared with traditional techniques used to detect halitosis: OralChroma™ and two calibrated odor judges enrolled for the organoleptic assessments. Twenty patients (10 treated and 10 placebo), suffering from active phase halitosis were included in the study. Treatment consisted of Lactobacillus brevis (CD2)-containing lozenges or placebo, 4 tablets/day for 14 days. t0 was before the beginning of the study; t1 was day 7 and t2 was day 14. The effectiveness of treatment was assessed through: (1) Rosenberg score; (2) Winkel tongue coating index (WTCI) anterior and posterior; (2) OralChroma™; (3) the new developed multi-sensor approach, called BIONOTE(®) (test technique). Only the WTCI anterior revealed statistically significant changes between t0 and t2 data (p = 0.014) in the treated group. Except for the WTCI anterior, all diagnostic methods revealed the lack of effectiveness for halitosis of a 14-days treatment with Lactobacillus brevis (CD2)-containing lozenges. The BIONOTE(®) multisensor system seems accurate in addition to OralChroma™ to assess the initial condition of halitosis and its mitigation during treatment.

  16. Differential effects of serotonin (5-HT)2 receptor-targeting ligands on locomotor responses to nicotine-repeated treatment.

    PubMed

    Zaniewska, Magdalena; McCreary, Andrew C; Wydra, Karolina; Filip, Małgorzata

    2010-07-01

    We verified the hypothesis that serotonin (5-HT)(2) receptors control the locomotor effects of nicotine (0.4 mg kg(-1)) in rats by using the 5-HT(2A) receptor antagonist M100907, the preferential 5-HT(2A) receptor agonist DOI, the 5-HT(2C) receptor antagonist SB 242084, and the 5-HT(2C) receptor agonists Ro 60-0175 and WAY 163909. Repeated pairings of a test environment with nicotine for 5 days, on Day 10 significantly augmented the locomotor activity following nicotine administration. Of the investigated 5-HT(2) receptor ligands, M100907 (2 mg kg(-1)) or DOI (1 mg kg(-1)) administered during the first 5 days in combination with nicotine attenuated or enhanced, respectively, the development of nicotine sensitization. Given acutely on Day 10, M100907 (2 mg kg(-1)), Ro 60-0175 (1 mg kg(-1)), and WAY 163909 (1.5 mg kg(-1)) decreased the expression of nicotine sensitization. In another set of experiments, where the nicotine challenge test was performed on Day 15 in animals treated repeatedly (Days: 1-5, 10) with nicotine, none of 5-HT(2) receptor ligands administered during the second withdrawal period (Days: 11-14) to nicotine-treated rats altered the sensitizing effect of nicotine given on Day 15. Our data indicate that 5-HT(2A) receptors (but not 5-HT(2C) receptors) play a permissive role in the sensitizing effects of nicotine, while stimulation of 5-HT(2A) receptors enhances the development of nicotine sensitization and activation of 5-HT(2C) receptors is essential for the expression of nicotine sensitization. Repeated treatment with the 5-HT(2) receptor ligands within the second nicotine withdrawal does not inhibit previously established sensitization.

  17. The reinforcement enhancing effects of nicotine depend on the incentive value of non-drug reinforcers and increase with repeated drug injections.

    PubMed

    Palmatier, Matthew I; Matteson, Gina L; Black, Jessica J; Liu, Xiu; Caggiula, Anthony R; Craven, Laure; Donny, Eric C; Sved, Alan F

    2007-06-15

    We have hypothesized that nicotine has two effects on reinforcement; it increases the probability of responses resulting in nicotine delivery (primary reinforcement) and enhances the apparent reward value of non-nicotine reinforcers (reinforcement enhancing effect). The present studies investigated two predictions generated by this hypothesis: (1) that the reinforcement enhancing effect will depend on apparent stimulus reward value and (2) that the temporal profile of this effect would depend on the pharmacological profile of nicotine. In Experiment 1, rats were trained to lever press for one of two audio-visual stimuli that differed in their intrinsic reinforcing value and then the effect of pre-session nicotine (0.4 mg/kg base) or saline injections was tested. The stimulus that supported very low rates of operant responding displayed smaller increases in responding after pre-session injections of nicotine. In Experiment 2 the effect of nicotine injected 5 min before the session was compared to the effect of nicotine injected 1h after the session using the more reinforcing stimulus condition from the first experiment. A control group received only vehicle injections. In contrast to nicotine injected just prior to the session, post-session injections of nicotine had no detectable effect on responding for the more reinforcing stimulus. These results indicate that the reinforcement enhancing action of nicotine depends on the intensity of the primary reinforcer and that enhanced reinforcement by nicotine depends on coincident access to a stimulus with reinforcing properties.

  18. Hydrogenation behavior of the R4MgCo (R=Y, La, Nd, Tb) compounds

    NASA Astrophysics Data System (ADS)

    Shtender, V. V.; Paul-Boncour, V.; Riabov, A. B.; Denys, R. V.; Zavaliy, I. Yu.

    2015-09-01

    The hydrogen absorption properties of the R4MgCo compounds (R=Y, La, Nd, Tb; str. type Gd4RhIn; sp.gr. F 4 bar 3 m) have been studied for the first time. It was shown that their hydrogen storage capacity reaches about 2 wt%. At low pressure hydrogenation and moderately elevated temperatures the formed hydrides preserve the original structure of the metallic matrix. The crystal structure of the R4MgCoHx hydrides have been determined by XRD. Experimental hydrogen storage capacity (12 at.H/f.u. for Y4MgCo) is in good agreement with the theoretically calculated models, which allow also to estimate the distribution of H-atoms in metal lattice. TDS and DSC experiments demonstrated the multistep desorption process. XRD studies of the Tb4MgCoHx sample after TDS demonstrated the formation of TbH2 as the main phase and disproportionation of the parent compound.

  19. 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.

  20. 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.

  1. Chronic nicotine and withdrawal affect glutamatergic but not nicotinic receptor expression in the mesocorticolimbic pathway in a region-specific manner.

    PubMed

    Pistillo, Francesco; Fasoli, Francesca; Moretti, Milena; McClure-Begley, Tristan; Zoli, Michele; Marks, Michael J; Gotti, Cecilia

    2016-01-01

    Tobacco addiction is a complex form of dependence process that leads high relapse rates in people seeking to stop smoking. Nicotine elicits its primary effects on neuronal nicotinic cholinergic receptors (nAChRs), alters brain reward systems, and induces long-term changes during chronic nicotine use and withdrawal. We analysed the effects of chronic nicotine treatment and withdrawal on the mesocorticolimbic pathway (a brain reward circuit in which addictive drugs induce widespread adaptations) by analysing the expression of nAChRs in the midbrain, striatum and prefrontal cortex (PFC) of mice receiving intravenous infusions of nicotine (4mg/kg/h) or saline (control) for 14 days and mice sacrified two hours, and one, four and 14 days after treatment withdrawal. We biochemically fractionated whole tissue homogenates in order to obtain crude synaptosomal membranes. Western blotting analyses of these membrane fractions, ligand binding and immunoprecipitation studies, showed that chronic nicotine up-regulates heteromeric β2* nAChRs in all three mesocorticolimbic areas, and that these receptors are rapidly removed from synapses upon the cessation of nicotine treatment. The extent of nicotine-induced nAChR up-regulation, and the time course of its reversal were comparable in all three areas. We also analysed the expression of glutamate receptor subunits (GluRs) and scaffold proteins, and found that it was altered in an area-specific manner during nicotine exposure and withdrawal. As the functional properties of GluRs are determined by their subunit composition, the observed changes in subunit expression may indicate alterations in the excitability of mesocorticolimbic circuitry, and this may underlie the long-term biochemical and behavioural effects of nicotine dependence.

  2. Nicotine inhibits memory CTL programming.

    PubMed

    Sun, Zhifeng; Smyth, Kendra; Garcia, Karla; Mattson, Elliot; Li, Lei; Xiao, Zhengguo

    2013-01-01

    Nicotine is the main tobacco component responsible for tobacco addiction and is used extensively in smoking and smoking cessation therapies. However, little is known about its effects on the immune system. We confirmed that multiple nicotinic receptors are expressed on mouse and human cytotoxic T lymphocytes (CTLs) and demonstrated that nicotinic receptors on mouse CTLs are regulated during activation. Acute nicotine presence during activation increases primary CTL expansion in vitro, but impairs in vivo expansion after transfer and subsequent memory CTL differentiation, which reduces protection against subsequent pathogen challenges. Furthermore, nicotine abolishes the regulatory effect of rapamycin on memory CTL programming, which can be attributed to the fact that rapamycin enhances expression of nicotinic receptors. Interestingly, naïve CTLs from chronic nicotine-treated mice have normal memory programming, which is impaired by nicotine during activation in vitro. In conclusion, simultaneous exposure to nicotine and antigen during CTL activation negatively affects memory development.

  3. Behavioral mechanisms underlying nicotine reinforcement.

    PubMed

    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 (CS), 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 CS, 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.

  4. Randomized Trial of Reduced-Nicotine Standards for Cigarettes

    PubMed Central

    Donny, Eric C.; Denlinger, Rachel L.; Tidey, Jennifer W.; Koopmeiners, Joseph S.; Benowitz, Neal L.; Vandrey, Ryan G.; al’Absi, Mustafa; Carmella, Steven G.; Cinciripini, Paul M.; Dermody, Sarah S.; Drobes, David J.; Hecht, Stephen S.; Jensen, Joni; Lane, Tonya; Le, Chap T.; McClernon, F. Joseph; Montoya, Ivan D.; Murphy, Sharon E.; Robinson, Jason D.; Stitzer, Maxine L.; Strasser, Andrew A.; Tindle, Hilary; Hatsukami, Dorothy K.

    2015-01-01

    BACKGROUND The Food and Drug Administration can set standards that reduce the nicotine content of cigarettes. METHODS We conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking. Participants were randomly assigned to smoke for 6 weeks either their usual brand of cigarettes or one of six types of investigational cigarettes, provided free. The investigational cigarettes had nicotine content ranging from 15.8 mg per gram of tobacco (typical of commercial brands) to 0.4 mg per gram. The primary outcome was the number of cigarettes smoked per day during week 6. RESULTS A total of 840 participants underwent randomization, and 780 completed the 6-week study. During week 6, the average number of cigarettes smoked per day was lower for participants randomly assigned to cigarettes containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 16.3, and 14.9 cigarettes, respectively) than for participants randomly assigned to their usual brand or to cigarettes containing 15.8 mg per gram (22.2 and 21.3 cigarettes, respectively; P<0.001). Participants assigned to cigarettes with 5.2 mg per gram smoked an average of 20.8 cigarettes per day, which did not differ significantly from the average number among those who smoked control cigarettes. Cigarettes with lower nicotine content, as compared with control cigarettes, reduced exposure to and dependence on nicotine, as well as craving during abstinence from smoking, without significantly increasing the expired carbon monoxide level or total puff volume, suggesting minimal compensation. Adverse events were generally mild and similar among groups. CONCLUSIONS In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. (Funded by

  5. 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.

  6. Nicotine and health.

    PubMed

    2014-07-01

    Nicotine, an alkaloid derived from the leaves of tobacco plants (Nicotiana tabacum and Nicotiana rustica) is the primary addictive agent in tobacco products.(1,2) There are different ways of administering the various products including smoking cigarettes, chewing tobacco, holding moist snuff in the mouth, inhaling dry snuff through the nose, inhaling smoke from a waterpipe and inhaling vapour from an electronic cigarette.(3-6) It can be difficult differentiating the effects of nicotine from the many other toxic substances these products also contain. Here we review the pharmacological effects of nicotine but we will not review the well-known harmful effects of cigarettes, where it is primarily the toxins and carcinogens in tobacco smoke rather than the nicotine that cause illness and death.(7) A future article will consider the use of electronic cigarettes.

  7. Crystal structure and cyclic hydrogenation property of Pr4MgNi19.

    PubMed

    Iwase, Kenji; Terashita, Naoyoshi; Mori, Kazuhiro; Yokota, Hitoshi; Suzuki, Tetsuya

    2013-12-16

    The hydrogen absorption-desorption property and the crystal structure of Pr4MgNi19 was investigated by pressure-composition isotherm measurement and X-ray diffraction (XRD). Pr4MgNi19 consisted of two phases: 52.9% Ce5Co19-type structure (3R) and 47.0% Gd2Co7-type structure (3R). Sm5Co19-type structure (2H) and Ce2Ni7-type structure (2H) were not observed in the XRD profile. The Mg atoms substituted at the Pr sites in a MgZn2-type cell. The maximum hydrogen capacity reached 1.14 H/M (1.6 mass%) at 2 MPa. The hysteresis factor, Hf = ln(Pabs/Pdes), was 1.50. The cyclic hydrogenation property of Pr4MgNi19 was investigated up to 1000 absorption-desorption cycles. After 250, 500, 750, and 1000 cycles, the retention rates of hydrogen were reduced to 94%, 92%, 91%, and 90%, respectively. These properties were superior to those of Pr2MgNi9 and Pr3MgNi14.

  8. Nicotine therapy for ulcerative colitis.

    PubMed

    Kennedy, L D

    1996-09-01

    Smoking has been associated with a decreased frequency of UC. Currently, the role of nicotine for the treatment of UC is not established. Several studies have evaluated nicotine gum and transdermal patches as supplemental therapy for stable UC, but nicotine has not been compared with other treatment modalities. Nicotine dosages in the studies have varied from 5 to 30 mg/d without apparent dose-related therapeutic effects, and many patients have found relief from placebo treatment. Patients often do not tolerate nicotine therapy's adverse effects, which can include nausea, light-headedness, and headache. Due to the cyclic disease course of UC and the potential addictiveness of nicotine, further large studies are warranted to assess the benefits of nicotine therapy for UC. These studies should be conducted using a randomized, double-blind design with an extensive follow-up period. Until further trials are conducted, nicotine should generally not be recommended for UC treatment.

  9. 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

  10. 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.

  11. [Study on THz spectra of nicotinic acid, nicotinamide and nicotine].

    PubMed

    Yu, Bin; Huang, Zhen; Wang, Xiao-yan; Zhao, Guo-zhong

    2009-09-01

    The terahertz (THz) spectra of nicotinic acid, nicotinamide and nicotine were studied at room temperature. The time-domain THz spectra were measured. The frequency-domain spectra were obtained by fast Fourier transform (FFT). The spectral response and the dispersive relationship of refractive index in THz spectral range were obtained. The results show that the samples have obvious spectral response in THz spectral range except nicotine. The corresponding stimulated spectra were given by using density functional theory (DFT) method for both nicotinamide and nicotinic acid. The origin of the absorption peaks of nicotinic acid and nicotinamide was explored. It is thought that the absorption peak of nicotinic acid is caused by the torsion and wagging of the molecule, but the absorption peaks of nicotinamide (except 1.93 THz) are caused by intermolecular or phonon mode. It was shown that the molecule structure and vibrational modes of nicotinic acid and nicotinamide can be analyzed by the combination of simulation and experimental results.

  12. 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.

  13. 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…

  14. Pilot study on lower nitrosamine smokeless tobacco products compared with medicinal nicotine.

    PubMed

    Mendoza-Baumgart, M Irene; Tulunay, Ozlem E; Hecht, Stephen S; Zhang, Yan; Murphy, Sharon; Le, Chap; Jensen, Joni; Hatsukami, Dorothy K

    2007-12-01

    Smokeless tobacco (ST) products have the potential to be used as a harm reduction method for cigarette smokers. These products can deliver significantly less toxicants than cigarettes, although they are not toxicant free nor harmless. It is important to examine potential health risks and benefits of these products. These two small pilot studies examined the effects of two different ST products (Exalt and Ariva) compared with medicinal nicotine, another potential harm reduction product. Dependent, healthy adult cigarette smokers, who were motivated to quit smoking, underwent 1 week of baseline smoking measurement. They were then asked to quit smoking and were randomly assigned to use either an ST product or a medicinal nicotine lozenge (MNL, Commit) for 2 weeks, then crossed over to use the other product for 2 weeks. In the last week, following the sampling phase, subjects could choose the product they wished to use. Assessments were made repeatedly during baseline cigarette use and throughout the 5 weeks of treatment. Outcome measures included biomarkers for tobacco exposure and subjective, physiological, and behavioral responses. Tobacco-specific carcinogen uptake was greater from Exalt than from the MNL, and was comparable between the MNL and Ariva. Physiological effects and subjective effects on withdrawal and craving were comparable among Exalt, Ariva, and the MNL. Ariva was preferred over the MNL, which was preferred over Exalt. With the exception of medicinal nicotine products, low-nitrosamine ST products have the greatest potential to result in reduced toxicant exposure compared with other combustible reduced exposure products and have promise for reducing individual risk for disease. However, the population effect of marketing of such products as reduced exposure/reduced risk is unknown. The need for further research in this area and regulation of tobacco products is evident.

  15. 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.

  16. Vitamin E Nicotinate.

    PubMed

    Duncan, Kimbell R; Suzuki, Yuichiro J

    2017-03-13

    Vitamin E refers to a family of compounds that function as lipid-soluble antioxidants capable of preventing lipid peroxidation. Naturally occurring forms of vitamin E include tocopherols and tocotrienols. Vitamin E in dietary supplements and fortified foods is often an esterified form of α-tocopherol, the most common esters being acetate and succinate. The vitamin E esters are hydrolyzed and converted into free α-tocopherol prior to absorption in the intestinal tract. Because its functions are relevant to many chronic diseases, vitamin E has been extensively studied in respect to a variety of diseases as well as cosmetic applications. The forms of vitamin E most studied are natural α-tocopherol and the esters α-tocopheryl acetate and α-tocopheryl succinate. A small number of studies include or focus on another ester form, α-tocopheryl nicotinate, an ester of vitamin E and niacin. Some of these studies raise the possibility of differences in metabolism and in efficacy between vitamin E nicotinate and other forms of vitamin E. Recently, through metabolomics studies, we identified that α-tocopheryl nicotinate occurs endogenously in the heart and that its level is dramatically decreased in heart failure, indicating the possible biological importance of this vitamin E ester. Since knowledge about vitamin E nicotinate is not readily available in the literature, the purpose of this review is to summarize and evaluate published reports, specifically with respect to α-tocopheryl nicotinate with an emphasis on the differences from natural α-tocopherol or α-tocopheryl acetate.

  17. Vitamin E Nicotinate

    PubMed Central

    Duncan, Kimbell R.; Suzuki, Yuichiro J.

    2017-01-01

    Vitamin E refers to a family of compounds that function as lipid-soluble antioxidants capable of preventing lipid peroxidation. Naturally occurring forms of vitamin E include tocopherols and tocotrienols. Vitamin E in dietary supplements and fortified foods is often an esterified form of α-tocopherol, the most common esters being acetate and succinate. The vitamin E esters are hydrolyzed and converted into free α-tocopherol prior to absorption in the intestinal tract. Because its functions are relevant to many chronic diseases, vitamin E has been extensively studied in respect to a variety of diseases as well as cosmetic applications. The forms of vitamin E most studied are natural α-tocopherol and the esters α-tocopheryl acetate and α-tocopheryl succinate. A small number of studies include or focus on another ester form, α-tocopheryl nicotinate, an ester of vitamin E and niacin. Some of these studies raise the possibility of differences in metabolism and in efficacy between vitamin E nicotinate and other forms of vitamin E. Recently, through metabolomics studies, we identified that α-tocopheryl nicotinate occurs endogenously in the heart and that its level is dramatically decreased in heart failure, indicating the possible biological importance of this vitamin E ester. Since knowledge about vitamin E nicotinate is not readily available in the literature, the purpose of this review is to summarize and evaluate published reports, specifically with respect to α-tocopheryl nicotinate with an emphasis on the differences from natural α-tocopherol or α-tocopheryl acetate. PMID:28335380

  18. Patterning an epidermal field: Drosophila lozenge, a member of the AML-1/Runt family of transcription factors, specifies olfactory sense organ type in a dose-dependent manner.

    PubMed

    Gupta, B P; Flores, G V; Banerjee, U; Rodrigues, V

    1998-11-15

    Sense organ development in the Drosophila antenna is initiated by the selection of a founder cell from an epidermal field. This cell is believed to recruit neighbours to form a cluster of cells which then divides to form a mature sense organ. In most systems so far studied, sense organ type appears to be specified by the identity of proneural genes involved in the selection of precursors. The regulation of proneural gene expression is, in turn, controlled by the prepatterning genes. In the antenna, the only known proneural function is that of atonal, a gene that is involved in founder cell choice in the sensilla coeloconica, and no prepatterning gene function has yet been demonstrated. In this study, we show that Lozenge, a protein which possesses a DNA binding domain similar to that of the Acute myeloid leukemia-1/Runt transcription factors, functions in a dose-dependent manner to specify the fate of the other two types of sense organs in the antenna: the sensilla trichoidea and the sensilla basiconica. Our results suggest that Lozenge may act on the epidermal field, resulting in founder cells acquiring specific cell fates that lead to the development of an appropriate type of sense organ.

  19. Nicotine ameliorates impairment of working memory in methamphetamine-treated rats.

    PubMed

    Mizoguchi, Hiroyuki; Ibi, Daisuke; Takase, Fumiaki; Nagai, Taku; Kamei, Hiroyuki; Toth, Erika; Sato, Jun; Takuma, Kazuhiro; Yamada, Kiyofumi

    2011-06-20

    Nicotine is hypothesized to have therapeutic effects on attentional and cognitive abnormalities in psychosis. In this study, we investigated the effect of nicotine on impaired spatial working memory in repeated methamphetamine (METH)-treated rats. Rats were administered METH (4 mg/kg, s.c.) once a day for 7 days, and their working memory was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Control animals showed impaired performance in the test phase when the delay time was increased to 120 min or longer, while METH-treated rats showed impaired performance with a shorter delay time of 90 min. Memory impairment in METH-treated rats persisted for at least 14 days after drug withdrawal. METH-induced impairment of working memory was reversed by nicotine (0.3mg/kg, p.o., for 7 days), but the effect was diminished 7 days after the withdrawal. In control rats, nicotine decreased the number of working memory errors in the test with delay time of 120 min when administered before the training phase. Neither post-training nor pre-test administration of nicotine had any effect on working memory. These findings suggest that nicotine may have some protective effect against the impairment of working memory.

  20. Intravenous and oral suicidal e-liquid poisonings with confirmed nicotine and cotinine concentrations.

    PubMed

    Sommerfeld, Karina; Łukasik-Głębocka, Magdalena; Kulza, Maksymilian; Drużdż, Artur; Panieński, Paweł; Florek, Ewa; Zielińska-Psuja, Barbara

    2016-05-01

    The increasing availability of e-cigarettes is a potential toxicological concern. E-cigarettes appeared on the Polish market in 2006, and since 2009 they have been widely available with a new source of nicotine, the so-called e-liquid. In this paper two cases of suicidal oral and intravenous poisonings with the e-liquid are described. The clinical courses of these poisonings are presented. Nicotine and cotinine concentrations in the patient's blood were determined using high performance liquid chromatography with diode array detection. In the course of intoxication patient No. 1, classic symptoms of acute nicotine poisoning without convulsions were observed. Nicotine and cotinine concentrations measured in serum were 0.096 and 4.4mg/L, respectively. The case of patient No. 2, admission with no typical symptoms of nicotine poisoning was identified, except unconsciousness and slow respiration. Nicotine and cotinine concentrations in the serum at the time of No. 2 admissions were determined to be 0.8 and 1.3mg/L, respectively. With the increasing number of e-liquid poisonings cases, it should be aware that these products can be a readily available source of poison.

  1. Adolescent exposure to nicotine alters the aversive effects of cocaine in adult rats.

    PubMed

    Hutchison, Mary Anne; Riley, Anthony L

    2008-01-01

    Nicotine is one of the most commonly used drugs in adolescence and has been shown to alter the rewarding effects of cocaine when administered in adulthood. Although the abuse potential of a drug has been suggested to be a balance between its rewarding and aversive effects, the long-term effects of nicotine on the aversive properties of other drugs had not been studied. To that end, in the present study rats exposed to nicotine (0.4 mg/kg) during adolescence (postnatal days 35-44) were tested for the acquisition and extinction of a cocaine-induced conditioned taste aversion (10, 18 or 32 mg/kg) in adulthood. Conditioning consisted of four saccharin-drug pairings followed by six extinction trials. Although cocaine-induced aversions at all doses, no effect of nicotine preexposure was seen during acquisition. During extinction, the nicotine-preexposed groups conditioned with 10 and 18 mg/kg cocaine displayed a decreased rate of extinction compared to their respective controls. These results suggest that while adolescent nicotine exposure does not appear to directly alter the aversive properties of cocaine it may affect other processes related to the response to drugs given in adulthood.

  2. 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.

  3. Nicotinic receptors, memory, and hippocampus.

    PubMed

    Kutlu, Munir Gunes; Gould, Thomas J

    2015-01-01

    Nicotinic acetylcholine receptors (nAChRs) modulate the neurobiological processes underlying hippocampal learning and memory. In addition, nicotine's ability to desensitize and upregulate certain nAChRs may alter hippocampus-dependent memory processes. Numerous studies have examined the effects of nicotine on hippocampus-dependent learning, as well as the roles of low- and high-affinity nAChRs in mediating nicotine's effects on hippocampus-dependent learning and memory. These studies suggested that while acute nicotine generally acts as a cognitive enhancer for hippocampus-dependent learning, withdrawal from chronic nicotine results in deficits in hippocampus-dependent memory. Furthermore, these studies demonstrated that low- and high-affinity nAChRs functionally differ in their involvement in nicotine's effects on hippocampus-dependent learning. In the present chapter, we reviewed studies using systemic or local injections of acute or chronic nicotine, nAChR subunit agonists or antagonists; genetically modified mice; and molecular biological techniques to characterize the effects of nicotine on hippocampus-dependent learning.

  4. 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.

  5. 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

  6. 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.

  7. Recognising nicotine: the neurobiological basis of nicotine discrimination.

    PubMed

    Smith, Janice W; Stolerman, Ian P

    2009-01-01

    Drug discrimination methodology makes possible the objective, quantitative study of the perception of psychoactive drug effects in either human or animal subjects. Investigations of the nicotine discriminative stimulus complex have contributed to our present understanding of nicotine psychopharmacology by defining the origin of its effects at specific subtypes of nicotinic receptor and the role of diverse neurotransmitter systems as mediating and modulating mechanisms. The evidence strongly supports central sites as the origins of the nicotine stimulus, and these are likely to be located in the mesocorticolimbic dopaminergic neurons; the medial prefrontal cortex is primarily involved, with the Nucleus accumbens and ventral tegmental area of secondary importance, while another element of the complex stimulus may arise in the dorsal hippocampus. Additionally, it appears that interactions of nicotine with the dopamine, serotonin, cannabinoid and probably glutamate systems all contribute to the final perceived stimulus. The resemblance between the nicotine discriminative stimulus and those of the psychomotor stimulant drugs amphetamine and cocaine contributes to defining the nature of the addictive properties of nicotine. It is particularly interesting that acute and chronic exposure to caffeine produce quantitative and qualitative changes in the characteristics of the nicotine stimulus. Interactions of nicotine with caffeine and cannabinoids strengthen proposals that the use of one substance serves as a "gateway" in sequential shifts of the target substance for drug-seeking behaviour, with profound implications for the human use of the substances concerned. Drug discrimination is also an important standard technique used in assessments of the abuse liability of novel psychoactive compounds, with relevance to attempts to develop novel nicotinic agonists for use as cognitive enhancers.

  8. The effects of chronic nicotine on meal patterns, food intake, metabolism and body weight of male rats.

    PubMed

    Bellinger, L L; Wellman, P J; Harris, R B S; Kelso, E W; Kramer, P R

    2010-03-01

    It is unclear what contribution food intake and metabolism have in causing weight loss after administering a dose of nicotine equivalent to smoking one to three packs of cigarettes per day because previous studies have been of a very short duration. To address this question, male Sprague Dawley rats were housed in computerized food intake modules and fed 45 mg pellets: Group 1 [nicotine injected with 1.4 mg/kg/day (free base), fed ad libitum]; and Group 2 [saline injected and pair-fed by computer with Group 2]; and Group 3 [saline injected (i.p.), fed ad libitum]. The rats received 4 equally spaced injections over the dark phase. Treatment consisted of: Phase 1 (nicotine or saline for 14 days), Phase 2 (all rats saline for 8 days and Phase 3 (pair-fed group "unyoked" for 6 days)). Nicotine inhibited food intake over the first 6 days. On termination of nicotine, there was no compensatory hyperphagia in either Groups 1 or 2; and their body weight was reduced starting on day 5 until day 28. In another study, rats were housed in an indirect calorimetry system. Saline or nicotine was injected for 14 days, as noted above; then all rats were injected with saline for 4 days and then no injections for 10 days to follow changes in body weight. Energy expenditure (Kcal/Kg(0.75)) was measured for 18 days. Nicotine significantly reduced food intake on 7 of 14 days of nicotine injections. The body weight of the nicotine injected rats was significantly reduced starting on day 3 until day 25. There were no differences in energy expenditures of the groups, which suggested that a decrease in food intake and not an increase in metabolism was the reason the rats lost weight after administering nicotine.

  9. 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.

  10. Sex Differences in the Acquisition and Maintenance of Cocaine and Nicotine Self-Administration in Rats

    PubMed Central

    Swalve, Natashia; Smethells, John R.; Carroll, Marilyn E.

    2015-01-01

    Rationale Consistent sex differences are observed in human drug addiction, with females often exceeding males on drug intake. However, there is still a need for animal models for some aspects of addiction such as acquisition of drug self-administration and the subsequent development of drug-seeking. Objectives The present study examined sex differences in the acquisition of self-administration of two widely used stimulants, cocaine and nicotine. Methods Male and female rats self-administered cocaine (0.4 mg/kg/infusion) or nicotine (0.03 mg/kg/infusion) daily under a fixed-ratio 1 (FR 1) schedule until acquisition criteria were met (maximum of 30 sessions). The self-administration criterion for cocaine was ≥20 infusions in a 2 h session and ≥5 infusions in a 1 h session for nicotine. Sex differences were assessed by examining the percentage of rats that met acquisition criteria, the number of sessions to meet criteria and the number of infusions earned during the maintenance phase. Results A significantly higher percentage of male rats acquired both cocaine and nicotine self-administration than females, and males met acquisition criteria in fewer sessions. However, after criteria were met, females self-administered more cocaine than males during the first 5 days of maintenance. There were no sex differences in nicotine infusions post acquisition. Conclusions Differences in acquisition amongst sexes can reveal factors that are integral to initiation of drug use, an often overlooked phase of drug addiction. PMID:26685990

  11. Enhanced nicotine-seeking behavior following pre-exposure to repeated cocaine is accompanied by changes in BDNF in the nucleus accumbens of rats.

    PubMed

    Leão, Rodrigo M; Cruz, Fábio C; Carneiro-de-Oliveira, Paulo E; Rossetto, Daniella B; Valentini, Sandro R; Zanelli, Cleslei F; Planeta, Cleopatra S

    2013-03-01

    We investigated the behavioral and molecular interactions between cocaine and nicotine, through evaluating locomotor activity, nicotine intravenous self-administration and gene expression. Locomotor sensitization was induced in male Wistar rats by repeated cocaine (20 mg/kg; i.p.) or saline injections once a day over 7 days. Three days after the last injection, rats were challenged with either saline or cocaine (15 mg/kg; i.p.) and the locomotor activity was measured. The very next day animals received either saline or nicotine (0.4 mg/kg; s.c.) and the locomotor cross-sensitization was tested. Animals were then prepared with intrajugular catheters for nicotine self-administration. Nicotine self-administration patterns were evaluated using fixed or progressive ratio schedules of reinforcement and a 24-h unlimited access binge. Immediately after the binge sessions animals were decapitated, the brains were removed and the nucleus accumbens was dissected. The dynorphin (DYN), μ-opioid receptor (mu opioid), neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), tropomyosin-related tyrosine kinase B receptor (TrkB) and corticotropin-releasing factor receptor type 1 (CRF-R1) gene expression were measured by the reverse transcription-polymerase chain reaction (RT-PCR). Pretreatment with cocaine caused sensitization of cocaine motor response and locomotor cross-sensitization with nicotine. In the self-administration experiments repeated cocaine administration caused an increase in the nicotine break point and nicotine intake during a 24 h binge session.

  12. Interoceptive Pavlovian conditioning with nicotine as the conditional stimulus varies as a function of the number of conditioning trials and unpaired sucrose deliveries.

    PubMed

    Wilkinson, Jamie L; Murray, Jennifer E; Li, Chia; Wiltgen, Steven M; Penrod, Rachel D; Berg, Sarah A; Bevins, Rick A

    2006-03-01

    In rats, the pharmacological (interoceptive) effects of nicotine can serve as a signal (conditional stimulus) in a Pavlovian (classical) conditioning task. In this task, nicotine administration (0.4 mg base/kg, subcutaneous) is typically paired with intermittent access to a liquid sucrose unconditional stimulus; sucrose is withheld on saline sessions. An increase in sucrose receptacle entries (goal tracking) on nicotine sessions indicates conditioning. Given our limited understanding of the functional relationships controlling conditioned responding to a nicotine conditional stimulus, the present research examined nicotine's sensitivity to several manipulations shown to affect the conditioned responding in more widely studied Pavlovian conditioning tasks that use exteroceptive conditional stimuli: number of nicotine conditional stimulus-sucrose unconditional stimulus pairings per session (0, 3, 9, 18, or 36) and the impact of sucrose deliveries in saline sessions. Differential goal tracking developed in fewer sessions and asymptotic conditioned responding magnitude was greater with more nicotine-sucrose pairings. Further, goal tracking was more resistant to extinction (unconditional stimulus withheld) with more conditional-unconditional stimulus pairings during the acquisition phase. The discrimination was not acquired when sucrose presentations (9 or 18) also occurred during saline sessions. Furthermore, expression of the discrimination was disrupted when sucrose was presented in saline sessions; this disruption resulted from goal tracking in saline sessions. These results are consistent with the notion that nicotine-evoked goal tracking results from interoceptive conditioning processes.

  13. 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.

  14. Evaluation of nicotine in tobacco-free-nicotine commercial products.

    PubMed

    Hellinghausen, Garrett; Lee, Jauh T; Weatherly, Choyce A; Lopez, Diego A; Armstrong, Daniel W

    2016-12-11

    Recently, a variety of new tobacco-free-nicotine, TFN, products have been commercialized as e-liquids. Tobacco-derived nicotine contains predominantly (S)-(-)-nicotine, whereas TFN products may not. The TFN products are said to be cleaner, purer substances, devoid of toxic components that come from the tobacco extraction process. A variety of commercial tobacco and TFN products were analyzed to identify the presence and composition of each nicotine enantiomer. A rapid and effective enantiomeric separation of nicotine has been developed using a modified macrocyclic glycopeptide bonded to superficially porous particles. The enantiomeric assay can be completed in <2 min with high resolution and accuracy using high performance liquid chromatography with electrospray ionization mass spectrometry. The results of this study suggest the need for pharmacological studies of (R)-(+)-nicotine, which is present in much greater quantities in commercial TFN products compared to commercial tobacco-derived products. Such studies are required by the FDA for new enantiomeric pharmacological products. Copyright © 2016 John Wiley & Sons, Ltd.

  15. Changing the dehydrogenation pathway of LiBH4-MgH2via nanosized lithiated TiO2.

    PubMed

    Puszkiel, J A; Castro Riglos, M V; Karimi, F; Santoru, A; Pistidda, C; Klassen, T; Bellosta von Colbe, J M; Dornheim, M

    2017-03-15

    Nanosized lithiated titanium oxide (LixTiO2) noticeably improves the kinetic behaviour of 2LiBH4 + MgH2. The presence of LixTiO2 reduces the time required for the first dehydrogenation by suppressing the intermediate reaction to Li2B12H12, leading to direct MgB2 formation.

  16. Interoceptive conditioning with the nicotine stimulus: extinction learning as a method for assessing stimulus similarity across doses.

    PubMed

    Polewan, Robert J; Savala, Stephanie A; Bevins, Rick A

    2013-02-01

    Interoceptive conditioning involving the nicotine stimulus likely contributes to chronic tobacco use. To better understand the nature of this interoceptive conditioning, we compared generalization during repeated extinction with generalization in a 'transfer of extinction' test using a wide range of test doses. Rats were first trained in the discriminated goal-tracking task in which nicotine (0.2 or 0.4 mg/kg), but not saline, was paired with repeated intermittent access to sucrose. Across sessions, nicotine acquired control of approach behavior directed at the location of previous sucrose deliveries. Extinction followed with eight 20-min sessions without sucrose access; extinction doses of nicotine ranged from 0.05 to 0.6 mg/kg. In rats trained with 0.4 mg/kg, the 0.1, 0.2, and 0.6 mg/kg doses evoked comparable responding across extinction sessions; substitution was only partial at 0.05 and 0.075 mg/kg (i.e. above saline controls, but less than the training dose). With the 0.2 mg/kg training dose, complete generalization was seen only at the 0.1 and 0.4 mg/kg doses. After extinction, rats were given a transfer test with their training dose. Rats trained with 0.4 mg/kg showed full transfer of extinction learning with 0.1, 0.2, and 0.6 mg/kg (i.e. responding comparable with extinction with the training dose). Partial transfer was observed at 0.075 mg/kg. With the 0.2 mg/kg nicotine dose, only 0.4 mg/kg fully generalized; 0.075, 0.1, and 0.6 mg/kg showed partial transfer. Extinction with 0.05 mg/kg dose did not show transfer to either training dose. These findings indicated that conclusions regarding stimulus similarity across nicotine doses can vary with testing protocol.

  17. Distinct Effects of Enriched Environment on Dopamine Clearance in Nucleus Accumbens Shell and Core Following Systemic Nicotine Administration

    PubMed Central

    ZHU, JUN; BARDO, MICHAEL T.; DWOSKIN, LINDA P.

    2013-01-01

    Environmental enrichment during development may reduce drug abuse liability by modulating dopamine transporter (DAT) function. Nucleus accumbens (NAc) shell and core respond differentially to regulate the rewarding properties and locomotor stimulant effects of psychostimulants. The current study evaluated dopamine (DA) clearance (CLDA) in the NAc shell and core using in vivo voltammetry in rats raised in an enriched condition (EC) or an impoverished condition (IC) and determined the effect of nicotine (0.4 mg/kg) on CLDA. Baseline CLDA in NAc shell and core was not different between EC and IC rats. In the saline control group, CLDA in NAc shell was greater across time in IC when compared with EC rats, whereas CLDA in NAc core was greater in EC rats when compared with IC rats. Consistent with these findings, opposite effects of enrichment on DA clearance in shell and core were obtained following acute nicotine administration. In NAc shell, nicotine increased CLDA in EC rats, but not in IC rats. Conversely, in NAc core, nicotine increased CLDA in IC rats, but not in EC rats. The current results demonstrate that environmental enrichment differentially regulates the response to nicotine in NAc shell and core via alterations in DAT function, which may explain how environmental enrichment reduces the behavioral response to nicotine. PMID:23065942

  18. 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

  19. Reduced G-protein coupling to the GABAB receptor in the nucleus accumbens and the medial prefrontal cortex of the rat after chronic treatment with nicotine.

    PubMed

    Amantea, Diana; Tessari, Michela; Bowery, Norman G

    2004-01-30

    The effect of repeated administration of nicotine (0.4 mg/kg, daily, s.c., for 14 days) on GABAB receptor density, affinity and G-protein coupling was investigated in the mesocorticolimbic system of the rat brain. Baclofen-stimulated [35S]GTPgammaS binding autoradiography revealed that the level of G-protein coupling to GABAB receptors was significantly reduced in the medial prefrontal cortex and the nucleus accumbens of nicotine-treated rats as compared to vehicle-injected controls. By contrast, GABAB receptor density and affinity, as revealed by [3H]GABA saturation binding autoradiography, were not altered by the nicotine exposure in any of the regions examined. Reduced G-protein coupling to the GABAB receptor may result in disinhibition of mesocorticolimbic dopaminergic neurones, which would contribute to the development of sensitised dopaminergic responses to repeated administration of nicotine.

  20. Nicotine vaccines to treat tobacco dependence

    PubMed Central

    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. PMID:23108361

  1. Ultrathin magnetite in Fe3O4/MgO superlattices: Investigating the enhanced thin film magnetic moment

    NASA Astrophysics Data System (ADS)

    Mauit, Ozhet; Fleischer, Karsten; O'Coileáin, Cormac; Bulfin, Brendan; Fox, Daniel S.; Smith, Christopher M.; Mullarkey, Daragh; Sugurbekova, Gulnar; Zhang, Hongzhou; Shvets, Igor V.

    2017-03-01

    The electrical, crystallographic, and magnetic properties of ultrathin magnetite (Fe3O4 ) have been studied in detail, by employing superlattice structures of Fe3O4 /MgFe2O4 and Fe3O4 /MgO on a variety of substrates. By careful analysis of their properties, the influence of substrate stoichiometry, Fe3O4 thin film thickness, antiphase boundaries on the magnetic properties can be separated. In particular, the controversial enhanced magnetic moment in ultrathin films (<5 nm) was confirmed to be related to the substrate stoichiometry, specifically the migration of oxygen vacancies into the Fe3O4 thin films. The multilayer concept can be employed with many other such systems and offers methods of tuning the properties of thin magnetic oxides.

  2. 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

  3. 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.

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

    PubMed

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

    2015-10-16

    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.

  5. 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.

  6. Nicotine effects on the impact of stress

    DTIC Science & Technology

    2013-09-01

    administer it to Soldiers (e.g., transdermal patch ). Our research involves a model of nicotine use (voluntary intravenous self-administration of nicotine ...AD_________________ Award Number: W81XWH-12-1-0454 TITLE: Nicotine effects on the impact of stress...Annual 3. DATES COVERED 1 September 2012 - 31 August 2013 4. TITLE AND SUBTITLE Nicotine effects on the impact of stress 5a. CONTRACT NUMBER

  7. 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).

  8. 27 CFR 21.119 - Nicotine solution.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Nicotine solution. 21.119....119 Nicotine solution. (a) Composition. Five gallons of an aqueous solution containing 40 percent.... One ml of the nicotine solution (previously agitated in the presence of air) is measured into 100...

  9. 27 CFR 21.119 - Nicotine solution.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false Nicotine solution. 21.119....119 Nicotine solution. (a) Composition. Five gallons of an aqueous solution containing 40 percent.... One ml of the nicotine solution (previously agitated in the presence of air) is measured into 100...

  10. 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...

  11. 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...

  12. 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...

  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. 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...

  15. 27 CFR 21.119 - Nicotine solution.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2014-04-01 2014-04-01 false Nicotine solution. 21.119....119 Nicotine solution. (a) Composition. Five gallons of an aqueous solution containing 40 percent nicotine; 3.6 avoirdupois ounces of methylene blue, U.S.P.; water sufficient to make 100 gallons. (b)...

  16. 27 CFR 21.119 - Nicotine solution.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2013-04-01 2013-04-01 false Nicotine solution. 21.119....119 Nicotine solution. (a) Composition. Five gallons of an aqueous solution containing 40 percent nicotine; 3.6 avoirdupois ounces of methylene blue, U.S.P.; water sufficient to make 100 gallons. (b)...

  17. Electronic cigarettes and nicotine clinical pharmacology

    PubMed Central

    Schroeder, Megan J; Hoffman, Allison C

    2014-01-01

    Objective To review the available literature evaluating electronic cigarette (e-cigarette) nicotine clinical pharmacology in order to understand the potential impact of e-cigarettes on individual users, nicotine dependence and public health. Methods Literature searches were conducted between 1 October 2012 and 30 September 2013 using key terms in five electronic databases. Studies were included in the review if they were in English and publicly available; non-clinical studies, conference abstracts and studies exclusively measuring nicotine content in e-cigarette cartridges were excluded from the review. Results Nicotine yields from automated smoking machines suggest that e-cigarettes deliver less nicotine per puff than traditional cigarettes, and clinical studies indicate that e-cigarettes deliver only modest nicotine concentrations to the inexperienced e-cigarette user. However, current e-cigarette smokers are able to achieve systemic nicotine and/or cotinine concentrations similar to those produced from traditional cigarettes. Therefore, user experience is critically important for nicotine exposure, and may contribute to the products’ ability to support and maintain nicotine dependence. Conclusions Knowledge about e-cigarette nicotine pharmacology remains limited. Because a user's e-cigarette experience may significantly impact nicotine delivery, future nicotine pharmacokinetic and pharmacodynamic studies should be conducted in experienced users to accurately assess the products’ impact on public health. PMID:24732160

  18. Nicotine's defensive function in nature.

    PubMed

    Steppuhn, Anke; Gase, Klaus; Krock, Bernd; Halitschke, Rayko; Baldwin, Ian T

    2004-08-01

    Plants produce metabolites that directly decrease herbivore performance, and as a consequence, herbivores are selected for resistance to these metabolites. To determine whether these metabolites actually function as defenses requires measuring the performance of plants that are altered only in the production of a certain metabolite. To date, the defensive value of most plant resistance traits has not been demonstrated in nature. We transformed native tobacco(Nicotiana attenuata) with a consensus fragment of its two putrescine N-methyl transferase (pmt) genes in either antisense or inverted-repeat (IRpmt) orientations. Only the latter reduced (by greater than 95%) constitutive and inducible nicotine. With D(4)-nicotinic acid (NA), we demonstrate that silencing pmt inhibits nicotine production, while the excess NA dimerizes to form anatabine. Larvae of the nicotine-adapted herbivore Manduca sexta (tobacco hornworm) grew faster and, like the beetle Diabrotica undecimpunctata, preferred IRpmt plants in choice tests. When planted in their native habitat, IRpmt plants were attacked more frequently and, compared to wild-type plants, lost 3-fold more leaf area from a variety of native herbivores, of which the beet armyworm, Spodoptera exigua, and Trimerotropis spp. grasshoppers caused the most damage. These results provide strong evidence that nicotine functions as an efficient defense in nature and highlights the value of transgenic techniques for ecological research.

  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. The Serotonin 2C Receptor Agonist Lorcaserin Attenuates Intracranial Self-Stimulation and Blocks the Reward-Enhancing Effects of Nicotine.

    PubMed

    Zeeb, Fiona D; Higgins, Guy A; Fletcher, Paul J

    2015-07-15

    Lorcaserin, a serotonin (5-hydroxytryptamine, 5-HT) 2C receptor agonist, was recently approved for the treatment of obesity. We previously suggested that 5-HT2C receptor agonists affect reward processes and reduce the rewarding effects of drugs of abuse. Here, we determined whether lorcaserin (1) decreases responding for brain stimulation reward (BSR) and (2) prevents nicotine from enhancing the efficacy of BSR. Rats were trained on the intracranial self-stimulation (ICSS) paradigm to nosepoke for BSR of either the dorsal raphé nucleus or left medial forebrain bundle. In Experiment 1, lorcaserin (0.3-1.0 mg/kg) dose-dependently reduced the efficacy of BSR. This effect was blocked by prior administration of the 5-HT2C receptor antagonist SB242084. In Experiment 2, separate groups of rats received saline or nicotine (0.4 mg/kg) for eight sessions prior to testing. Although thresholds were unaltered in saline-treated rats, nicotine reduced reward thresholds. An injection of lorcaserin (0.3 mg/kg) prior to nicotine prevented the reward-enhancing effect of nicotine across multiple test sessions. These results demonstrated that lorcaserin reduces the rewarding value of BSR and also prevents nicotine from facilitating ICSS. Hence, lorcaserin may be effective in treating psychiatric disorders, including obesity and nicotine addiction, by reducing the value of food or drug rewards.

  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. Baseline impulsive choice predicts the effects of nicotine and nicotine withdrawal on impulsivity in rats.

    PubMed

    Kayir, Hakan; Semenova, Svetlana; Markou, Athina

    2014-01-03

    Impulsive choice, a form of impulsivity, is associated with tobacco smoking in humans. Trait impulsivity may be a vulnerability factor for smoking, or smoking may lead to impulsive behaviors. We investigated the effects of 14-day nicotine exposure (6.32mg/kg/day base, subcutaneous minipumps) and spontaneous nicotine withdrawal on impulsive choice in low impulsive (LI) and high impulsive (HI) rats. Impulsive choice was measured in the delayed reward task in which rats choose between a small immediate reward and a large delayed reward. HI and LI rats were selected from the highest and lowest quartiles of the group before exposure to nicotine. In non-selected rats, nicotine or nicotine withdrawal had no effect on impulsive choice. In LI rats, chronic nicotine exposure decreased preference for the large reward with larger effects at longer delays, indicating increased impulsive choice. Impulsive choices for the smaller immediate rewards continued to increase during nicotine withdrawal in LI rats. In HI rats, nicotine exposure and nicotine withdrawal had no effect on impulsive choice, although there was a tendency for decreased preference for the large reward at short delays. These results indicate that nicotine- and nicotine withdrawal-induced increases in impulsive choice depend on trait impulsivity with more pronounced increases in impulsive choice in LI compared to HI subjects. Increased impulsivity during nicotine exposure may strengthen the addictive properties of nicotine and contribute to compulsive nicotine use.

  3. 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.

  4. Pharmacology of nicotine: addiction and therapeutics.

    PubMed

    Benowitz, N L

    1996-01-01

    Nicotine maintains tobacco addiction and has therapeutic utility to aid smoking cessation and possibly to treat other medical diseases. Nicotine acts on nicotinic cholinergic receptors, which demonstrate diversity in subunit structure, function, and distribution within the nervous system, presumably mediating the complex actions of nicotine described in tobacco users. The effects of nicotine in people are influenced by the rate and route of dosing and by the development of tolerance. The metabolism of nicotine is now well characterized in humans. A few individuals with deficient C-oxidation of nicotine, unusually slow metabolism of nicotine, and little generation of cotinine have been described. Nicotine affects most organ systems in the body, although its contribution to smoking-related disease is still unclear. Nicotine as a medication is currently available as a gum, a transdermal delivery device, and a nasal spray, all of which are used for smoking cessation. Nicotine is also being investigated for therapy of ulcerative colitis, Alzheimer's disease, Parkinson's disease, Tourette's syndrome, sleep apnea, and attention deficit disorder.

  5. 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

  6. Nicotine: abused substance and therapeutic agent.

    PubMed Central

    Le Houezec, J

    1998-01-01

    Tobacco dependence is a complex phenomenon that is not fully understood. Nicotine is the main alkaloid in tobacco and the addictive compound of tobacco. It can improve both mood and cognitive functioning; these positive effects are strong reinforcements for smokers and contribute to their addiction. Opposite results also have been reported, however, and the effects of nicotine remain controversial. Recent epidemiological and empirical studies have indicated that smoking or nicotine or both may have protective effects against certain diseases. These findings have suggested that nicotine may be used as a therapeutic agent. However, because a variety of nicotinic cholinergic receptors are present in the brain, new agonist compounds may prove to be more effective than nicotine for therapeutic purposes. Studies are reviewed and the suggestion made that nicotine may prove useful as a tool to help us understand normal and pathological brain functioning. PMID:9549250

  7. 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.

  8. Determination of Nicotine Absorption from Multiple Tobacco Products and Nicotine Gum

    PubMed Central

    Digard, Helena; Proctor, Christopher; Kulasekaran, Anuradha; Malmqvist, Ulf

    2013-01-01

    Introduction: Snus is a smokeless tobacco product traditionally used in Scandinavia and available in pouched or loose forms. The objective of this study was to determine nicotine absorption for current pouched and loose snus products in comparison with a cigarette and an over-the-counter nicotine gum. Methods: We conducted an open-label, randomized, 6-way, crossover study involving 20 healthy snus and cigarette users. One of 6 products (2 pouched snus, 2 weights of loose snus, a cigarette, and a nicotine gum) was administered at each of 6 visits. Blood samples were taken at intervals over 120 min and sensory perception assessed by questionnaire. Results: For the 4 smokeless tobacco products and the nicotine gum, blood plasma levels of nicotine were ranked according to total nicotine content as follows: loose snus (27.1 mg nicotine) > pouched snus (14.7 mg nicotine) > loose snus (10.8 mg nicotine) = pouched snus (10.7 mg nicotine) > nicotine gum (4.2 mg nicotine). The area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax) of nicotine ranged from 26.9 to 13.1 ng.h/ml and 17.9 to 9.1 ng.h/ml, respectively across all the products. Nicotine was absorbed more rapidly from the cigarette but systemic exposure was within the range of the smokeless tobacco products (AUC = 14.8 ng.h/ml; Cmax = 12.8 ng.h/ml). Conclusions: This study has generated new information on comparative nicotine absorption from a cigarette, loose snus, and pouched snus typical of products sold in Scandinavia. The similar nicotine absorption for 1 g portions of loose and pouched snus with approximately 11 mg of nicotine indicate that absorption kinetics were dependent on quantity of tobacco by weight and total nicotine content rather than product form. PMID:22585541

  9. Metabolism and biochemical effects of nicotine for primary care providers.

    PubMed

    Metz, Christine N; Gregersen, Peter K; Malhotra, Anil K

    2004-11-01

    Nicotine is a colorless and volatile liquid alkaloid naturally occurring in the leaves and stems of Nicotiana tabacum and Nicotiana rustica. Nicotine, the primary component of tobacco, is responsible for both tobacco product addiction (with chronic exposure) and the odor associated with tobacco. In addition to cigarettes, nicotine is found in chewing gum, transdermal patches, nasal spray, and sublingual tablets. Following its inhalation and absorption, nicotine and its metabolic products exert diverse physiologic and pharmacologic effects. This article covers the absorption and metabolism of nicotine, nicotine toxicity, pharmacologic effects of nicotine, nicotine-drug interactions, and the use of nicotine for the treatment of disease.

  10. Discriminative stimulus effects of nicotine in humans.

    PubMed

    Perkins, Kenneth A

    2009-01-01

    Behavioral discrimination procedures clearly demonstrate that nicotine elicits interoceptive stimulus effects in humans that are malleable by various pharmacological manipulations as well as by some behavioral manipulations. The parameters of nicotine discrimination and both chronic and acute factors that may alter discrimination behavior are addressed in this chapter, which emphasizes research by the author involving nicotine delivered by nasal spray. Human discrimination of nicotine is centrally mediated, as the central and peripheral nicotine antagonist mecamylamine blocks discrimination but the peripheral antagonist trimethaphan does not. The threshold dose for discrimination of nicotine via spray appears to be very low in smokers as well as nonsmokers. Because smoked tobacco delivers nicotine more rapidly than spray, the threshold dose of nicotine via smoking is probably even lower. In terms of individual differences, smokers may become tolerant to the discriminative stimulus effects of higher nicotine doses but not of low doses. Men may be more sensitive than women to nicotine's discriminative stimulus effects, consistent with other research suggesting that nicotine is more reinforcing in men than in women. Other potential individual differences in nicotine discrimination have not been clearly tested, but may include genetics, obesity, and dependence on other drugs. Acute environmental factors that alter nicotine discrimination include the specific training and testing conditions, pointing to the need for careful control over such conditions during research. Other factors, such as concurrent acute use of alcohol or caffeine, do not appear to alter nicotine discrimination, suggesting that changes in nicotine discrimination are not likely explanations for the association of smoking behavior with use of those drugs. Concurrent physical activity also does not appear to alter nicotine discrimination, indicating that results from studies of discrimination in

  11. 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

  12. A common profile of prefrontal cortical activation following exposure to nicotine- or chocolate-associated contextual cues.

    PubMed

    Schroeder, B E; Binzak, J M; Kelley, A E

    2001-01-01

    Conditioning and learning factors are likely to play key roles in the process of addiction and in relapse to drug use. In nicotine addiction, for example, contextual cues associated with smoking can be powerful determinants of craving and relapse, even after considerable periods of abstinence. Using the detection of the immediate-early gene product, Fos, we examined which regions of the brain are activated by environmental cues associated with nicotine administration, and compared this profile to the pattern induced by cues associated with a natural reward, chocolate. In the first experiment, rats were treated with either nicotine (0.4 mg/ml/kg) or saline once per day for 10 days in a test environment distinct from their home cages. In the second experiment, rats were given access to either a bowl of chocolate chips or an empty bowl in the distinct environment for 10 days. After a 4-day interval, rats were re-introduced to the environment where they previously received either nicotine treatment or chocolate access. Nicotine-associated sensory cues elicited marked and specific activation of Fos expression in prefrontal cortical and limbic regions. Moreover, exposure to cues associated with the natural reward, chocolate, induced a pattern of gene expression that showed many similarities with that elicited by drug cues, particularly in prefrontal regions. These observations support the hypothesis that addictive drugs induce long-term neuroadaptations in brain regions subserving normal learning and memory for motivationally salient stimuli.

  13. Sex differences in nicotine action.

    PubMed

    Pogun, Sakire; Yararbas, Gorkem

    2009-01-01

    Accumulating evidence suggests that the antecedents, consequences, and mechanisms of drug abuse and dependence are not identical in males and females and that gender may be an important variable in treatment and prevention. Although there has been a decline in smoking prevalence in developed countries, females are less successful in quitting. Tobacco use is accepted to be a form of addiction, which manifests sex differences. There is also evidence for sex differences in the central effects of nicotine in laboratory animals. Although social factors impact smoking substantially in humans, findings from nonhuman subjects in controlled experiments provide support that sex differences in nicotine/tobacco addiction have a biological basis. Differences in the pharmacokinetic properties of nicotine or the effect of gonadal hormones may underlie some but not all sex differences observed. Laboratory-based information is very important in developing treatment strategies. Literature findings suggest that including sex as a factor in nicotine/tobacco-related studies will improve our success rates in individually tailored smoking cessation programs.

  14. Nitrosamines as nicotinic receptor ligands

    PubMed Central

    Schuller, Hildegard M.

    2007-01-01

    Nitrosamines are carcinogens formed in the mammalian organism from amine precursors contained in food, beverages, cosmetics and drugs. The potent carcinogen, NNK, and the weaker carcinogen, NNN, are nitrosamines formed from nicotine. Metabolites of the nitrosamines react with DNA to form adducts responsible for genotoxic effects. We have identified NNK as a high affinity agonist for the alpha7 nicotinic acetylcholine receptor (α7nAChR) whereas NNN bound with high affinity to epibatidine-sensitive nAChRs. Diethylnitrosamine (DEN) bound to both receptors but with lower affinity. High levels of the α7nAChR were expressed in human small cell lung cancer (SCLC) cell lines and in hamster pulmonary neuroendocrine cells (PNECs), which serve as a model for the cell of origin of human SCLC. Exposure of SCLC or PNECs to NNK or nicotine increased expression of the a7nAChR and caused influx of Ca2+, activation of PKC, Raf-1, ERK1/2, and c-myc, resulting in the stimulation of cell proliferation. Signaling via the α7nAChR was enhanced when cells were maintained in an environment of 10–15% CO2 similar to that in the diseased lung. Hamsters with hyperoxia-induced pulmonary fibrosis developed neuroendocrine lung carcinomas similar to human SCLC when treated with NNK, DEN, or nicotine. The development of the NNK-induced tumors was prevented by green tea or theophylline. The beta-adrenergic receptor agonist, isoproterenol or theophylline blocked NNK-induced cell proliferation in vitro. NNK and nicotine-induced hyperactivity of the α7nAChR/RAF/ERK1/2 pathway thus appears to play a crucial role in the development of SCLC in smokers and could be targeted for cancer prevention. PMID:17459420

  15. Nitrosamines as nicotinic receptor ligands.

    PubMed

    Schuller, Hildegard M

    2007-05-30

    Nitrosamines are carcinogens formed in the mammalian organism from amine precursors contained in food, beverages, cosmetics and drugs. The potent carcinogen, NNK, and the weaker carcinogen, NNN, are nitrosamines formed from nicotine. Metabolites of the nitrosamines react with DNA to form adducts responsible for genotoxic effects. We have identified NNK as a high affinity agonist for the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) whereas NNN bound with high affinity to epibatidine-sensitive nAChRs. Diethylnitrosamine (DEN) bound to both receptors but with lower affinity. High levels of the alpha7nAChR were expressed in human small cell lung cancer (SCLC) cell lines and in hamster pulmonary neuroendocrine cells (PNECs), which serve as a model for the cell of origin of human SCLC. Exposure of SCLC or PNECs to NNK or nicotine increased expression of the alpha7nAChR and caused influx of Ca(2+), activation of PKC, Raf-1, ERK1/2, and c-myc, resulting in the stimulation of cell proliferation. Signaling via the alpha7nAChR was enhanced when cells were maintained in an environment of 10-15% CO(2) similar to that in the diseased lung. Hamsters with hyperoxia-induced pulmonary fibrosis developed neuroendocrine lung carcinomas similar to human SCLC when treated with NNK, DEN, or nicotine. The development of the NNK-induced tumors was prevented by green tea or theophylline. The beta-adrenergic receptor agonist, isoproterenol or theophylline blocked NNK-induced cell proliferation in vitro. NNK and nicotine-induced hyperactivity of the alpha7nAChR/RAF/ERK1/2 pathway thus appears to play a crucial role in the development of SCLC in smokers and could be targeted for cancer prevention.

  16. Nicotine-induced damages in testicular tissue of rats; evidences for bcl-2, p53 and caspase-3 expression

    PubMed Central

    Mosadegh, Maryam; Hasanzadeh, Shapour; Razi, Mazdak

    2017-01-01

    Objective(s): Present study was performed in order to uncover new aspects for nicotine-induced damages on spermatogenesis cell lineage. Materials and Methods: For this purpose, 36 mature male Wistar rats were divided into three groups as; control-sham (0.2 ml, saline normal, IP), low dose (0.2 mg/kg BW-1, IP) nicotine-received and high dose (0.4 mg/kg BW-1, IP) nicotine-received groups. Following 7 weeks, the expression of bcl-2, p53 and caspase-3 at mRNA and protein levels were investigated by using reverse-transcriptase PCR (RT-PCR) and immunohistochemical (IHC) analyses, respectively. Moreover, the serum level of FSH, LH and testosterone were evaluated. Finally, the mRNA damage was analyzed by using special fluorescent staining. Results: Nicotine, at both dose levels, decreased tubular differentiation, spermiogenesis and repopulation indices and enhanced cellular depletion. Animals in nicotine-received groups exhibited a significant (P<0.05) reduction at mRNA and protein levels of bcl-2. More analyses revealed a remarkable (P<0.05) enhancement in expression of p53 and caspase-3 in comparison to control-sham animals. Finally, nicotine resulted in a significant (P<0.05) reduction in serum level of testosterone and elevated mRNA damage. Conclusion: Our data showed that, nicotine by suppressing the testosterone biosynthesis, reducing mRNA and protein levels of bcl-2 and up regulating the p53 and caspase-3 mRNA and protein levels adversely affects the spermatogenesis and results in cellular depletion. PMID:28293398

  17. 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.

  18. Systemic nicotine exposure in tobacco harvesters.

    PubMed

    D'Alessandro, A; Benowitz, N L; Muzi, G; Eisner, M D; Filiberto, S; Fantozzi, P; Montanari, L; Abbritti, G

    2001-01-01

    Several epidemics of nicotine intoxication have been described among tobacco harvesters; however, little is known about nicotine absorption under typical working conditions. To assess systemic nicotine absorption during a regular working shift, the authors performed an observational field study. Included in the study were 10 healthy, nonsmoking, female tobacco harvesters and a control group of 5 healthy, nonsmoking, female hospital workers. Nicotine and cotinine were measured in sequential samples of blood and urine during a regular workshift. Blood nicotine levels rose from a nadir value of 0.79 +/- 0.12 ng/ml to a peak value of 3.45 +/- 0.84 ng/ml (p < .05 [Tukey's modified t test]) in the exposed group. In the control group, levels were stable at 0.1 +/- 0.1 ng/ml (p < .01). Moreover, the mean blood nicotine level measured 3 mo following the end of exposure in 6 of 10 exposed subjects was 0.24 +/- 0.12 ng/ml (p < .01). Corresponding higher values of urine nicotine and urine cotinine were observed in the exposed versus control group (comparative p values were < .01 and < .05, respectively). Overall, tobacco harvesters absorbed approximately 0.8 mg of nicotine daily. Given that nicotine can induce adverse health effects, the authors believe that prevention of nicotine absorption in tobacco harvesters should be sought and that workers should be informed about occupational risks.

  19. Pharmacogenetics of nicotine and associated smoking behaviors.

    PubMed

    Tanner, Julie-Anne; Chenoweth, Meghan J; Tyndale, Rachel F

    2015-01-01

    This chapter summarizes genetic factors that contribute to variation in nicotine pharmacokinetics and nicotine's pharmacological action in the central nervous system (CNS), and how this in turn influences smoking behaviors. Nicotine, the major psychoactive compound in cigarette smoke, is metabolized by a number of enzymes, including CYP2A6, CYP2B6, FMOs, and UGTs, among others. Variation in the genes encoding these enzymes, in particular CYP2A6, can alter the rate of nicotine metabolism and smoking behaviors. Faster nicotine metabolism is associated with higher cigarette consumption and nicotine dependence, as well as lower quit rates. Variation in nicotine's CNS targets and downstream signaling pathways can also contribute to interindividual differences in smoking patterns. Binding of nicotine to neuronal nicotinic acetylcholine receptors (nAChRs) mediates the release of several neurotransmitters including dopamine and serotonin. Genetic variation in nAChRs, and in transporter and enzyme systems that leads to altered CNS levels of dopamine and serotonin, is associated with a number of smoking behaviors. To date, the precise mechanism underpinning many of these findings remains unknown. Considering the complex etiology of nicotine addiction, a more comprehensive approach that assesses the contribution of multiple gene variants, and their interaction with environmental factors, will likely improve personalized therapeutic approaches and increase smoking cessation rates.

  20. Nicotine reinforcement in never-smokers

    PubMed Central

    Duke, Angela N.; Johnson, Matthew W.; Reissig, Chad J.; Griffiths, Roland R.

    2015-01-01

    Rationale Global tobacco-related mortality dwarfs that of all other drugs. Nicotine is believed to be the primary agent responsible for tobacco use and addiction. However, nicotine is a relatively weak and inconsistent reinforcer in nonhumans and nicotine reinforcement has not been demonstrated in never-smokers. Objectives This study investigated the discriminative, subjective, and reinforcing effects of nicotine in never-smokers. Methods Eighteen never-smokers (<50 lifetime nicotine exposures) participated in a double-blind study. During a drug discrimination phase, volunteers ingested oral nicotine and placebo capsules (quasi-random order) at least 2 hours apart and rated subjective effects repeatedly for 2 hours after ingestion in daily sessions. Blocks of 10 sessions were continued until significant discrimination was achieved (p≤.05, binomial test; ≥8 of 10). Following discrimination, nicotine choice was tested by having volunteers choose which capsule set to ingest on each daily session. Successive blocks of 10 sessions were conducted until choice for nicotine or placebo met significance within each volunteer (≥8 of 10 sessions). Results All 18 volunteers significantly discriminated nicotine from placebo; the lowest dose discriminated ranged from 1.0–4.0 mg/70kg. Nine volunteers significantly chose nicotine (choosers) and nine significantly chose placebo (nicotine avoiders). The choosers reported predominately positive nicotine subjective effects (e.g., alert/attentive, good effects, liking), while avoiders tended to report negative effects (e.g., dizzy, upset stomach, disliking). Both choosers and avoiders attributed their choice to the qualitative nature of drug effects. Conclusions These results provide the first evidence that nicotine can function as a reinforcer in some never-smokers. PMID:26345343

  1. Nicotinic involvement in memory function in zebrafish.

    PubMed

    Levin, Edward D; Chen, Elaine

    2004-01-01

    Zebrafish are an emerging model for the study of the molecular mechanisms of brain function. To conduct studies of the neural bases of behavior in zebrafish, we must understand the behavioral function of zebrafish and how it is altered by perturbations of brain function. This study determined nicotine actions on memory function in zebrafish. With the methods that we have developed to assess memory in zebrafish using delayed spatial alternation (DSA), we determined the dose effect function of acute nicotine on memory function in zebrafish. As in rodents and primates, low nicotine doses improve memory in zebrafish, while high nicotine doses have diminished effect and can impair memory. This study shows that nicotine affects memory function in zebrafish much like in rats, mice, monkeys and humans. Now, zebrafish can be used to help understand the molecular mechanisms crucial to nicotine effects on memory.

  2. Nicotine Dependence Measures for Perinatal Women.

    PubMed

    Yang, Irene; Hall, Lynne A

    2016-03-02

    This integrative review provides an overview of nicotine dependence measures used with perinatal women and an evaluation of their psychometric properties. Fifty-five articles that met inclusion and exclusion criteria were identified from five different databases. Most of the studies used the Fagerström Test for Nicotine Dependence (FTND). Other approaches included diagnostic tests, the Wisconsin Inventory of Smoking Dependence Motives (WISDM), the Tobacco Dependence Screener, and single-item measures. This review indicated that the FTND may not be the best option for measuring nicotine dependence in this population. The WISDM is a newer instrument that has excellent psychometric properties and captures nonnicotinic dimensions of nicotine dependence relevant to women. Future research is needed to assess its reliability in the perinatal population. Other recommendations from this review include the use of biomarker validation, thorough psychometric reporting on nicotine dependence instruments, and the use of multiple instruments to maximize comparability between nicotine dependence instruments.

  3. 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.

  4. 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.

  5. Thermal and irradiation induced interdiffusion in Fe 3O 4/MgO(0 0 1) thin film

    NASA Astrophysics Data System (ADS)

    Kim-Ngan, N.-T. H.; Balogh, A. G.; Meyer, J. D.; Brötz, J.; Hummelt, S.; Zając, M.; Ślęzak, T.; Korecki, J.

    2009-05-01

    The interface reactions in an epitaxial 10 nm-thick Fe3O4/MgO(0 0 1) film were investigated by using Rutherford Backscattering spectrometry (RBS), channeling (RBS-C) and X-ray reflectometry (XRR). The as-grown film had a good crystallinity indicated by the minimum yield and the half-angle value for Fe, respectively, χmin(Fe) = 22% and ψ1/2(Fe) = 0.62°. Annealing the films under partial argon pressure up to 600 °C led to a large enhancement of Mg out-diffusion into the film forming a wustite-type phase, but the total layer thickness did not change much. Ion irradiation of the film by 1 MeV Ar ion beam caused a strong Fe ion mixing resulting in a large interfacial zone with a thickness of 23 nm.

  6. Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence

    PubMed Central

    Zuo, Lingjun; Garcia-Milian, Rolando; Guo, Xiaoyun; Zhong, Chunlong; Tan, Yunlong; Wang, Zhiren; Wang, Jijun; Wang, Xiaoping; Kang, Longli; Lu, Lu; Chen, Xiangning; Li, Chiang-Shan R.; Luo, Xingguang

    2016-01-01

    It has been hypothesized that the nicotinic acetylcholine receptors (nAChRs) play important roles in nicotine dependence (ND) and influence the number of cigarettes smoked per day (CPD) in smokers. We compiled the associations between nicotinic cholinergic receptor genes (CHRNs) and ND/CPD that were replicated across different studies, reviewed the expression of these risk genes in human/mouse brains, and verified their expression using independent samples of both human and mouse brains. The potential functions of the replicated risk variants were examined using cis-eQTL analysis or predicted using a series of bioinformatics analyses. We found replicated and significant associations for ND/CPD at 19 SNPs in six genes in three genomic regions (CHRNB3-A6, CHRNA5-A3-B4 and CHRNA4). These six risk genes are expressed in at least 18 distinct areas of the human/mouse brain, with verification in our independent human and mouse brain samples. The risk variants might influence the transcription, expression and splicing of the risk genes, alter RNA secondary or protein structure. We conclude that the replicated associations between CHRNB3-A6, CHRNA5-A3-B4, CHRNA4 and ND/CPD are very robust. More research is needed to examine how these genetic variants contribute to the risk for ND/CPD. PMID:27827986

  7. Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence.

    PubMed

    Zuo, Lingjun; Garcia-Milian, Rolando; Guo, Xiaoyun; Zhong, Chunlong; Tan, Yunlong; Wang, Zhiren; Wang, Jijun; Wang, Xiaoping; Kang, Longli; Lu, Lu; Chen, Xiangning; Li, Chiang-Shan R; Luo, Xingguang

    2016-11-07

    It has been hypothesized that the nicotinic acetylcholine receptors (nAChRs) play important roles in nicotine dependence (ND) and influence the number of cigarettes smoked per day (CPD) in smokers. We compiled the associations between nicotinic cholinergic receptor genes (CHRNs) and ND/CPD that were replicated across different studies, reviewed the expression of these risk genes in human/mouse brains, and verified their expression using independent samples of both human and mouse brains. The potential functions of the replicated risk variants were examined using cis-eQTL analysis or predicted using a series of bioinformatics analyses. We found replicated and significant associations for ND/CPD at 19 SNPs in six genes in three genomic regions (CHRNB3-A6, CHRNA5-A3-B4 and CHRNA4). These six risk genes are expressed in at least 18 distinct areas of the human/mouse brain, with verification in our independent human and mouse brain samples. The risk variants might influence the transcription, expression and splicing of the risk genes, alter RNA secondary or protein structure. We conclude that the replicated associations between CHRNB3-A6, CHRNA5-A3-B4,CHRNA4 and ND/CPD are very robust. More research is needed to examine how these genetic variants contribute to the risk for ND/CPD.

  8. Nicotine trapping causes the persistent desensitization of alpha4beta2 nicotinic receptors expressed in oocytes.

    PubMed

    Jia, Li; Flotildes, Karen; Li, Maureen; Cohen, Bruce N

    2003-02-01

    To determine whether prolonged nicotine exposure persistently inactivates rat alpha4beta2 nicotinic receptors expressed in Xenopus oocytes, we measured the voltage-clamped alpha4beta2 response to acetylcholine (ACh) before and 24 h after, 1-h or 12-h incubations in 10 microm nicotine. A 12-h incubation in 10 microm nicotine depressed the alpha4beta2 ACh response for 24 h without affecting total or surface alpha4beta2 expression. To determine whether oocyte-mediated nicotine release caused this depression, we co-incubated an alpha4beta2-expressing oocyte with an un-injected one (pre-incubated in 10 microm nicotine for 12 h) for 24 h and measured the change in the alpha4beta2 ACh response. The response decreased by the same factor after the co-incubation as it did after a 12-h incubation in 10 microm nicotine and a 24-h incubation in nicotine-free media. Thus, oocyte-mediated nicotine release caused the persistent desensitization we observed after a 12-h incubation in 10 microm nicotine. Consistent with this result, measurements of [3H]nicotine release show that oocytes release enough nicotine into the wash media to desensitize alpha4beta2 receptors and that prolonged incubation in 300 microm ACh (which cannot readily cross the membrane or accumulate in acidic vesicles) did not persistently depress the alpha4beta2 response.

  9. 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…

  10. Nicotine Effects on the Impact of Stress

    DTIC Science & Technology

    2016-03-01

    nicotine. There is good evidence that drugs produce fundamentally different physiological effects when taken voluntarily as opposed to when it is...possible to devise safer ways of delivering nicotine or develop new drugs that possess only the helpful effects of the drug . The outcome of our research...after their service. We proposed to determine if the putative beneficial effects of nicotine on contextual fear conditioning are retained when the drug

  11. 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

  12. 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

    2008-08-08

    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.

  13. 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

  14. 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

  15. Pharmacology of Nicotine: Addiction, Smoking-Induced Disease, and Therapeutics

    PubMed Central

    Benowitz, Neal L.

    2010-01-01

    Nicotine sustains tobacco addiction, a major cause of disability and premature death. Nicotine binds to nicotinic cholinergic receptors, facilitating neurotransmitter release and thereby mediating the complex actions of nicotine in tobacco users. Dopamine, glutamate, and gamma aminobutyric acid release are particularly important in the development of nicotine dependence, and corticotropin-releasing factor appears to contribute to nicotine withdrawal. Nicotine dependence is highly heritable. Genetic studies indicate roles for nicotinic receptor subtypes, as well as genes involved in neuroplasticity and learning, in development of dependence. Nicotine is primarily metabolized byCYP2A6, and variability in rate of metabolism contributes to vulnerability to tobacco dependence, response to smoking cessation treatment, and lung cancer risk. Tobacco addiction is much more common in persons with mental illness and substance abuse disorders, representing a high proportion of current smokers. Pharmacotherapeutic approaches to tobacco addiction include nicotine replacement, bupropion, and varenicline, the latter a selective nicotine receptor partial agonist. PMID:18834313

  16. Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics.

    PubMed

    Benowitz, Neal L

    2009-01-01

    Nicotine sustains tobacco addiction, a major cause of disability and premature death. Nicotine binds to nicotinic cholinergic receptors, facilitating neurotransmitter release and thereby mediating the complex actions of nicotine in tobacco users. Dopamine, glutamate, and gamma aminobutyric acid release are particularly important in the development of nicotine dependence, and corticotropin-releasing factor appears to contribute to nicotine withdrawal. Nicotine dependence is highly heritable. Genetic studies indicate roles for nicotinic receptor subtypes, as well as genes involved in neuroplasticity and learning, in development of dependence. Nicotine is primarily metabolized by CYP 2A6, and variability in rate of metabolism contributes to vulnerability to tobacco dependence, response to smoking cessation treatment, and lung cancer risk. Tobacco addiction is much more common in persons with mental illness and substance abuse disorders, representing a high proportion of current smokers. Pharmacotherapeutic approaches to tobacco addiction include nicotine replacement, bupropion, and varenicline, the latter a selective nicotine receptor partial agonist.

  17. Responding for a conditioned reinforcer, and its enhancement by nicotine, is blocked by dopamine receptor antagonists and a 5-HT(2C) receptor agonist but not by a 5-HT(2A) receptor antagonist.

    PubMed

    Guy, Elizabeth Glenn; Fletcher, Paul J

    2014-10-01

    An aspect of nicotine reinforcement that may contribute to tobacco addiction is the effect of nicotine to enhance the motivational properties of reward-associated cues, or conditioned stimuli (CSs). Several studies have now shown that nicotine enhances responding for a stimulus that has been paired with a natural reinforcer. This effect of nicotine to enhance responding for a conditioned reinforcer is likely due to nicotine-induced enhancements in mesolimbic dopaminergic activity, but this has not been directly assessed. In this study, we assessed roles for dopamine (DA) D1 or D2 receptors, and two serotonin (5-HT) receptor subtypes known to modulate DA activity, the 5-HT2C or 5-HT2A subtypes, on nicotine-enhanced responding for a conditioned reinforcer. Water-restricted rats were exposed to Pavlovian conditioning sessions, where a CS was paired with water delivery. Then, in a second phase, animals were required to perform a novel, lever-pressing response for presentations of the CS as a conditioned reinforcer. Nicotine (0.4 mg/kg) enhanced responding for the conditioned reinforcer. To examine potential roles for dopamine (DA) and serotonin (5-HT) receptors in this effect, separate groups of animals were used to assess the impact of administering the D1 receptor antagonist SCH 23390, D2 receptor antagonist eticlopride, 5-HT2C receptor agonist Ro 60-0175, or 5-HT2A receptor antagonist M100907 on nicotine-enhanced responding for conditioned reinforcement. SCH 23390, eticlopride, and Ro 60-0175 all reduced responding for conditioned reinforcement, and the ability of nicotine to enhance this effect. M100907 did not alter this behavior. Together, these studies indicate that DA D1 and D2 receptors, but not 5-HT2A receptors, contribute to the effect of nicotine to enhance responding for a conditioned reinforcer. This effect can also be modulated by 5-HT2C receptor activation.

  18. 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…

  19. 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.

  20. Interactions of serotonin (5-HT)2 receptor-targeting ligands and nicotine: locomotor activity studies in rats.

    PubMed

    Zaniewska, Magdalena; McCreary, Andrew C; Filip, Małgorzata

    2009-08-01

    Male Wistar rats were used to verify the hypothesis that serotonin (5-HT)(2A) or 5-HT(2C) receptors may control the locomotor effects evoked by nicotine (0.4 mg/kg). The 5-HT(2A) receptor antagonist (M100,907), the 5-HT(2A) receptor agonist (DOI), the 5-HT(2C) receptor antagonist (SB 242,084), and the 5-HT(2C) receptor agonists (Ro 60-0175 and WAY 163,909) were used. M100,907 (0.5-2mg/kg) did not alter, while DOI (1 mg/kg) enhanced the nicotine-induced hyperlocomotion. The effect of DOI was antagonized by M100,907 (1 mg/kg). SB 242,084 (0.25-1 mg/kg) augmented, while Ro 60-0175 (1 and 3 mg/kg) and WAY 163,909 (1.5 mg/kg) decreased the overall effect of acute nicotine; effects of Ro 60-0175 and WAY 163,909 were attenuated by SB 242,084 (0.125 mg/kg). In another set of experiments, M100,907 (2 mg/kg) on Day 10 attenuated, while DOI (0.1-1 mg/kg) enhanced the nicotine-evoked conditioned hyperlocomotion in rats repeatedly (Days 1-5) treated with nicotine in experimental chambers. SB 242,084 (0.125 or 1 mg/kg) did not change, while Ro 60-0175 (1 mg/kg) or WAY 163,909 (1.5 mg/kg) decreased the expression of nicotine-induced conditioned hyperactivity. Only DOI (0.3 and 1 mg/kg) and SB 242,084 (1 mg/kg) enhanced the basal locomotion. The present data indicate that 5-HT(2A) receptors are significant for the expression of nicotine-evoked conditioned hyperactivity. Conversely, 5-HT(2C) receptors play a pivotal role in the acute effects of nicotine. Pharmacological stimulation of 5-HT(2A) receptors enhances the conditioned hyperlocomotion, while activation of 5-HT(2C) receptors decreases both the response to acute nicotine and conditioned hyperactivity.

  1. Alcohol's actions on neuronal nicotinic acetylcholine receptors.

    PubMed

    Davis, Tiffany J; de Fiebre, Christopher M

    2006-01-01

    Although it has been known for many years that alcoholism and tobacco addiction often co-occur, relatively little information is available on the biological factors that regulate the co-use and abuse of nicotine and alcohol. In the brain, nicotine acts at several different types of receptors collectively known as nicotinic acetylcholine receptors (nAChRs). Alcohol also acts on at least some of these receptors, enhancing the function of some nAChR subtypes and inhibiting the activity of others. Chronic alcohol and nicotine administration also lead to changes in the numbers of nAChRs. Natural variations (i.e., polymorphisms) in the genes encoding different nAChR subunits may be associated with individual differences in the sensitivity to some of alcohol's and nicotine's effects. Finally, at least one subtype of nAChR may help protect cells against alcohol-induced neurotoxicity.

  2. 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.

  3. Prenatal nicotine and/or cocaine differentially alters nicotine-induced sensitization in aging offspring.

    PubMed

    Sobrian, Sonya K; Johnston, Matthew; Wright, Jewel; Kuhn, Daniela; Ameis, Kamal

    2008-10-01

    Repeated exposure to psychostimulant drugs can result in behavioral sensitization, an amplified response in locomotor activity and stereotypy, which is used to model aspects of drug addiction. The expression of behavioral sensitization, induced by i.p. injections of nicotine once daily for 5 days, was examined in 450-day-old male rats exposed prenatally on GD 8-20 to one of the following conditions: (1) low nicotine: 2.5 mg/kg/day nicotine [LN]; (2) high nicotine: 5.0 mg/kg/day nicotine [HN]; (3) low nicotine/high cocaine: 2.5 mg/kg/day nicotine plus 40 mg/kg/day cocaine [LN/HC]; (4) high nicotine/low cocaine: 5.0 mg/kg/day nicotine plus 20 mg/kg/day cocaine [HN/LC]; (5) pair-fed controls: food intake yoked to HC dams [PF]; and (6) saline controls: daily injections of 0.9% NaCl solution[SAL]. Initial injection of nicotine did not alter activity or stereotypy in comparison to saline injections, with offspring in all prenatal treatment groups showing a desensitization to nicotine. Five consecutive daily nicotine injections resulted in behavioral sensitization in HN and HN/LC prenatal drug groups. Offspring exhibited an increase in horizontal activity that was evident on day 3, and still present after a 1.0 mg/kg i.p. nicotine challenge 72 hours after the last injection (day 8). SAL offspring exhibited attenuated sensitization. In contrast, nicotine sensitization was not seen in the LN, HC/LN, and the PF offspring; activity remained at the level seen after the initial injection of nicotine. Moreover, nicotine significantly reduced total activity in the LN and PF groups in comparison with their saline-injected counterparts. These data suggest that gestational exposure to high-dose nicotine, either alone or in combination with cocaine, may carry a greater risk than low-dose nicotine exposure of stimulant abuse in later life.

  4. Nicotine exposure in adolescence alters the response of serotonin systems to nicotine administered subsequently in adulthood.

    PubMed

    Slotkin, Theodore A; Seidler, Frederic J

    2009-01-01

    Developmental nicotine exposure produces lasting changes in serotonin (5-HT) function. We gave nicotine to adolescent rats (postnatal days, PD, 30-47), simulating plasma levels in smokers, and then examined the subsequent effects of nicotine given again in young adulthood (PD 90-107), focusing on 5-HT(1A) and 5-HT(2) receptors and the 5-HT transporter during nicotine treatment (PD 105) and withdrawal (PD 110, 120, 130), and long-term changes (PD 180). Adolescent nicotine exposure by itself evoked long-term elevations in cerebrocortical binding parameters in males that emerged in young adulthood. Nicotine given in adulthood produced transient elevations in 5-HT receptor expression in both males and females during withdrawal, and persistent upregulation in the male cerebral cortex. In contrast, females showed decrements in cerebrocortical 5-HT receptors by PD 180. Adolescent nicotine exposure altered the responses to nicotine given in adulthood, sensitizing the initial effects and changing both the withdrawal response and long-term actions. Our results thus provide mechanistic evidence that nicotine exposure, during the period in which nearly all smokers begin to use tobacco, reprograms the future response of 5-HT systems to nicotine.

  5. Nicotine Dependence Reveals Distinct Responses from Neurons and Their Resident Nicotinic Receptors in Medial Habenula

    PubMed Central

    Shih, Pei-Yu; McIntosh, J. Michael

    2015-01-01

    Nicotinic acetylcholine receptors (nAChRs) are the molecular target of nicotine. nAChRs in the medial habenula (MHb) have recently been shown to play a role in nicotine dependence, but it is not clear which nAChR subtypes or MHb neuron types are most important. To identify MHb nAChRs and/or cell types that play a role in nicotine dependence, we studied these receptors and cells with brain slice electrophysiology using both acute and chronic nicotine application. Cells in the ventroinferior (MHbVI) and ventrolateral MHb (MHbVL) subregions expressed functional nAChRs with different pharmacology. Further, application of nicotine to cells in these subregions led to different action potential firing patterns. The latter result was correlated with a differing ability of nicotine to induce nAChR desensitization. Chronic nicotine caused functional upregulation of nAChRs selectively in MHbVI cells, but did not change nAChR function in MHbVL. Importantly, firing responses were also differentially altered in these subregions following chronic nicotine. MHbVI neurons treated chronically with nicotine exhibited enhanced basal pacemaker firing but a blunted nicotine-induced firing response. MHbVL neurons did not change their firing properties in response to chronic nicotine. Together, these results suggest that acute and chronic nicotine differentially affect nAChR function and output of cells in MHb subregions. Because the MHb extensively innervates the interpeduncular nucleus, an area critical for both affective and somatic signs of withdrawal, these results could reflect some of the neurophysiological changes thought to occur in the MHb to the interpeduncular nucleus circuit in human smokers. PMID:26429939

  6. 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.

  7. [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.

  8. Nicotine metabolic rate predicts successful smoking cessation with transdermal nicotine: a validation study.

    PubMed

    Schnoll, Robert A; Patterson, Freda; Wileyto, E Paul; Tyndale, Rachel F; Benowitz, Neal; Lerman, Caryn

    2009-03-01

    Transdermal nicotine is widely used for smoking cessation, but only approximately 20% of smokers quit successfully with this medication. Interindividual variability in nicotine metabolism rate may influence treatment response. This study sought to validate, and extend in a larger sample, our previous finding that the ratio of plasma nicotine metabolites 3'-hydroxycotinine (3-HC)/cotinine, a measure of nicotine metabolism rate, predicts response to nicotine patch. A sample of 568 smokers was enrolled in a study that provided counseling and 8-weeks of 21 mg nicotine patch. Pretreatment 3-HC/cotinine ratio was examined as a predictor of 7-day point prevalence abstinence, verified with breath carbon monoxide (CO), 8 weeks after the quit date. Controlling for sex, race, age, and nicotine dependence, smokers in the upper 3 quartiles of 3-HC/cotinine ratio (faster metabolizers) were approximately 50% less likely to be abstinent vs. smokers in the first quartile (slow metabolizers; 28% vs. 42%; OR=.54 [95% CI:.36-.82], p=.003). Among abstainers, plasma nicotine levels (assessed 1 week after treatment began) decreased linearly across the 3-HC/cotinine ratio (beta=-3.38, t[355]=-3.09, p<.05). These data support the value of the 3-HC/cotinine ratio as a biomarker to predict success with transdermal nicotine for smoking cessation.

  9. Nicotine and Nicotinic Receptor Drugs: Potential for Parkinson's Disease and Drug-Induced Movement Disorders.

    PubMed

    Quik, Maryka; Bordia, Tanuja; Zhang, Danhui; Perez, Xiomara A

    2015-01-01

    Parkinson's disease is a progressive neurodegenerative disorder associated with tremor, rigidity, and bradykinesia, as well as nonmotor symptoms including autonomic impairments, olfactory dysfunction, sleep disturbances, depression, and dementia. Although the major neurological deficit is a loss of nigrostriatal dopaminergic neurons, multiple neurotransmitters systems are compromised in Parkinson's disease. Consistent with this observation, dopamine replacement therapy dramatically improves Parkinson's disease motor symptoms. Additionally, drugs targeting the serotonergic, glutamatergic, adenosine, and other neurotransmitter systems may be beneficial. Recent evidence also indicates that nicotinic cholinergic drugs may be useful for the management of Parkinson's disease. This possibility initially arose from the results of epidemiological studies, which showed that smoking was associated with a decreased incidence of Parkinson's disease, an effect mediated in part by the nicotine in smoke. Further evidence for this idea stemmed from preclinical studies which showed that nicotine administration reduced nigrostriatal damage in parkinsonian rodents and monkeys. In addition to a potential neuroprotective role, emerging work indicates that nicotinic receptor drugs improve the abnormal involuntary movements or dyskinesias that arise as a side effect of l-dopa treatment, the gold standard therapy for Parkinson's disease. Both nicotine and nicotinic receptor drugs reduced l-dopa-induced dyskinesias by over 50% in parkinsonian rodent and monkey models. Notably, nicotine also attenuated the abnormal involuntary movements or tardive dyskinesias that arise with antipsychotic treatment. These observations, coupled with reports that nicotinic receptor drugs have procognitive and antidepressant effects, suggest that central nervous system (CNS) nicotinic receptors may represent useful targets for the treatment of movement disorders.

  10. Honey Attenuates the Detrimental Effects of Nicotine on Testicular Functions in Nicotine Treated Wistar Rats.

    PubMed

    Kolawole, T A; Oyeyemi, W A; Adigwe, C; Leko, B; Udeh, C; Dapper, D V

    2015-12-20

    Effect of honey on reproductive functions of male rats exposed to nicotine was examined in this study. Thirty-two adult male wistar rats (n=8/Group) were grouped as Control (distilled water), Nicotine (1.0mg/kg bwt), Honey (100mg/kg bwt) and Nicotine with Honey. The animals were orally treated for 35 days consecutively. Epididymis sperm motility, viability, morphology and counts were estimated, serum Follicle Stimulating Hormone (FSH), Leutinizing Hormone (LH) and Testosterone were assayed using ELISA method and testicular histology were also assessed. Significant reduction in percentage sperm motility, viability, morphology and counts were observed in nicotine group compared to control. Serum FSH, LH and testosterone levels were significantly reduced in nicotine group when compared with the control. There was significant improvement in sperm motility, viability, morphology, counts, FSH, LH and Testosterone in group co-treated with nicotine and honey  relative to nicotine group. Also, the degenerative seminiferous tubule architecture due to nicotine was improved by honey. In conclusion, honey may suppress nicotine toxic effect on reproductive functions in male Wistar rats.

  11. Nicotine restores morphine-induced memory deficit through the D1 and D2 dopamine receptor mechanisms in the nucleus accumbens.

    PubMed

    Azizbeigi, Ronak; Ahmadi, Shamseddin; Babapour, Vahab; Rezayof, Ameneh; Zarrindast, Mohammad Reza

    2011-08-01

    Involvement of the dopamine D1 and D2 receptors in the nucleus accumbens (NAc) with interaction between morphine and nicotine on inhibitory avoidance (IA) memory was investigated. A step-through type of inhibitory avoidance tasks was used to assess memory in male Wistar rats. The results showed that subcutaneous (s.c.) administration of morphine (7.5 mg/kg) after training decreased retrieval of IA memory in the animals when tested 24 h later. Pre-test administration of the same dose of morphine significantly reversed the deficiency in retrieval. The results also showed that pre-test administration of nicotine (0.2 and 0.4 mg/kg, s.c.) by itself mimicked the effect of pre-test morphine, and lower doses of nicotine (0.1 and 0.2 mg/kg) also improved the effect of a low dose of morphine (2.5 mg/kg) on retrieval of IA memory. Pre-test intra-NAc administration of the dopamine D1 receptor antagonist, SCH 23390 (0.001 and 0.01 µg/rat), and the dopamine D2 receptor antagonist, sulpiride (0.5 and 1 µg/rat) caused no significant effects on IA memory by themselves, but both prevented reinstatement of the retrieval of IA memory by the effective dose of nicotine (0.4 mg/kg). It can be concluded that the dopaminergic mechanism(s) in the NAc is a crosslink for the effect of morphine and nicotine on reinstatement of retrieval of IA memory impaired by post-training administration of morphine.

  12. Effects of Chronic Buspirone Treatment on Nicotine and Concurrent Nicotine+Cocaine Self-Administration

    PubMed Central

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

    2013-01-01

    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

  13. U.S. adults' addiction and harm beliefs about nicotine and low nicotine cigarettes.

    PubMed

    O'Brien, Erin Keely; Nguyen, Anh B; Persoskie, Alexander; Hoffman, Allison C

    2017-03-01

    This research described U.S. adults' beliefs about nicotine and low nicotine cigarettes (LNCs) using the nationally-representative Health Information National Trends Survey (HINTS-FDA 2015; N=3738). About three quarters of people either were unsure of the relationship between nicotine and cancer or incorrectly believed that nicotine causes cancer. People who were non-White, less educated, age 65+, and never established smokers were most likely to be unaware that nicotine is not a cause of cancer. More than a quarter of people held the potentially inaccurate beliefs that LNCs would be less harmful and addictive than typical cigarettes. Whites were more likely than Blacks to believe LNCs were less harmful than typical cigarettes, and never smokers were more likely to believe this than established quitters. Whites and people with at least a college degree were more likely to believe that LNCs would be less addictive than typical cigarettes. Overall, we found that many people, particularly the demographic subgroups identified here, held incorrect beliefs about nicotine and potentially inaccurate beliefs about LNCs. Findings should be considered in assessing the public health impact of marketing low nicotine products. Incorrectly believing that nicotine causes cancer could discourage smokers from switching to safer nicotine-containing alternatives, and could lead nonsmokers to experiment with low nicotine tobacco products, believing that cancer risk would be reduced. Findings underscore the need to educate the public on the health effects of nicotine and LNCs, and can help public health practitioners determine which subgroups should be prioritized in targeted educational efforts.

  14. 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.

  15. U.S. adults' addiction and harm beliefs about nicotine and low nicotine cigarettes☆

    PubMed Central

    O'Brien, Erin Keely; Nguyen, Anh B.; Persoskie, Alexander; Hoffman, Allison C.

    2017-01-01

    This research described U.S. adults' beliefs about nicotine and low nicotine cigarettes (LNCs) using the nationally-representative Health Information National Trends Survey (HINTS-FDA 2015; N = 3738). About three quarters of people either were unsure of the relationship between nicotine and cancer or incorrectly believed that nicotine causes cancer. People who were non-White, less educated, age 65+, and never established smokers were most likely to be unaware that nicotine is not a cause of cancer. More than a quarter of people held the potentially inaccurate beliefs that LNCs would be less harmful and addictive than typical cigarettes. Whites were more likely than Blacks to believe LNCs were less harmful than typical cigarettes, and never smokers were more likely to believe this than established quitters. Whites and people with at least a college degree were more likely to believe that LNCs would be less addictive than typical cigarettes. Overall, we found that many people, particularly the demographic subgroups identified here, held incorrect beliefs about nicotine and potentially inaccurate beliefs about LNCs. Findings should be considered in assessing the public health impact of marketing low nicotine products. Incorrectly believing that nicotine causes cancer could discourage smokers from switching to safer nicotine-containing alternatives, and could lead nonsmokers to experiment with low nicotine tobacco products, believing that cancer risk would be reduced. Findings underscore the need to educate the public on the health effects of nicotine and LNCs, and can help public health practitioners determine which subgroups should be prioritized in targeted educational efforts. PMID:28034733

  16. Nicotine Effects on the Impact of Stress

    DTIC Science & Technology

    2015-09-01

    Most importantly, however, there is good evidence that drugs produce fundamentally different physiological effects when taken voluntarily as opposed to...possible to devise safer ways of delivering nicotine or develop new drugs that possess only the helpful effects of the drug . The outcome of our research...putative beneficial effects of nicotine on contextual fear conditioning are retained when the drug is given by a different (safer) 7 route of

  17. 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.

  18. Hormones, Nicotine and Cocaine: Clinical Studies

    PubMed Central

    Mello, Nancy K.

    2009-01-01

    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 (two 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 implications for treatment of these addictive disorders is discussed. PMID:19835877

  19. 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...

  20. [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.

  1. Effects of Chronic Varenicline Treatment on Nicotine, Cocaine, and Concurrent Nicotine+Cocaine Self-Administration

    PubMed Central

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

    2014-01-01

    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

  2. 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

  3. 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.

  4. 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

  5. Neuronal nicotinic acetylcholine receptors are modulated by zinc.

    PubMed

    Vázquez-Gómez, Elizabeth; García-Colunga, Jesús

    2009-01-01

    It is known that zinc modulates nicotinic acetylcholine receptors (nAChRs). Here, we studied the effects of zinc on neuronal alpha4beta4 nAChRs, expressed in Xenopus oocytes and activated by nicotine. Membrane ion currents elicited by nicotine (10 nM to 100 microM) were enhanced by zinc (100 microM). Maximal zinc potentiation of the nicotine-activated current (2530%) occurred at 50 nM nicotine, and potentiation gradually decreased as the nicotine concentration increased. The EC(50) and IC(50) for the nicotine-activated current were 639 nM and 14.7 microM nicotine, respectively. Both parameters decreased in the presence of zinc to 160 nM and 4.6 microM, respectively, probably due to an increase of sensitivity of nAChRs for nicotine. We used different concentrations and durations of exposure to nicotine, due to desensitization of nAChRs directly depends on both these factors. With 500 nM nicotine and 20 min washing periods between nicotine applications, zinc potentiation remained constant, 901% for 2 min and 813% for 20 min of nicotine exposure. With continuous application of nicotine, zinc potentiation decreased as the time of nicotine exposure increased, 721% for 2 min and 254% for 48 min of nicotine exposure. Our results indicate that zinc-potentiating effects on alpha4beta4 nAChRs strongly depend on both concentration and time of exposure to nicotine, suggesting that zinc potentiation depends on the degree of desensitization.

  6. Partitioning of Homologous Nicotinic Acid Ester Prodrugs (Nicotinates) into Dipalmitoylphosphatidylcholine (DPPC) Membrane Bilayers

    PubMed Central

    Ojogun, Vivian; Vyas, Sandhya M.; Lehmler, Hans-Joachim; Knutson, Barbara L

    2010-01-01

    The partitioning behavior of a series of perhydrocarbon nicotinic acid esters (nicotinates) between aqueous solution and dipalmitoylphosphatidylcholine (DPPC) membrane bilayers is investigated as a function of increasing alkyl chain length. The hydrocarbon nicotinates represent putative prodrugs, derivatives of the polar drug nicotinic acid, whose functionalization provides the hydrophobic character necessary for pulmonary delivery in a hydrophobic, fluorocarbon solvent, such as perfluorooctyl bromide. Independent techniques of differential scanning calorimetry and 1,6-diphenyl-1,3,5 hexatriene (DPH) fluorescence anisotropy measurements are used to analyze the thermotropic phase behavior and lipid bilayer fluidity as a function of nicotinate concentration. At increasing concentrations of nicotinates over the DPPC mole fraction range examined (XDPPC = 0.6 – 1.0), all the nicotinates (ethyl (C2H5); butyl (C4H9); hexyl (C6H13); and octyl (C8H17)) partition into the lipid bilayer at sufficient levels to eliminate the pretransition, and decrease and broaden the gel to fluid phase transition temperature. The concentration at which these effects occur is chain length-dependent; the shortest chain nicotinate, C2H5, elicits the least dramatic response. Similarly, the DPH anisotropy results demonstrate an alteration of the bilayer organization in the liposomes as a consequence of the chain length-dependent partitioning of the nicotinates into DPPC bilayers. The membrane partition coefficients (logarithm values), determined from the depressed bilayer phase transition temperatures, increase from 2.18 for C2H5 to 5.25 for C8H17. The DPPC membrane/water partitioning of the perhydrocarbon nicotinate series correlates with trends in the octanol/water partitioning of these solutes, suggesting that their incorporation into the bilayer is driven by increasing hydrophobicity. PMID:20227859

  7. 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

  8. 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.

  9. Pyrilamine inhibits nicotine-induced catecholamine secretion.

    PubMed

    Kim, Dong-Chan; Yun, So Jeong; Park, Yong-Soo; Jun, Dong-Jae; Kim, Dongjin; Jiten Singh, N; Kim, Sanguk; Kim, Kyong-Tai

    2014-07-01

    Function of nicotine, which induces activation of all parts of the body including our brain, has been receiving much attention for a long period of time and also been actively studied by researchers for its pharmacological actions in the central nervous system. The modulation of nicotine concentration and the inhibition of nicotine binding on target receptors in the brain are the key factors for smoking addiction therapy. In previous studies showed that influx of nicotine at the blood-brain barrier was through the pyrilamine-sensitive organic cation transporters. But the direct interacting mechanism of pyrilamine on the nicotine binding target receptors has not yet been clarified. The aim of the present study is to investigate the direct binding mechanisms of a pyrilamine on the nicotinic acetylcholine receptors (nAChRs). We found that pyrilamine shares the same ligand binding pocket of nicotine (NCT) on nAChRs but interacts with more amino acid residues than NCT does. The extended part of pyrilamine interacts with additional residues in the ligand binding pocket of nAChRs which are located nearby the entrance of the binding pocket. The catecholamine (CA) secretion induced by nAChR agonist (NCT') was significantly inhibited by the pyrilamine pretreatment. Real time carbon-fiber amperometry confirmed the inhibition of the NCT'-induced exocytosis by pyrilamine in a single cell level. We also found that pyrilamine inhibited the NCT'-induced [Ca(2+)]i. In contrast, pyrilamine did not affect the increase in calcium induced by high K(+). Overall, these data suggest that pyrilamine directly docks into the ligand binding site of nAChRs and specifically inhibits the nAChR-mediated effects thereby causing inhibition of CA secretion. Therefore, pyrilamine may play an important role to explore new treatments to aid smoking cessation.

  10. 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

  11. 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.

  12. Individual differences in oral nicotine intake in rats.

    PubMed

    Nesil, Tanseli; Kanit, Lutfiye; Collins, Allan C; Pogun, Sakire

    2011-01-01

    To study individual differences in nicotine preference and intake, male and female rats were given free access to a choice of oral nicotine (10 or 20 mg/L) or water for 24 h/day for periods of at least six weeks, starting at adolescence or adulthood. A total of 341 rats, were used in four different experiments; weight, nicotine intake and total liquid consumption were recorded weekly. Results show that rats can discriminate nicotine from water, can regulate their intake, and that there are readily detected individual differences in nicotine preference. Ward analyses indicated that the animals could be divided into minimum, median and maximum preferring subgroups in all experiments. The effect of saccharine on nicotine intake was also evaluated; although the addition of saccharine increased total intake, rats drank unsweetened nicotine solutions and those with higher preferences for nicotine, preferred nicotine over water with or without saccharine added. Nicotine reduced weight gain and the effect was more pronounced in females than males. The average nicotine consumption of adolescent rats was higher than adults and nicotine exposure during adolescence reduced nicotine intake in adult rats. About half of the rats which had access to nicotine as adolescents and also as adults had a persistent pattern of consumption; the behavior was very stable in the female minimum preferring groups and a much higher ratio of rats sustained their adolescent behavior as adults. The change in preference was more pronounced when there was an interval between adolescent and adult exposure; female rats showed a more stable behavior than males suggesting a greater role for environmental influences on males. In conclusion, marked individual differences were observed in oral nicotine intake as measured in a continuous access 2-bottle choice test. Age and sex of the subjects and previous exposure to nicotine are significant factors which affect preference in rats.

  13. The metabolic fate of nectar nicotine in worker honey bees.

    PubMed

    du Rand, Esther E; Pirk, Christian W W; Nicolson, Susan W; Apostolides, Zeno

    2017-04-01

    Honey bees (Apis mellifera) are generalist pollinators that forage for nectar and pollen of a very large variety of plant species, exposing them to a diverse range of secondary metabolites produced as chemical defences against herbivory. Honey bees can tolerate high levels of many of these toxic compounds, including the alkaloid nicotine, in their diet without incurring apparent fitness costs. Very little is known about the underlying detoxification processes mediating this tolerance. We examined the metabolic fate of nicotine in newly emerged worker bees using radiolabeled nicotine and LC-MS/MS analysis to determine the kinetic distribution profile of nicotine as well as the absence or presence and identity of any nicotine-derived metabolites. Nicotine metabolism was extensive; virtually no unmetabolised nicotine were recovered from the rectum. The major metabolite found was 4-hydroxy-4-(3-pyridyl) butanoic acid, the end product of 2'C-oxidation of nicotine. It is the first time that 4-hydroxy-4-(3-pyridyl) butanoic acid has been identified in an insect as a catabolite of nicotine. Lower levels of cotinine, cotinine N-oxide, 3'hydroxy-cotinine, nicotine N-oxide and norcotinine were also detected. Our results demonstrated that formation of 4-hydroxy-4-(3-pyridyl) butanoic acid is quantitatively the most significant pathway of nicotine metabolism in honey bees and that the rapid excretion of unmetabolised nicotine does not contribute significantly to nicotine tolerance in honey bees. In nicotine-tolerant insects that do not rely on the rapid excretion of nicotine like the Lepidoptera, it is possible that the 2'C-oxidation of nicotine is the conserved metabolic pathway instead of the generally assumed 5'C-oxidation pathway.

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

    PubMed Central

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

    2015-01-01

    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. PMID:26626731

  15. 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.…

  16. 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

  17. 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

  18. Early nicotine withdrawal and transdermal nicotine effects on neurocognitive performance in schizophrenia.

    PubMed

    AhnAllen, Christopher G; Nestor, Paul G; Shenton, Martha E; McCarley, Robert W; Niznikiewicz, Margaret A

    2008-03-01

    As cigarette smoking prevalence rates approach 90% in schizophrenia, an important emerging question is the role of nicotine in the disease-related disturbance in cognition. We therefore tested a total of 38 male cigarette smokers (22 schizophrenia, 16 normal control), matched on nicotine dependence, on the Attention Network Test (ANT) at three nicotine conditions (baseline, 8 h overnight withdrawal, 3 h 21 mg nicotine patch). The results indicated that the groups did not differ in performance on either of three ANT measures (alertness, orienting, and executive) across baseline, patch, and withdrawal conditions. However, in comparison to the controls, the participants with schizophrenia showed faster ANT reaction time (RT) for the nicotine patch in relation to the baseline condition. In comparison to controls, the participants with schizophrenia also showed reduced ANT accuracy at withdrawal but not at patch condition. These results suggest that overall processing speed and accuracy are affected differently by nicotine levels in participants with schizophrenia, with evidence supporting greater impairment from withdrawal and greater improvement from nicotine administration.

  19. Nicotine enhances alcohol intake and dopaminergic responses through β2* and β4* nicotinic acetylcholine receptors

    PubMed Central

    Tolu, Stefania; Marti, Fabio; Morel, Carole; Perrier, Carole; Torquet, Nicolas; Pons, Stephanie; de Beaurepaire, Renaud; Faure, Philippe

    2017-01-01

    Alcohol and nicotine are the most widely co-abused drugs. Both modify the activity of dopaminergic (DA) neurons of the Ventral Tegmental Area (VTA) and lead to an increase in DA release in the Nucleus Accumbens, thereby affecting the reward system. Evidences support the hypothesis that distinct nicotinic acetylcholine receptors (nAChRs), the molecular target of acetylcholine (ACh) and exogenous nicotine, are also in addition implicated in the response to alcohol. The precise molecular and neuronal substrates of this interaction are however not well understood. Here we used in vivo electrophysiology in the VTA to characterise acute and chronic interactions between nicotine and alcohol. Simultaneous injections of the two drugs enhanced their responses on VTA DA neuron firing and chronic exposure to nicotine increased alcohol-induced DA responses and alcohol intake. Then, we assessed the role of β4 * nAChRs, but not β2 * nAChRs, in mediating acute responses to alcohol using nAChR subtypes knockout mice (β2−/− and β4−/− mice). Finally, we showed that nicotine-induced modifications of alcohol responses were absent in β2−/− and β4−/− mice, suggesting that nicotine triggers β2* and β4 * nAChR-dependent neuroadaptations that subsequently modify the responses to alcohol and thus indicating these receptors as key mediators in the complex interactions between these two drugs. PMID:28332590

  20. Reduced inhibitory action of a GABAB receptor agonist on [3H]-dopamine release from rat ventral tegmental area in vitro after chronic nicotine administration

    PubMed Central

    Amantea, Diana; Bowery, Norman G

    2004-01-01

    Background The activation of GABAB receptors in the ventral tegmental area (VTA) has been suggested to attenuate the rewarding properties of psychostimulants, including nicotine. However, the neurochemical mechanism that underlie this effect remains unknown. Since GABAB receptors modulate the release of several neurotransmitters in the mammalian brain, we have characterised the effect of the GABAB receptor agonist baclofen on the release of [3H]-dopamine ([3H]-DA) from VTA slices of naïve rats and of rats pre-treated with nicotine. Results In naïve rats, baclofen concentration-dependently inhibited the electrically evoked release of [3H]-DA from the isolated VTA (EC50 = 0.103 μM, 95% CI = 0.043–0.249), without affecting the basal [3H]-monoamine overflow. This effect was mediated by activation of GABAB receptors as it was blocked by the selective receptor antagonist CGP55845A. Chronic administration of nicotine (0.4 mg kg-1, s.c., for 14 days) affected neither the basal nor the electrically evoked release of [3H]-DA from VTA slices. However, the inhibitory effect of baclofen (10 μM) on the stimulated [3H]-monoamine overflow was abolished in rats pre-treated with nicotine as compared to saline-injected controls. Conclusions Our results demonstrate that GABAB receptor activation reduces the release of DA from the rat VTA. In addition, a reduced sensitivity of VTA GABAB receptors appears to develop after chronic exposure to nicotine. The resulting disinhibition of VTA DA neurones might therefore contribute to the sensitised dopaminergic responses observed in the rat mesocorticolimbic system following repeated administration of nicotine. PMID:15494079

  1. The benefits and risks of over-the-counter availability of nicotine polacrilex ("nicotine gum").

    PubMed

    Oster, G; Delea, T E; Huse, D M; Regan, M M; Colditz, G A

    1996-05-01

    Nicotine polacrilex ("nicotine gum") is effective in helping persons to quit smoking cigarettes. Because many persons try to quit without formal assistance, it may be an appropriate product for over-the-counter (OTC) purchase. Some smokers, however, might use such a product in lieu of more effective methods of cessation, and still others might use it to cope with enforced periods of nicotine abstinence (eg, at the work place) and thereby delay their decision to quit. The study's objective was to assess the public health benefits and risks of OTC availability of nicotine gum. A Markov model was developed and used to contrast two alternative policy scenarios: one in which nicotine gum was assumed to remain available only by prescription, and another in which it was assumed to be made available for OTC purchase. Various data sources were used to estimate the model, including the Health Promotion and Disease Prevention Supplement to the 1991 National Health Interview Survey and the 1986 Adult Use of Tobacco Survey. Primary outcome measures included the numbers of persons who would try to quit smoking, the numbers who would use various methods of smoking cessation, including OTC nicotine gum, and the numbers of current adult smokers who would be abstinent at the end of 10 years. Findings suggest that an average of 3 million persons each year would use OTC nicotine gum. As a consequence of OTC availability, an additional 450,000 smokers would be abstinent at the end of 10 years. These results are sensitive to assumptions regarding the effectiveness of OTC nicotine gum, as well as to the effect of OTC availability on the use of other methods of smoking cessation. The number of persons who would quit smoking, however, increases under a fairly wide range of assumptions. Over-the-counter availability of nicotine gum may confer significant public health benefits.

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

    PubMed Central

    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.

    2015-01-01

    α6β2* nicotinic acetylcholine receptors (nACh Rs) 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 [3H]nicotine and [3H]methyllyca-conitine 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 [3H]nicotine or [3H]methylly-caconitine 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 molecule

  3. The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: Dual role in nicotine addiction and lung cancer

    PubMed Central

    Improgo, Ma. Reina D.; Scofield, Michael D.; Tapper, Andrew R.; Gardner, Paul D.

    2010-01-01

    More than 1 billion people around the world smoke, with 10 million cigarettes sold every minute. Cigarettes contain thousands of harmful chemicals including the psychoactive compound, nicotine. Nicotine addiction is initiated by the binding of nicotine to nicotinic acetylcholine receptors, ligand-gated cation channels activated by the endogenous neurotransmitter, acetylcholine. These receptors serve as prototypes for all ligand-gated ion channels and have been extensively studied in an attempt to elucidate their role in nicotine addiction. Many of these studies have focused on heteromeric nicotinic acetylcholine receptors containing α4 and β2 subunits and homomeric nicotinic acetylcholine receptors containing the α7 subunit, two of the most abundant subtypes expressed in the brain. Recently however, a series of linkage analyses, candidate-gene analyses and genome-wide association studies have brought attention to three other members of the nicotinic acetylcholine receptor family: the α5, α3 and β4 subunits. The genes encoding these subunits lie in a genomic cluster that contains variants associated with increased risk for several diseases including nicotine dependence and lung cancer. The underlying mechanisms for these associations have not yet been elucidated but decades of research on the nicotinic receptor gene family as well as emerging data provide insight on how these receptors may function in pathological states. Here, we review this body of work, focusing on the clustered nicotinic acetylcholine receptor genes and evaluating their role in nicotine addiction and lung cancer. PMID:20685379

  4. 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...

  5. 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

  6. Nicotine decreases the activity of glutamate transporter type 3.

    PubMed

    Yoon, Hea-Jo; Lim, Young-Jin; Zuo, Zhiyi; Hur, Wonseok; Do, Sang-Hwan

    2014-02-10

    Nicotine, the main ingredient of tobacco, elicits seizures in animal models and cigarette smoking is regarded as a behavioral risk factor associated with epilepsy or seizures. In the hippocampus, the origin of nicotine-induced seizures, most glutamate uptake could be performed primarily by excitatory amino acid transporter type 3 (EAAT3). An association between temporal lobe epilepsy and EAAT3 downregulation has been reported. Therefore, we hypothesized that nicotine may elicit seizures through the attenuation of EAAT3 activity. We investigated chronic nicotine exposure (72 h) cause reduction of the activity of EAAT3 in a Xenopus oocyte expression system using a two-electrode voltage clamp. The roles of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) were also determined. Nicotine (0.001-1 μM) resulted in a time- and dose-dependent decrease in EAAT3 activity with maximal inhibition at nicotine concentrations of 0.03 μM or higher and at an exposure time of 72 h. Vmax on the glutamate response was significantly reduced in the nicotine group (0.03 μM for 72 h), but the Km value of EAAT3 for glutamate was not altered. When nicotine-exposed oocytes (0.03 μM for 72 h) were pretreated with phorbol-12-myristate-13-acetate (PMA, a PKC activator), the nicotine-induced reduction in EAAT3 activity was abolished. PKC inhibitors (staurosporine, chelerythrine, and calphostin C) significantly reduced basal EAAT3 activity, but there were no significant differences among the PKC inhibitors, nicotine, and PKC inhibitors+nicotine groups. Similar response patterns were observed among PI3K inhibitors (wortmannin and LY294002), nicotine, and PI3K inhibitors+nicotine. In conclusion, this study suggests that nicotine decreases EAAT3 activity, and that this inhibition seems to be dependent on PKC and PI3K. Our results may provide an additional mechanism for nicotine-induced seizure.

  7. 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.

  8. Adolescent nicotine induces persisting changes in development of neural connectivity.

    PubMed

    Smith, Robert F; McDonald, Craig G; Bergstrom, Hadley C; Ehlinger, Daniel G; Brielmaier, Jennifer M

    2015-08-01

    Adolescent nicotine induces persisting changes in development of neural connectivity. A large number of brain changes occur during adolescence as the CNS matures. These changes suggest that the adolescent brain may still be susceptible to developmental alterations by substances which impact its growth. Here we review recent studies on adolescent nicotine which show that the adolescent brain is differentially sensitive to nicotine-induced alterations in dendritic elaboration, in several brain areas associated with processing reinforcement and emotion, specifically including nucleus accumbens, medial prefrontal cortex, basolateral amygdala, bed nucleus of the stria terminalis, and dentate gyrus. Both sensitivity to nicotine, and specific areas responding to nicotine, differ between adolescent and adult rats, and dendritic changes in response to adolescent nicotine persist into adulthood. Areas sensitive to, and not sensitive to, structural remodeling induced by adolescent nicotine suggest that the remodeling generally corresponds to the extended amygdala. Evidence suggests that dendritic remodeling is accompanied by persisting changes in synaptic connectivity. Modeling, electrophysiological, neurochemical, and behavioral data are consistent with the implication of our anatomical studies showing that adolescent nicotine induces persisting changes in neural connectivity. Emerging data thus suggest that early adolescence is a period when nicotine consumption, presumably mediated by nicotine-elicited changes in patterns of synaptic activity, can sculpt late brain development, with consequent effects on synaptic interconnection patterns and behavior regulation. Adolescent nicotine may induce a more addiction-prone phenotype, and the structures altered by nicotine also subserve some emotional and cognitive functions, which may also be altered. We suggest that dendritic elaboration and associated changes are mediated by activity-dependent synaptogenesis, acting in part

  9. Nicotine facilitates memory consolidation in perceptual learning.

    PubMed

    Beer, Anton L; Vartak, Devavrat; Greenlee, Mark W

    2013-01-01

    Perceptual learning is a special type of non-declarative learning that involves experience-dependent plasticity in sensory cortices. The cholinergic system is known to modulate declarative learning. In particular, reduced levels or efficacy of the neurotransmitter acetylcholine were found to facilitate declarative memory consolidation. However, little is known about the role of the cholinergic system in memory consolidation of non-declarative learning. Here we compared two groups of non-smoking men who learned a visual texture discrimination task (TDT). One group received chewing tobacco containing nicotine for 1 h directly following the TDT training. The other group received a similar tasting control substance without nicotine. Electroencephalographic recordings during substance consumption showed reduced alpha activity and P300 latencies in the nicotine group compared to the control group. When re-tested on the TDT the following day, both groups responded more accurately and more rapidly than during training. These improvements were specific to the retinal location and orientation of the texture elements of the TDT suggesting that learning involved early visual cortex. A group comparison showed that learning effects were more pronounced in the nicotine group than in the control group. These findings suggest that oral consumption of nicotine enhances the efficacy of nicotinic acetylcholine receptors. Our findings further suggest that enhanced efficacy of the cholinergic system facilitates memory consolidation in perceptual learning (and possibly other types of non-declarative learning). In that regard acetylcholine seems to affect consolidation processes in perceptual learning in a different manner than in declarative learning. Alternatively, our findings might reflect dose-dependent cholinergic modulation of memory consolidation. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

  10. Constitutional mechanisms of vulnerability and resilience to nicotine dependence.

    PubMed

    Hiroi, N; Scott, D

    2009-07-01

    The core nature of nicotine dependence is evident in wide variations in how individuals become and remain smokers. Individuals with pre-existing behavioral traits are more likely to develop nicotine dependence and experience difficulty when attempting to quit. Many molecular factors likely contribute to individual variations in the development of nicotine dependence and behavioral traits in complex manners. However, the identification of such molecules has been hampered by the phenotypic complexity of nicotine dependence and the complex ways molecules affect elements of nicotine dependence. We hypothesize that nicotine dependence is, in part, a result of interactions between nicotine and pre-existing behavioral traits. This perspective suggests that the identification of the molecular bases of such pre-existing behavioral traits will contribute to the development of effective methods for reducing smoking dependence and for helping smokers to quit.

  11. 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.

  12. Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence.

    PubMed

    Castañé, A; Valjent, E; Ledent, C; Parmentier, M; Maldonado, R; Valverde, O

    2002-10-01

    Cannabis is the most widely consumed illicit drug and its consumption is currently associated with tobacco, which contains another psychoactive compound, namely nicotine. Interactions between cannabinoids and other drugs of abuse, such as opioids, have been previously reported. The aim of the present study was to evaluate the possible role of CB1 cannabinoid receptor in responses induced by acute and repeated nicotine administration by using knockout mice lacking the CB1 cannabinoid receptor and their wild-type littermates. Acute nicotine (0.5, 1, 3 and 6 mg/kg, sc) administration decreased locomotor activity and induced antinociceptive responses in the tail-immersion and the hot-plate test, in wild-type animals. The antinociceptive effects in the tail-immersion test were significantly enhanced in CB1 knockout mice. In wild-type mice nicotine (0.5 mg/kg, sc) produced a significant rewarding effect, as measured by a conditioned place preference paradigm. This response was absent in CB1 knockout mice. Finally, a model of mecamylamine-induced abstinence in chronic nicotine-treated mice (10 mg/kg/day, sc) was developed. Mecamylamine (1 and 2 mg/kg, sc) precipitated several somatic signs of nicotine withdrawal in wild-type dependent mice. However, no difference in the severity of nicotine withdrawal was observed in CB1 knockout mice. These results demonstrate that some acute effects and motivational responses elicited by nicotine can be modulated by the endogenous cannabinoid system and support the existence of a physiological interaction between these two systems.

  13. Detoxification and elimination of nicotine by nectar-feeding birds.

    PubMed

    Lerch-Henning, S; Du Rand, E E; Nicolson, S W

    2017-02-01

    Many dilute nectars consumed by bird pollinators contain secondary metabolites, potentially toxic chemicals produced by plants as defences against herbivores. Consequently, nectar-feeding birds are challenged not only by frequent water excess, but also by the toxin content of their diet. High water turnover, however, could be advantageous to nectar consumers by enabling them to excrete secondary metabolites or their transformation products more easily. We investigated how the alkaloid nicotine, naturally present in nectar of Nicotiana species, influences osmoregulation in white-bellied sunbirds Cinnyris talatala and Cape white-eyes Zosterops virens. We also examined the metabolic fate of nicotine in these two species to shed more light on the post-ingestive mechanisms that allow nectar-feeding birds to tolerate nectar nicotine. A high concentration of nicotine (50 µM) decreased cloacal fluid output and increased its osmolality in both species, due to reduced food intake that led to dehydration. White-eyes excreted a higher proportion of the ingested nicotine-containing diet than sunbirds. However, sugar concentration did not affect nicotine detoxification and elimination. Both species metabolised nicotine, excreting very little unchanged nicotine. Cape white-eyes mainly metabolised nicotine through the cotinine metabolic pathway, with norcotinine being the most abundant metabolite in the excreta, while white-bellied sunbirds excreted mainly nornicotine. Both species also utilized phase II conjugation reactions to detoxify nicotine, with Cape white-eyes depending more on the mercapturic acid pathway to detoxify nicotine than white-bellied sunbirds. We found that sunbirds and white-eyes, despite having a similar nicotine tolerance, responded differently and used different nicotine-derived metabolites to excrete nicotine.

  14. Nicotine Induces Podocyte Apoptosis through Increasing Oxidative Stress

    PubMed Central

    Lan, Xiqian; Lederman, Rivka; Eng, Judith M.; Shoshtari, Seyedeh Shadafarin Marashi; Saleem, Moin A.; Malhotra, Ashwani; Singhal, Pravin C.

    2016-01-01

    Background Cigarette smoking plays an important role in the progression of chronic kidney disease (CKD). Nicotine, one of the major components of cigarette smoking, has been demonstrated to increase proliferation of renal mesangial cells. In this study, we examined the effect of nicotine on podocyte injury. Methods To determine the expression of nicotinic acetylcholine receptors (nAChR subunits) in podocytes, cDNAs and cell lysate of cultured human podocytes were used for the expression of nAChR mRNAs and proteins, respectively; and mouse renal cortical sections were subjected to immunofluorescant staining. We also studied the effect of nicotine on podocyte nephrin expression, reactive oxygen species (ROS) generation (via DCFDA loading followed by fluorometric analysis), proliferation, and apoptosis (morphologic assays). We evaluated the effect of nicotine on podocyte downstream signaling including phosphorylation of ERK1/2, JNK, and p38 and established causal relationships by using respective inhibitors. We used nAChR antagonists to confirm the role of nicotine on podocyte injury. Results Human podocytes displayed robust mRNA and protein expression of nAChR in vitro studies. In vivo studies, mice renal cortical sections revealed co-localization of nAChRs along with synaptopodin. In vitro studies, nephrin expression in podocyte was decreased by nicotine. Nicotine stimulated podocyte ROS generation; nonetheless, antioxidants such as N-acetyl cysteine (NAC) and TEMPOL (superoxide dismutase mimetic agent) inhibited this effect of nicotine. Nicotine did not modulate proliferation but promoted apoptosis in podocytes. Nicotine enhanced podocyte phosphorylation of ERK1/2, JNK, and p38, and their specific inhibitors attenuated nicotine-induced apoptosis. nAChR antagonists significantly suppressed the effects of nicotine on podocyte. Conclusions Nicotine induces podocyte apoptosis through ROS generation and associated downstream MAPKs signaling. The present study provides

  15. Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability

    PubMed Central

    Fowler, Christie D.; Kenny, Paul J.

    2013-01-01

    Nicotine stimulates brain reward circuitries, most prominently the mesocorticolimbic dopamine system, and this action is considered critical in establishing and maintaining the tobacco smoking habit. Compounds that attenuate nicotine reward are considered promising therapeutic candidates for tobacco dependence, but many of these agents have other actions that limit their potential utility. Nicotine is also highly noxious, particularly at higher doses, and aversive reactions to nicotine after initial exposure can decrease the likelihood of developing a tobacco habit in many first time smokers. Nevertheless, relatively little is known about the mechanisms of nicotine aversion. The purpose of this review is to present recent new insights into the neurobiological mechanisms that regulate avoidance of nicotine. First, the role of the mesocorticolimbic system, so often associated with nicotine reward, in regulating nicotine aversion is highlighted. Second, genetic variation that modifies noxious responses to nicotine and thereby influences vulnerability to tobacco dependence, in particular variation in the CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptor (nAChR) subunit gene cluster, will be discussed. Third, the role of the habenular complex in nicotine aversion, primarily medial habenular projections to the interpeduncular nucleus (IPN) but also lateral habenular projections to rostromedial tegmental nucleus (RMTg) and ventral tegmental area (VTA) are reviewed. Forth, brain circuits that are enriched in nAChRs, but whose role in nicotine avoidance has not yet been assessed, will be proposed. Finally, the feasibility of developing novel therapeutic agents for tobacco dependence that act not by blocking nicotine reward but by enhancing nicotine avoidance will be considered. PMID:24055497

  16. Stimulus properties of nicotine, amphetamine, and chlordiazepoxide as positive features in a pavlovian appetitive discrimination task in rats.

    PubMed

    Palmatier, Matthew I; Wilkinson, Jamie L; Metschke, Dawn M; Bevins, Rick A

    2005-04-01

    Recent experiments from our laboratory have demonstrated that drug states can signal when environmental cues will be followed by rewarding outcomes (ie Pavlovian conditioning). However, little is known about the generality of this approach and whether it can be used for studying the pharmacological properties of drug states. Accordingly, the present experiments tested the pharmacological specificity of nicotine (0.4 mg/kg), amphetamine (1 mg/kg), and chlordiazepoxide (CDP, 5 mg/kg) in this Pavlovian drug discrimination procedure. Following drug administration, presentation of a conditional stimulus (CS) was followed by brief access to sucrose. When saline was administered, the same CS was presented but sucrose was withheld. In substitution tests, rats in each condition received varying doses of all training drugs and caffeine. Anticipatory food seeking developed during the CS on drug sessions but not on saline sessions for all drug features (ie drug state-specific conditional response (CR)). In generalization tests, this CR decreased as a function of decreases in the training dose. Median effective doses (ED50s) were calculated for nicotine (0.054 mg/kg), amphetamine (0.26 mg/kg), and CDP (2.48 mg/kg). No compound tested substituted for the CDP training drug. Partial substitution was evident between nicotine and amphetamine; CDP did not substitute for either of these drug features. Caffeine fully substituted for nicotine (ED50 = 15.45 mg/kg) and amphetamine (ED50 = 3.70 mg/kg), but not for CDP. These results are consistent with the hypothesis that drug states can occasion appetitive Pavlovian CRs in a pharmacologically specific manner.

  17. Baclofen prevents drug-induced reinstatement of extinguished nicotine-seeking behaviour and nicotine place preference in rodents.

    PubMed

    Fattore, Liana; Spano, Maria Sabrina; Cossu, Gregorio; Scherma, Maria; Fratta, Walter; Fadda, Paola

    2009-07-01

    The gamma-aminobutyric acid(GABA)-B receptor agonist baclofen is known to reduce drug intake in both animals and humans and to prevent reinstatement of cocaine-, opioid-, and alcohol-seeking in rats after a period of extinction, but its effect on nicotine reinstatement is unknown. This study investigated the effect of baclofen on nicotine-seeking reinstatement both using the extinction/reinstatement model of nicotine self-administration and conditioned place preference (CPP). Results showed that in rats previously trained to intravenously self-administer nicotine (30 microg/kg/inf) under a FR-1 schedule of reinforcement, acute nicotine (0.15 mg/kg) priming effectively reinstates nicotine-seeking behaviour following extinction. At doses used in this study (up to 2.5 mg/kg) baclofen alone did not affect locomotor activity and did not reinstate responding. However, baclofen dose-dependently attenuated drug-induced reinstatement of nicotine-seeking in rats. Moreover, baclofen (1.25 mg/kg) completely blocked nicotine-induced reinstatement of extinguished nicotine (0.3 mg/kg) CPP in mice. Altogether, our results showed that baclofen is able to antagonise reinstatement of nicotine-seeking and CPP triggered by nicotine primings, suggesting its potential clinical utility as an anti-relapse agent.

  18. Negative allosteric modulation of nicotinic acetylcholine receptors blocks nicotine self-administration in rats.

    PubMed

    Yoshimura, Ryan F; Hogenkamp, Derk J; Li, Wen Y; Tran, Minhtam B; Belluzzi, James D; Whittemore, Edward R; Leslie, Frances M; Gee, Kelvin W

    2007-12-01

    Drugs that antagonize nicotinic acetylcholine receptors (nAChRs) can be used to inhibit nicotine-induced behavior in both humans and animals. The aim of our experiments is to establish a proof-of-principle that antagonism of nAChRs by negative allosteric modulation can alter behavior in a relevant animal model of addiction, nicotine self-administration. We have identified a novel, negative allosteric modulator of nAChRs, UCI-30002 [N-(1,2,3,4-tetrahydro-1-naphthyl)-4-nitroaniline], with selectivity for the major neuronal nAChR subtypes over muscle-type nAChRs. After systemic administration, UCI-30002 significantly reduces nicotine self-administration in rats on both fixed ratio and progressive ratio schedules of reinforcement. The minimum effective dose that significantly alters nicotine self-administration corresponds to brain concentrations of UCI-30002 that produce at least 30% inhibition of the major neuronal nAChR subtypes measured in vitro. UCI-30002 has no effect on responding for food reinforcement in rats on either type of schedule, indicating that there is no effect on general responding or natural reward. UCI-30002 represents validation of the concept that negative allosteric modulators may have significant benefits as a strategy for treating nicotine addiction and encourages the development of subtype-selective modulators.

  19. Nicotine is highly effective at producing desensitization of rat α4β2 neuronal nicotinic receptors

    PubMed Central

    Paradiso, K G; Steinbach, Joe Henry

    2003-01-01

    We examined desensitization by acetylcholine (ACh) and nicotine at the rat α4β2 neuronal nicotinic receptor stably expressed in HEK cells. For both agonists, the decay in response due to desensitization (‘onset’) was best fitted by the sum of two exponentials with the fast component dominant at concentrations > 1 μm. The time constants for onset were similar for both agonists, and showed little concentration dependence over the range of 0.1–100 μm. Recovery from desensitization also showed two exponential components. In contrast to the similarity in onset, nicotine produced longer lasting desensitization, resulting from an increase in the proportion of receptors in the slowly recovering population and from an increase in the time constant for the slow recovery process. The proportion of receptors in the slowly recovering population increased as the duration of the desensitizing pulse increased. Desensitization was also induced by low concentrations of agonist, with no apparent macroscopic response. A 100 s application of 10 nm nicotine desensitized 70 % of the peak response, while 100 s of 10 nm ACh desensitized only 15 %. At higher concentrations of agonist, which result in a macroscopic response, desensitization in the absence of activation also can occur. Nicotine is a very potent and efficacious desensitizing agent at this neuronal nicotinic receptor. PMID:14555718

  20. Nicotine therapy for ulcerative colitis: a review of rationale, mechanisms, pharmacology, and clinical results.

    PubMed

    Sandborn, W J

    1999-05-01

    Smoking is protective against developing ulcerative colitis. Nicotine may be the cause of this protective effect. Controlled trials have demonstrated efficacy of transdermal nicotine for active ulcerative colitis. Side effects observed with transdermal nicotine include contact dermatitis, nausea, and lightheadedness. Topical administration of nicotine to the colon reduces nicotine blood concentrations and side effects, and may be of clinical benefit.

  1. 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.

  2. 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…

  3. Nicotinic Receptor Polymorphism in Lung Cancer

    DTIC Science & Technology

    2013-10-01

    bronchial cells to the tobacco nitrosamine -induced carcinogenic transformation of human bronchial cells [1-2]. 15. SUBJECT TERMS nicotinic receptor...cells to the tobacco nitrosamine -induced carcinogenic transformation of human bronchial cells [1-2]. Body According to the Statement of Works

  4. 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.

  5. 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.

  6. Structural and Microstructural Study on the Arc-Plasma Synthesized (APS) FeAl2O4-MgAl2O4 Transitional Refractory Compound

    NASA Astrophysics Data System (ADS)

    Jastrzębska, Ilona; Jacek, Szczerba; Paweł, Stoch

    2017-03-01

    In this work, a pleonastic compound, a compound with a composition between hercynite and spinel sensu stricto FeAl2O4-MgAl2O4, was synthesized by a non-conventional method of arc-plasma synthesis (APS). The structure of the obtained spinel compound was characterized by means of X-ray diffraction and Mössbauer effect measurements. The microstructure was observed by applying scanning electron microscope (SEM)/energy dispersive spectrometer (EDS) method. It was found that the arc-plasma synthesized material was characterized by a monophasic character, a low-inversion parameter and a compact microstructure.

  7. 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

  8. Nicotine activates the chemosensory cation channel TRPA1.

    PubMed

    Talavera, Karel; Gees, Maarten; Karashima, Yuji; Meseguer, Víctor M; Vanoirbeek, Jeroen A J; Damann, Nils; Everaerts, Wouter; Benoit, Melissa; Janssens, Annelies; Vennekens, Rudi; Viana, Félix; Nemery, Benoit; Nilius, Bernd; Voets, Thomas

    2009-10-01

    Topical application of nicotine, as used in nicotine replacement therapies, causes irritation of the mucosa and skin. This reaction has been attributed to activation of nicotinic acetylcholine receptors (nAChRs) in chemosensory neurons. In contrast with this view, we found that the chemosensory cation channel transient receptor potential A1 (TRPA1) is crucially involved in nicotine-induced irritation. We found that micromolar concentrations of nicotine activated heterologously expressed mouse and human TRPA1. Nicotine acted in a membrane-delimited manner, stabilizing the open state(s) and destabilizing the closed state(s) of the channel. In the presence of the general nAChR blocker hexamethonium, nociceptive neurons showed nicotine-induced responses that were strongly reduced in TRPA1-deficient mice. Finally, TRPA1 mediated the mouse airway constriction reflex to nasal instillation of nicotine. The identification of TRPA1 as a nicotine target suggests that existing models of nicotine-induced irritation should be revised and may facilitate the development of smoking cessation therapies with less adverse effects.

  9. 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

  10. Transport Mechanism of Nicotine in Primary Cultured Alveolar Epithelial Cells.

    PubMed

    Takano, Mikihisa; Nagahiro, Machi; Yumoto, Ryoko

    2016-02-01

    Nicotine is absorbed from the lungs into the systemic circulation during cigarette smoking. However, there is little information concerning the transport mechanism of nicotine in alveolar epithelial cells. In this study, we characterized the uptake of nicotine in rat primary cultured type II (TII) and transdifferentiated type I-like (TIL) epithelial cells. In both TIL and TII cells, [(3)H]nicotine uptake was time and temperature-dependent, and showed saturation kinetics. [(3)H]Nicotine uptake in these cells was not affected by Na(+), but was sensitive to extracellular and intracellular pH, suggesting the involvement of a nicotine/proton antiport system. The uptake of [(3)H]nicotine in these cells was potently inhibited by organic cations such as clonidine, diphenhydramine, and pyrilamine, but was not affected by substrates and/or inhibitors of known organic cation transporters such as carnitine, 1-methyl-4-phenylpyridinium, and tetraethylammonium. In addition, the uptake of [(3)H]nicotine in TIL cells was stimulated by preloading the cells with unlabeled nicotine, pyrilamine, and diphenhydramine, but not with tetraethylammonium. These results suggest that a novel proton-coupled antiporter is involved in the uptake of nicotine in alveolar epithelial cells and its absorption from the lungs into the systemic circulation.

  11. Nicotine depresses the functions of multiple cardiac potassium channels.

    PubMed

    Wang, H; Shi, H; Wang, Z

    1999-01-01

    Nicotine is the main constituent of tobacco smoke responsible for the elevated risk of the cardiovascular disease and sudden coronary death associated with smoking, presumably by provoking cardiac arrhythmias. The cellular mechanisms may be related to the ability of nicotine to prolong action potentials and to depolarize membrane potential. However, the underlying ionic mechanisms remained unknown. We showed here that nicotine blocked multiple types of K+ currents, including the native currents in canine ventricular myocytes and the cloned channels expressed in Xenopus oocytes: A-type K+ currents (I(to)/Kv4.3), delayed rectifier K+ currents (I(Kr)/HERG) and inward rectifier K+ currents (I(K1)/Kir2.1). Most noticeably, nicotine at a concentration as low as of 10 nM significantly suppressed I(to) and Kv4.3 by approximately 20%. The effects of nicotine were independent of nicotinic receptor simulation or catecholamine release. Our results indicate that nicotine is a non-specific blocker of K+ channels and the inhibitory effects are the consequence of direct interactions between nicotine molecules and the channel proteins. Our study provided for the first time the evidence for the direct inhibition of cardiac K+ channels by nicotine and established a novel aspect of nicotine pharmacology.

  12. Nicotine enhances contextual fear memory reconsolidation in rats.

    PubMed

    Tian, Shaowen; Huang, Fulian; Li, Peng; Li, Zhenbang; Zhou, Shouhong; Deng, Haifeng; Yang, Yufeng

    2011-01-10

    There is increasing evidence that nicotine is involved in learning and memory. However, there remains no study that has explored the relationship between nicotine and memory reconsolidation. At present study, we tested the effects of nicotine on the reconsolidation of contextual fear memory in rats. Behavior procedure involved four training phases: habituation (Day 0), fear conditioning (Day 1), reactivation (Day 2) and test (Day 3). Rats were injected saline or nicotine (0.25, 0.5 and 1.0mg/kg) immediately after reactivation. Percent of time spent freezing was used to measure conditioned fear response. Results showed that compared with saline rats, rats with nicotine at 1.0mg/kg presented a significant increase of freezing response on Day 3. Nicotine at 1.0mg/kg was ineffective when injected 6h after reactivation. Further results showed that the enhancement of freezing response induced by nicotine at 1.0mg/kg was dependent on fear memory reconsolidation, and was not attributed to an enhancement of the nonspecific freezing response 24h after nicotine administration. The results suggest that nicotine administration immediately after reactivation enhances contextual fear memory reconsolidation. Our present finding extends previous research on the nicotinic effects on learning and memory.

  13. 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.

  14. 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.

  15. The Sensory Impact of Nicotine on Noradrenergic and Dopaminergic Neurons of the Nicotine Reward - Addiction Neurocircuitry.

    PubMed

    Rose, Jed E; Dehkordi, Ozra; Manaye, Kebreten F; Millis, Richard M; Cianaki, Salman Ameri; Jayam-Trouth, Annapurni

    2016-04-01

    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.

  16. Surveillance of smokeless tobacco nicotine, pH, moisture, and unprotonated nicotine content.

    PubMed

    Richter, Patricia; Spierto, Francis W

    2003-12-01

    Smokeless tobacco is a complex chemical mixture, including not only the components of the tobacco leaf but also chemicals added during the manufacturing process. Smokeless tobacco contains the addictive chemical nicotine and more than 20 cancer-causing chemicals, including the potent tobacco-specific nitrosamines. The National Toxicology Program of the National Institutes of Health has concluded that oral use of smokeless tobacco is a human carcinogen. Therefore, smokeless tobacco is not a safe alternative to cigarettes. In fact, smokeless tobacco use begins primarily during early adolescence and can lead to nicotine dependence and increased risk of becoming a cigarette smoker. Under the Comprehensive Smokeless Tobacco Health Education Act of 1986 (15 U.S.C. 4401 et seq., Pub. L. 99-252), tobacco manufacturers report annually to the Centers for Disease Control and Prevention (CDC) on the total nicotine, unprotonated nicotine, pH, and moisture content of their smokeless tobacco products. This information is considered "trade secret," or confidential, in accordance with 5 U.S.C. 552(b)(4) and 18 U.S.C. 1905 and cannot be released to the public. In an effort to provide consumers and researchers with information on the nicotine content of smokeless tobacco, CDC arranged for the analysis of popular brands of smokeless tobacco. The results of this CDC study show that pH is a primary factor in the amount of nicotine that is in the most readily absorbable, unprotonated form. Furthermore, this study found that the brands of moist snuff smokeless tobacco with the largest amount of unprotonated nicotine also are the most frequently sold brands.

  17. 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.

  18. Effect of CeH2.29 on the microstructures and hydrogen properties of LiBH4-Mg2NiH4 composites

    NASA Astrophysics Data System (ADS)

    Zhao, Xin; Han, Shu-min; Li, Yuan; Chen, Xiao-cui; Ke, Dan-dan

    2015-04-01

    A composite of LiBH4-Mg2NiH4 doped with 10wt% CeH2.29 was prepared by ball milling followed by dynamic interspace vacuum treatment at 573 K. The introduction of CeH2.29 caused a transformation in the morphology of Mg from complex spongy and lamellar to uniformly spongy, resulting in refined particle size and abundant H diffusion pathways. This LiBH4-Mg2NiH4 + 10wt% CeH2.29 composite exhibited excellent hydrogen storage properties. The starting temperature of rapid H absorption decreased to 375 K in the doped composite from 452 K for the unmodified material, and the onset decomposition temperature of its hydride was reduced from 536 K to 517 K. In addition, the time required for a hydrogen release of 1.5wt% (at 598 K) was 87 s less than that of the un-doped composite.

  19. Building of CoFe2/CoFe2O4/MgO architectures: Structure, magnetism and surface functionalized by TiO2

    NASA Astrophysics Data System (ADS)

    Wang, M.; Ma, Y. Q.; Sun, X.; Geng, B. Q.; Wu, M. Z.; Zheng, G. H.; Dai, Z. X.

    2017-01-01

    Well-dispersed uniform CoFe2O4 nanoparticles were prepared and then coated by MgO through thermal decomposition of a metal-organic salt in organic solvent. Then CoFe2O4/MgO were reduced in a H2/N2 mixture gas and subsequently oxidized in an ambient atmosphere in order to build CoFe2/CoFe2O4/MgO architectures with high magnetization, good chemical stability and dispersivity, which are useful in some practical applications. MgO can be dissolved by the HCl solution. The surfaces of CoFe2O4, CoFe2/MgO, CoFe2 and CoFe2/CoFe2O4 magnetic particles were functionalized by TiO2 to prepare the magnetically separable photocatalysts. The rattle-type particles were obtained without the assistance of template and etchant. The photocatalytic activity of these photocatalysts in degradation of methylene blue and the magnetic separability were investigated: The nanosheet-shaped TiO2 and rattle-type particles exhibited good photocatalytic performance; The highest degradation efficiency reaches 93% for the CoFe2/TiO2 sample which has the highest magnetization value of 42 emu/g, beneficial for the recovery of catalyst after degradation.

  20. Crystal structure and vibrational spectra of tetrasodium dimagnesium dihydrogen diphosphate octahydrate Na 4Mg 2(H 2P 2O 7) 4·8H 2O

    NASA Astrophysics Data System (ADS)

    Harcharras, M.; Ennaciri, A.; Assaaoudi, H.; Mattei, G.; D'Orazio, V.; Moliterni, A. G. G.; Capitelli, F.

    2003-04-01

    A tetrasodium dimagnesium dihydrogen diphosphate octahydrate Na 4Mg 2(H 2P 2O 7) 4·8H 2O was synthesized. It crystallizes in the monoclinic system, space group P2 1/ m (no. 11), Z=4, and its unit-cell parameters are: a=8.0445(3) Å, b=11.5244(5) Å, c=9.0825(4) Å, β=113.1401(2)°, V=774.28(6) Å 3. The structure was determined by single-crystal X-ray diffractometry and refined to a R index of 0.0294 (w R=0.0727) for 1878 independent reflections with I>2 σ( I). The framework is made by the alternance of layers of MgO 6/NaO 6 octahedra and double tetrahedra PO 4 along b-axis. Such layers are characterized by the presence of strong hydrogen bonds. (H 2P 2O 7) 2- anions exhibit bent eclipsed conformation. Besides, the crystal was analyzed by FT-IR and micro-Raman vibrational spectroscopy. No coincidences of the majority of the Raman and infrared spectra bands of Na 4Mg 2(H 2P 2O 7) 4·8H 2O confirms a centrosymmetric structure of this material. The vibrational spectra confirm the bent POP configuration in this compound.

  1. 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.

  2. 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.

  3. Neonatal nicotine exposure increases excitatory synaptic transmission and attenuates nicotine-stimulated GABA release in the adult rat hippocampus.

    PubMed

    Damborsky, Joanne C; Griffith, William H; Winzer-Serhan, Ursula H

    2015-01-01

    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.

  4. 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.

  5. Nicotine reward and affective nicotine withdrawal signs are attenuated in calcium/calmodulin-dependent protein kinase IV knockout mice.

    PubMed

    Jackson, Kia J; Sanjakdar, Sarah S; Chen, Xiangning; Damaj, M Imad

    2012-01-01

    The influx of Ca(2+) through calcium-permeable nicotinic acetylcholine receptors (nAChRs) leads to activation of various downstream processes that may be relevant to nicotine-mediated behaviors. The calcium activated protein, calcium/calmodulin-dependent protein kinase IV (CaMKIV) phosphorylates the downstream transcription factor cyclic AMP response element binding protein (CREB), which mediates nicotine responses; however the role of CaMKIV in nicotine dependence is unknown. Given the proposed role of CaMKIV in CREB activation, we hypothesized that CaMKIV might be a crucial molecular component in the development of nicotine dependence. Using male CaMKIV genetically modified mice, we found that nicotine reward is attenuated in CaMKIV knockout (-/-) mice, but cocaine reward is enhanced in these mice. CaMKIV protein levels were also increased in the nucleus accumbens of C57Bl/6 mice after nicotine reward. In a nicotine withdrawal assessment, anxiety-related behavior, but not somatic signs or the hyperalgesia response are attenuated in CaMKIV -/- mice. To complement our animal studies, we also conducted a human genetic association analysis and found that variants in the CaMKIV gene are associated with a protective effect against nicotine dependence. Taken together, our results support an important role for CaMKIV in nicotine reward, and suggest that CaMKIV has opposing roles in nicotine and cocaine reward. Further, CaMKIV mediates affective, but not physical nicotine withdrawal signs, and has a protective effect against nicotine dependence in human genetic association studies. These findings further indicate the importance of calcium-dependent mechanisms in mediating behaviors associated with drugs of abuse.

  6. 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

  7. Acute nicotine poisoning associated with a traditional remedy for eczema

    PubMed Central

    Davies, P; Levy, S; Pahari, A; Martinez, D

    2001-01-01

    We present a case of severe acute nicotine poisoning in an 8 year old boy with moderate eczema after topical application of a traditional remedy from a book published in Bangladesh. Symptoms consistent with nicotine poisoning developed within 30 minutes of application of the remedy. The child subsequently improved with supportive care and was discharged after five days with no neurological sequelae. Diagnosis of nicotine poisoning was not initially made due to difficulty in obtaining an accurate history via an interpreter from the parents who did not speak English. Samples taken 12 hours after application of the remedy showed a serum nicotine of 89 µg/l, serum cotinine of 1430 µg/l, urine nicotine of 1120 µg/l, and a urine cotinine of 6960 µg/l confirming acute nicotine poisoning.

 PMID:11719343

  8. 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.

  9. 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.

  10. Neuronal nicotinic acetylcholine receptors: neuroplastic changes underlying alcohol and nicotine addictions

    PubMed Central

    Feduccia, Allison A.; Chatterjee, Susmita; Bartlett, Selena E.

    2012-01-01

    Addictive drugs can activate systems involved in normal reward-related learning, creating long-lasting memories of the drug's reinforcing effects and the environmental cues surrounding the experience. These memories significantly contribute to the maintenance of compulsive drug use as well as cue-induced relapse which can occur even after long periods of abstinence. Synaptic plasticity is thought to be a prominent molecular mechanism underlying drug-induced learning and memories. Ethanol and nicotine are both widely abused drugs that share a common molecular target in the brain, the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are ligand-gated ion channels that are vastly distributed throughout the brain and play a key role in synaptic neurotransmission. In this review, we will delineate the role of nAChRs in the development of ethanol and nicotine addiction. We will characterize both ethanol and nicotine's effects on nAChR-mediated synaptic transmission and plasticity in several key brain areas that are important for addiction. Finally, we will discuss some of the behavioral outcomes of drug-induced synaptic plasticity in animal models. An understanding of the molecular and cellular changes that occur following administration of ethanol and nicotine will lead to better therapeutic strategies. PMID:22876217

  11. Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation.

    PubMed

    Nakajima, Miki; Yokoi, Tsuyoshi

    2005-08-01

    Nicotine has roles in the addiction to smoking, replacement therapy for smoking cessation, as a potential medication for several diseases such as Parkinson's disease, Alzheimer's disease, and ulcerative colitis. The absorbed nicotine is rapidly and extensively metabolized and eliminated to urine. A major pathway of nicotine metabolism is C-oxidation to cotinine, which is catalyzed by CYP2A6 in human livers. Cotinine is subsequently metabolized to trans-3'-hydroxycotinine by CYP2A6. Nicotine and cotinine are glucuronidated to N-glucuronides mainly by UGT1A4 and partly by UGT1A9. Trans-3'-hydroxycotinine is glucuronidated to O-glucuronide mainly by UGT2B7 and partly by UGT1A9. Approximately 90% of the total nicotine uptake is eliminated as these metabolites and nicotine itself. The nicotine metabolism is an important determinant of the clearance of nicotine. Recently, advances in the understanding of the interindividual variability in nicotine metabolism have been made. There are substantial data suggesting that the large interindividual differences in cotinine formation are associated with genetic polymorphisms of the CYP2A6 gene. Interethnic differences have also been observed in the cotinine formation and the allele frequencies of the CYP2A6 alleles. Since the genetic polymorphisms of the CYP2A6 gene have a major impact on nicotine clearance, its relationships with smoking behavior or the risk of lung cancer have been suggested. The metabolic pathways of the glucuronidation of nicotine, cotinine, and trans-3'-hydroxycotinine in humans would be one of the causal factors for the interindividual differences in nicotine metabolism. This review mainly summarizes recent results from our studies.

  12. Nicotine exposure and decontamination on tobacco harvesters' hands.

    PubMed

    Curwin, Brian D; Hein, Misty J; Sanderson, Wayne T; Nishioka, Marcia G; Buhler, Wayne

    2005-07-01

    Green tobacco sickness is an illness associated with nicotine exposures among tobacco harvesters. Agricultural workers manually harvest tobacco and thus have the potential for skin exposure to nicotine, particularly on the hands. Often gloves are not worn as it hinders the harvesters' ability to harvest the tobacco leaves. The purposes of this study were to measure the concentration of nicotine residue on the hands of tobacco harvesters and the effectiveness of hand washing at removing the residue. Wipe samples from the hands of 12 tobacco harvesters were collected at the end of morning and afternoon work periods over two consecutive days. Each harvester had one hand wiped before washing his hands, and the other hand wiped after washing his hands with soap and water. Eight samples per worker were collected over the two days for a total of 96 samples collected. In addition to the hand-wipe samples, leaf-wipe samples were collected from 15 tobacco plants to estimate the amount of nicotine residue on the plants. The average nicotine level in leaf-wipe samples was 1.0 microg cm(-2). The geometric mean pre-wash and post-wash nicotine levels on the hands were 10 and 0.38 microg cm(-2), respectively. Nicotine leaf-wipe level, right or left hand and time of sampling did not significantly influence exposure. Job position-working on the bottom versus the top of the tobacco harvesting machine-was associated with nicotine levels. Pre-wash nicotine levels were higher for workers on the bottom of the harvester but not significantly higher (P = 0.17). Post-wash nicotine levels were significantly higher for workers on the bottom of the harvester (P = 0.012). A substantial amount of nicotine was transferred to the hands, but washing with soap and water in the field significantly reduced nicotine levels by an average of 96% (P < 0.0001).

  13. Degradation of Nicotine in Chlorinated Water: Pathways and ...

    EPA Pesticide Factsheets

    Report The objective of the study is to illustrate how drinking water would affect alkaloid pesticides, and to address the issue by (a) investigating the fate of nicotine in chlorinated drinking water and deionized water, (b) determining the reaction rate and pathway of the reaction between nicotine and aqueous chlorine, (c) identifying nicotine’s degradation products, and (d) providing data that can be used to assess the potential threat from nicotine in drinking water.

  14. Cellular basis for the olfactory response to nicotine.

    PubMed

    Bryant, Bruce; Xu, Jiang; Audige, Valery; Lischka, Fritz W; Rawson, Nancy E

    2010-03-17

    Smokers regulate their smoking behavior on the basis of sensory stimuli independently of the pharmacological effects of nicotine (Rose J. E., et al. (1993) Pharmacol., Biochem. Behav.44 (4), 891-900). A better understanding of sensory mechanisms underlying smoking behavior may help to develop more effective smoking alternatives. Olfactory stimulation by nicotine makes up a considerable part of the flavor of tobacco smoke, yet our understanding of the cellular mechanisms responsible for olfactory detection of nicotine remains incomplete. We used biophysical methods to characterize the nicotine sensitivity and response mechanisms of neurons from olfactory epithelium. In view of substantial differences in the olfactory receptor repertoire between rodent and human (Mombaerts P. (1999) Annu. Rev. Neurosci.22, 487-509), we studied biopsied human olfactory sensory neurons (OSNs), cultured human olfactory cells (Gomez G., et al. (2000) J. Neurosci. Res.62 (5), 737-749), and rat olfactory neurons. Rat and human OSNs responded to S(-)-nicotine with a concentration dependent influx of calcium and activation of adenylate cyclase. Some rat OSNs displayed some stereoselectivity, with neurons responding to either enantiomer alone or to both. Freshly biopsied and primary cultured human olfactory neurons were less stereoselective. Nicotinic cholinergic antagonists had no effect on the responses of rat or human OSNs to nicotine. Patch clamp recording of rat OSNs revealed a nicotine-activated, calcium-sensitive nonspecific cation channel. These results indicate that nicotine activates a canonical olfactory receptor pathway rather than nicotinic cholinergic receptors on OSNs. Further, because the nicotine-sensitive mechanisms of rodents appear generally similar to those of humans, this animal model is an appropriate one for studies of nicotine sensation.

  15. Effects of the serotonin 5-HT2A and 5-HT2C receptor ligands on the discriminative stimulus effects of nicotine in rats.

    PubMed

    Zaniewska, Magdalena; McCreary, Andrew C; Przegaliński, Edmund; Filip, Malgorzata

    2007-10-01

    The present study tested the hypothesis that serotonergic (5-HT) 5-HT2A or 5-HT2C receptors or their pharmacological stimulation modulated the discriminative stimulus effects of nicotine in male Wistar rats. To this end the selective 5-HT2A receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (M100,907; 0.5-1 mg/kg, i.p.), the functional 5-HT2A receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI; 0.1-1 mg/kg, s.c.), the selective 5-HT2C receptor antagonist 6-chloro-5-methyl-1-{[2-(2-methylpyrid-3-yloxy)pyrid-5-yl]carbamoyl}indoline (SB 242,084; 0.25-1 mg/kg, i.p.) and the 5-HT2C receptor agonists (S)-2-chloro-5-fluoro-indol-1-yl)-1-methylethylamine fumarate (Ro 60-0175; 0.3-1 mg/kg, s.c.) and (7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole (WAY 163,909; 0.75-1.5 mg/kg, i.p.) were used. Additionally, the effects of the selective alpha4beta2 nicotinic acetylcholine receptor subtype agonist 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-IA; 0.01 mg/kg, s.c.) were investigated. In rats trained to discriminate (-)-nicotine (0.4 mg/kg, s.c.) from saline in a two-lever, water-reinforced fixed ratio 10 task, substitutions were not observed with 5-HT2 receptor ligands (<32% nicotine-lever responding), conversely 5-IA induced a full substitution (100% nicotine-lever responding). In combination studies, fixed doses of M100,907 (0.5-1 mg/kg) or SB 242,084 (0.25-1 mg/kg) did not alter the dose-response curve of nicotine, while DOI (0.3 mg/kg), Ro 60-0175 (1 mg/kg) and WAY 163,909 (1 and 1.5 mg/kg) attenuated the discriminative stimulus effects of nicotine. The decrease in the expression of the discriminative stimulus effects of nicotine produced by DOI was blocked by M100,907 (1 mg/kg), but not by SB 242,084 (1 mg/kg), while that evoked by Ro 60-0175 or WAY 163,909 was blocked by SB 242,084 (1 mg/kg), but not by M100,907 (1 mg/kg). Further studies showed that

  16. Unraveling the neurobiology of nicotine dependence using genetically engineered mice.

    PubMed

    Stoker, Astrid K; Markou, Athina

    2013-08-01

    This review article provides an overview of recent studies of nicotine dependence and withdrawal that used genetically engineered mice. Major progress has been made in recent years with mutant mice that have knockout and gain-of-function of specific neuronal nicotinic acetylcholine receptor (nAChR) subunit genes. Nicotine exerts its actions by binding to neuronal nAChRs that consist of five subunits. The different nAChR subunits that combine to compose a receptor determine the distinct pharmacological and kinetic properties of the specific nAChR. Recent findings in genetically engineered mice have indicated that while α4-containing and β2-containing nAChRs are involved in the acquisition of nicotine self-administration and initial stages of nicotine dependence, α7 homomeric nAChRs appear to be involved in the later stages of nicotine dependence. In the medial habenula, α5-containing, α3-containing, and β4-containing nAChRs were shown to be crucially important in the regulation of the aversive aspects of nicotine. Studies of the involvement of α6 nAChR subunits in nicotine dependence have only recently emerged. The use of genetically engineered mice continues to vastly improve our understanding of the neurobiology of nicotine dependence and withdrawal.

  17. Nicotine alters bovine oocyte meiosis and affects subsequent embryonic development.

    PubMed

    Liu, Ying; Li, Guang-Peng; White, Kenneth L; Rickords, Lee F; Sessions, Benjamin R; Aston, Kenneth I; Bunch, Thomas D

    2007-11-01

    The effects of nicotine on nuclear maturation and meiotic spindle dynamics of bovine oocytes and subsequent embryonic development were investigated. Maturation rates (85%-94%) derived from nicotine treatments at 0.01 to 1.0 mM were similar to the control (86%), but significantly decreased at 2.0 to 6.0 mM. Haploid complements of metaphase II oocytes in 0.01 to 1.0 mM nicotine (approximately 90%) were similar to the control, while lower (ranged from 63% to 76%, P < 0.05 or P < 0.01) haploid oocytes were observed in the 2.0 to 6.0 mM nicotine groups. The majority of the PB1-free oocytes derived from 3.0 to 6.0 mM nicotine treatments were diploidy (2n = 60). Spindle microtubules changed from characteristically being asymmetrical in the controls to being equally distributed into two separate chromosome groups in the nicotine treatments. Nicotine disorganized the microfilament organization and inhibited the movement of anaphase or telophase chromosomes to the cortical area. The inhibited two chromosome groups became two spindles that either moved close in proximity or merged entirely together resulting in diploidy within the affected oocyte. Nicotine treatment significantly reduced the rate of cleavage and blastocyst development after parthenogenetic activation. Diploidy and cell number were drastically reduced in the resultant blastocysts. In conclusion, nicotine can alter the normal process of bovine oocyte meiosis and affects subsequent embryonic development.

  18. 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.

  19. Neural Systems Governed by Nicotinic Acetylcholine Receptors: Emerging Hypotheses

    PubMed Central

    Miwa, Julie M.; Freedman, Robert; Lester, Henry A.

    2015-01-01

    Cholinergic neurons and nicotinic acetylcholine receptors (nAChRs) in the brain participate in diverse functions: reward, learning and memory, mood, sensory processing, pain, and neuroprotection. Nicotinic systems also have well-known roles in drug abuse. Here, we review recent insights into nicotinic function, linking exogenous and endogenous manipulations of nAChRs to alterations in synapses, circuits, and behavior. We also discuss how these contemporary advances can motivate attempts to exploit nicotinic systems therapeutically in Parkinson’s disease, cognitive decline, epilepsy, and schizophrenia. PMID:21482353

  20. 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

  1. 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.

  2. 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

  3. Neuronal Nicotinic Acetylcholine Receptors and Epilepsy

    PubMed Central

    Bertrand, Daniel

    2002-01-01

    The identification of a genetically transmissible form of epilepsy that is associated with a mutation in CHRNA4, the gene that encodes the α4 subunit of the high-affinity nicotinic acetylcholine receptor, was the first demonstration that an alteration in a ligand-gated ion channel can cause seizures. Since then, nine mutations have been found, and analysis of their physiologic properties has revealed that all of them enhance receptor function. PMID:15309115

  4. Nicotine Effects on the Impact of Stress

    DTIC Science & Technology

    2014-09-01

    ingested by Soldiers via smoking or chewing tobacco) affects vulnerability to develop post-traumatic stress disorder (PTSD). We have completed studies in...related illnesses such as post- traumatic stress disorder (PTSD). It is known, however, that people with PTSD are more likely to smoke when experiencing...AWARD NUMBER: W81XWH-12-1-0454 TITLE: Nicotine Effects on the Impact of Stress PRINCIPAL

  5. 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... of water and thoroughly mixed. Fifty ml of this colored solution is compared, using Nessler tubes, with 50 ml of a standard color solution containing 5 grams of CuSO4·5H2 O, C.P. in 100 ml of water....

  6. Lack of effect of menthol level and type on smokers' estimated mouth level exposures to tar and nicotine and perceived sensory characteristics of cigarette smoke.

    PubMed

    Ashley, Madeleine; Dixon, Mike; Sisodiya, Ajit; Prasad, Krishna

    2012-08-01

    Menthol can reduce sensory irritation and it has been hypothesised that this could result in smokers of mentholated cigarettes taking larger puffs and deeper post-puff inhalations thereby obtaining higher exposures to smoke constituents than smokers of non-mentholated cigarettes. The aim of our study was to use part-filter analysis methodology to assess the effects of cigarette menthol loading on regular and occasional smokers of mentholated cigarettes. We measured mouth level exposure to tar and nicotine and investigated the effects of mentholation on smokers' sensory perceptions such as cooling and irritation. Test cigarettes were produced containing no menthol and different loadings of synthetic and natural l-menthol at 1 and 4mg ISO tar yields. A target of 100 smokers of menthol cigarettes and 100 smokers who predominantly smoked non-menthol cigarettes from both 1 and 4mg ISO tar yield categories were recruited in Poland and Japan. Each subject was required to smoke the test cigarette types of their usual ISO tar yield. There were positive relationships between menthol loading and the perceived 'strength of menthol taste' and 'cooling' effect. However, we did not see marked menthol-induced reductions in perceived irritation or menthol-induced increases in mouth level exposure to tar and nicotine.

  7. 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.

  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. Activation and desensitization of nicotinic alpha7-type acetylcholine receptors by benzylidene anabaseines and nicotine.

    PubMed

    Papke, Roger L; Kem, William R; Soti, Ferenc; López-Hernández, Gretchen Y; Horenstein, Nicole A

    2009-05-01

    Nicotinic receptor activation is inextricably linked to desensitization. This duality affects our ability to develop useful therapeutics targeting nicotinic acetylcholine receptor (nAChR). Nicotine and some alpha7-selective experimental partial agonists produce a transient activation of alpha7 receptors followed by a period of prolonged residual inhibition or desensitization (RID). The object of the present study was to determine whether RID was primarily due to prolonged desensitization or due to channel block. To make this determination, we used agents that varied significantly in their production of RID and two alpha7-selective positive allosteric modulators (PAMs): 5-hydroxyindole (5HI), a type 1 PAM that does not prevent desensitization; and 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxanol-3-yl)-urea (PNU-120596), a type 2 PAM that reactivates desensitized receptors. The RID-producing compounds nicotine and 3-(2,4-dimethoxybenzylidene)anabaseine (diMeOBA) could obscure the potentiating effects of 5HI. However, through the use of nicotine, diMeOBA, and the RID-negative compound 3-(2,4-dihydroxybenzylidene)anabaseine (diOHBA) in combination with PNU-120596, we confirmed that diMeOBA produces short-lived channel block of alpha7 but that RID is because of the induction of a desensitized state that is stable in the absence of PNU-120596 and activated in the presence of PNU-120596. In contrast, diOHBA produced channel block but only readily reversible desensitization, whereas nicotine produced desensitization that could be converted into activation by PNU-120596 but no demonstrable channel block. Steady-state currents through receptors that would otherwise be desensitized could also be produced by the application of PNU-120596 in the presence of a physiologically relevant concentration of choline (60 microM), which may be significant for the therapeutic development of type 2 PAMs.

  10. Activation of Peripheral κ-Opioid Receptors Normalizes Caffeine Effects Modified in Nicotine-Dependent Rats during Nicotine Withdrawal.

    PubMed

    Sudakov, S K; Bogdanova, N G

    2016-10-01

    The study examined the effect of peripheral (intragastric) ICI-204,448, an agonist of gastric κ-opioid receptors, on the psychostimulating and anxiolytic effects of caffeine in nicotinedependent rats at the stage of nicotine withdrawal. In these rats, the effects of caffeine (10 mg/kg) were perverted. In nicotine-dependent rats, caffeine produced an anxiolytic effect accompanied by pronounced stimulation of motor activity, in contrast to anxiogenic effect induced by caffeine in intact rats without nicotine dependence. During nicotine withdrawal, nicotine-dependent rats demonstrated enhanced sensitivity to nicotine. Intragastric administration of κ-opioid receptor agonist ICI-204,448 normalized the effect of caffeine in nicotinedependent rats. We have previously demonstrated that activation of peripheral κ-opioid receptors inhibited central κ-opioid activity and eliminated manifestations of nicotine withdrawal syndrome in nicotine-dependent rats, e.g. metabolism activation, stimulation of motor activity, and enhancement of food consumption. In its turn, inhibition of central κ-opioid structures activates the brain adenosine system, which can attenuate the caffeine-induced effects in nicotine-dependent rats.

  11. 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.

  12. 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

  13. Differential effects of nicotine treatment and ethanol self-administration on CYP2A6, CYP2B6 and nicotine pharmacokinetics in African green monkeys.

    PubMed

    Ferguson, C S; Miksys, S; Palmour, R M; Tyndale, R F

    2012-12-01

    In primates, nicotine is metabolically inactivated in the liver by CYP2A6 and possibly CYP2B6. Changes in the levels of these two enzymes may affect nicotine pharmacokinetics and influence smoking behaviors. This study investigated the independent and combined effects of ethanol self-administration and nicotine treatment (0.5 mg/kg b.i.d. s.c.) on hepatic CYP2A6 and CYP2B6 levels (mRNA, protein, and enzymatic activity), in vitro nicotine metabolism, and in vivo nicotine pharmacokinetics in monkeys. CYP2A6 mRNA and protein levels and in vitro coumarin (selective CYP2A6 substrate) and nicotine metabolism were decreased by nicotine treatment but unaffected by ethanol. CYP2B6 protein levels and in vitro bupropion (selective CYP2B6 substrate) metabolism were increased by ethanol but unaffected by nicotine treatment; CYP2B6 mRNA levels were unaltered by either treatment. Combined ethanol and nicotine exposure decreased CYP2A6 mRNA and protein levels, as well as in vitro coumarin and nicotine metabolism, and increased CYP2B6 protein levels and in vitro bupropion metabolism, with no change in CYP2B6 mRNA levels. Chronic nicotine resulted in higher nicotine plasma levels achieved after nicotine administration, consistent with decreased CYP2A6. Ethanol alone, or combined with nicotine, resulted in lower nicotine plasma levels by a mechanism independent of the change in these enzymes. Thus, nicotine can decrease hepatic CYP2A6, reducing the metabolism of its substrates, including nicotine, whereas ethanol can increase hepatic CYP2B6, increasing the metabolism of CYP2B6 substrates. In vivo nicotine pharmacokinetics are differentially affected by ethanol and nicotine, but when both drugs are used in combination the effect more closely resembles ethanol alone.

  14. 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.

  15. Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking.

    PubMed

    Tessari, Michela; Pilla, Maria; Andreoli, Michela; Hutcheson, Daniel M; Heidbreder, Christian A

    2004-09-19

    Previous studies in metabotropic glutamate 5 receptor (mGlu5 receptor) deficient mice have indicated the importance of this receptor in the self-administration of cocaine and locomotor sensitisation to this stimulant. Both ionotropic and metabotropic receptors have been implicated in drug-seeking and drug-taking behaviours, but the specific role of each subtype of metabotropic glutamate receptors (mGlu receptors) is still unknown. In the present series of experiments we further investigated the role of mGlu5 receptors on nicotine, cocaine- and food-taking behaviour. We also investigated the effects of the mGlu5 receptor antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) on the acute locomotor activating effects of nicotine, the expression of sensitisation to its repeated, intermittent administration, and nicotine-triggered relapse to nicotine-seeking behaviour. The results indicate that MPEP treatment reduced nicotine-induced drug-seeking behaviour in a model of nicotine-triggered relapse to nicotine seeking. Furthermore, MPEP decreased both nicotine and cocaine self-administration without affecting food self-administration under similar schedules of reinforcement. Finally, MPEP reduced both the acute locomotor stimulant effects of nicotine as well as the expression of behavioural sensitisation to its repeated administration. Although the intravenous administration of MPEP at 1 and 10 mg/kg transiently reduced spontaneous locomotor activity during the first 25 min post-administration, we also demonstrated that performance on the accelerating rotarod was not affected when MPEP was given 5 and 30 min prior to the test. Altogether, the present findings strengthen the hypothesis that selective antagonism at mGlu5 receptors may be a new potential pharmacotherapeutic approach for the treatment of drug dependence and addiction.

  16. 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.

  17. Adolescent nicotine exposure transiently increases high-affinity nicotinic receptors and modulates inhibitory synaptic transmission in rat medial prefrontal cortex

    PubMed Central

    Counotte, Danielle S.; Goriounova, Natalia A.; Moretti, Milena; Smoluch, Marek T.; Irth, Hubertus; Clementi, Francesco; Schoffelmeer, Anton N. M.; Mansvelder, Huibert D.; Smit, August B.; Gotti, Cecilia; Spijker, Sabine

    2013-01-01

    Adolescence is a critical developmental period during which most adult smokers initiate their habit. Adolescents are more vulnerable than adults to nicotine’s long-term effects on addictive and cognitive behavior. We investigated whether adolescent nicotine exposure in rats modifies expression of nicotinic acetylcholine receptors (nAChRs) in medial prefrontal cortex (mPFC) in the short and/or long term, and whether this has functional consequences. Using receptor binding studies followed by immunoprecipitation of nAChR subunits, we showed that adolescent nicotine exposure, as compared with saline, caused an increase in mPFC nAChRs containing α4 or β2 subunits (24 and 18%, respectively) 24 h after the last injection. Nicotine exposure in adulthood had no such effect. This increase was transient and was not observed 5 wk following either adolescent or adult nicotine exposure. In line with increased nAChRs expression 1 d after adolescent nicotine exposure, we observed a 34% increase in amplitude of nicotine-induced spontaneous inhibitory postsynaptic currents in layer II/III mPFC pyramidal neurons. These effects were transient and specific, and observed only acutely after adolescent nicotine exposure, but not after 5 wk, and no changes were observed in adult-exposed animals. The acute nicotine-induced increase in α4β2-containing receptors in adolescents interferes with the normal developmental decrease (37%) of these receptors from early adolescence (postnatal day 34) to adulthood (postnatal day 104) in the mPFC. Together, this suggests that these receptors play a role in mediating the acute rewarding effects of nicotine and may underlie the increased sensitivity of adolescents to nicotine. PMID:22308197

  18. 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.

  19. Prenatal nicotine exposure alters the responses to subsequent nicotine administration and withdrawal in adolescence: Serotonin receptors and cell signaling.

    PubMed

    Slotkin, Theodore A; Tate, Charlotte A; Cousins, Mandy M; Seidler, Frederic J

    2006-11-01

    Offspring of women who smoke during pregnancy are themselves more likely to take up smoking in adolescence, effects that are associated with a high rate of depression and increased sensitivity to withdrawal symptoms. To evaluate the biological basis for this relationship, we assessed effects on serotonin (5-hydroxytryptamine, 5HT) receptors and 5HT-mediated cellular responses in rats exposed to nicotine throughout prenatal development and then given nicotine in adolescence (postnatal days PN30-47.5), using regimens that reproduce plasma nicotine levels found in smokers. Evaluations were then made during the period of adolescent nicotine treatment and for up to one month after the end of treatment. Prenatal nicotine exposure, which elicits damage to 5HT projections in the cerebral cortex and striatum, produced sex-selective changes in the expression of 5HT(1A) and 5HT2 receptors, along with induction of adenylyl cyclase (AC), leading to sensitization of heterologous inputs operating through this signaling pathway. Superimposed on these effects, the AC response to 5HT was shifted toward inhibition. By itself, adolescent nicotine administration, which damages the same pathways, produced similar effects on receptors and the 5HT-mediated response, but a smaller overall induction of AC. Animals exposed to prenatal nicotine showed a reduced response to nicotine administered in adolescence, results in keeping with earlier findings of persistent desensitization. Our results indicate that prenatal nicotine exposure alters parameters of 5HT synaptic communication lasting into adolescence and changes the response to nicotine administration and withdrawal in adolescence, actions which may contribute to a subpopulation especially vulnerable to nicotine dependence.

  20. 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

  1. 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…

  2. The molecular and cellular neurobiology of nicotine abuse in schizophrenia.

    PubMed

    Mobascher, A; Winterer, G

    2008-09-01

    People with schizophrenia suffer from a variety of symptoms that can be categorized as positive, negative and cognitive symptoms. Cognitive symptoms are not properly treated with antipsychotic medication and are the major cause of disability associated with the disorder. People with schizophrenia smoke more frequently and heavily than the general population. This observation in view of the well established role of nicotinic, cholinergic neurotransmission in cognition led to the hypothesis that people with schizophrenia may use nicotine as a self-medication to ameliorate cognitive symptoms associated with their disease. Furthermore genetic and post-mortem studies point to additional links between nicotinic cholinergic neurotransmission and schizophrenia. This article provides an insight in the possible relationship between schizophrenia and smoking behavior. We focus on the effects of nicotine on individual neurons as well as on neuronal networks. With respect to single neurons the immediate electrophysiological consequences of nicotinic stimulation and the more "metabotropic" effects related to intracellular signal transduction cascades that may lead to plastic changes in the neuron are discussed. With respect to the network level, three systems are discussed: cognition, reward and stress response. The effects of nicotine on cognition may be most pertinent to the problem of schizophrenia, but schizophrenics may also smoke to regulate mood and reduce stress. A better understanding of the molecular and cellular effects of nicotine and how they are related to the pathophysiology and symptomatology of schizophrenia may help to identify new targets for the pharmacotherapy of schizophrenia and of nicotine addiction in schizophrenia.

  3. Melatonin protects uterus and oviduct exposed to nicotine in mice

    PubMed Central

    Saadat, Seyedeh Nazanin Seyed; Jahromi, Sina Khajeh; Homafar, Mohammad Amin; Haghiri, Mostafa

    2014-01-01

    Smoking is associated with higher infertility risk. The aim of this study was to evaluate protective effects of melatonin on the uterus and oviduct in mice exposed to nicotine. Adult female mice (n=32) were divided into four groups. Group A: control animals received normal saline, Group B: injected with nicotine 40µg/kg, Group C: injected with melatonin 10 µg, Group D: injected with nicotine 40µg/kg and melatonin 10 µg. All animals were treated over 15 days intraperitoneally. On the 16th day, animals in the estrus phase were dissected and their uterus and oviducts were removed. Immunohistochemistry was recruited for studying apoptosis and for detection of estrogen receptor (ER) alpha in luminal epithelium of the uterus and oviduct. Enzyme-linked immunosorbent assay was used for serum estradiol level determination. Nicotine in group B decreased estradiol level and ERalpha numbers both in the uterus and oviduct (p<0.05). Co-administration of melatonin-nicotine in Group D ameliorated the histology of the uterus and oviduct, increased ERalpha numbers and reduced apoptosis in the uterus and oviduct compared with the nicotine Group B (p<0.05). This study indicates that nicotine impairs the histology of the uterus and oviduct and co-administration of melatonin-nicotine ameliorates these findings, partly through alteration in ERalpha numbers and reduction of apoptosis. PMID:26038675

  4. 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

  5. Noribogaine reduces nicotine self-administration in rats.

    PubMed

    Chang, Qing; Hanania, Taleen; Mash, Deborah C; Maillet, Emeline L

    2015-06-01

    Noribogaine, a polypharmacological drug with activities at opioid receptors, ionotropic nicotinic receptors, and serotonin reuptake transporters, has been investigated for treatment of substance abuse-related disorders. Smoking cessation has major benefits for both individuals and society, therefore the aim of this study was to evaluate the potential of noribogaine for use as a treatment for nicotine dependence. Adult male Sprague-Dawley rats were trained to self-administer nicotine intravenous. After initial food pellet training, followed by 26 sessions of nicotine self-administration training, the rats were administered noribogaine (12.5, 25 or 50 mg/kg orally), noribogaine vehicle, varenicline or saline using a within-subject design with a Latin square test schedule. Noribogaine dose-dependently decreased nicotine self-administration by up to 64% of saline-treated rats' levels and was equi-effective to 1.7 mg/kg intraperitoneal varenicline. Noribogaine was less efficient at reducing food pellets self-administration than at nicotine self-administration, inhibiting the nondrug reinforcing effects of palatable pellets by 23% at the highest dose. These results suggest that noribogaine dose-dependently attenuates drug-taking behavior for nicotine, attenuates the reinforcing effects of nicotine and is comparable to varenicline power in that regard. The findings from the present study hold promise for a new therapy to aid smoking cessation.

  6. 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…

  7. The therapeutic promise of positive allosteric modulation of nicotinic receptors

    PubMed Central

    Uteshev, Victor V.

    2014-01-01

    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, the nicotinic-PAM-based treatments are expected to be highly efficacious with fewer side effects as compared to a more indiscriminate action of exogenous orthosteric agonists. In this review, I will summarize the existing trends in therapeutic applications of nicotinic PAMs. PMID:24530419

  8. Binding of quinolizidine alkaloids to nicotinic and muscarinic acetylcholine receptors.

    PubMed

    Schmeller, T; Sauerwein, M; Sporer, F; Wink, M; Müller, W E

    1994-09-01

    Fourteen quinolizidine alkaloids, isolated from Lupinus albus, L. mutabilis, and Anagyris foetida, were analyzed for their affinity for nicotinic and/or muscarinic acetylcholine receptors. Of the compounds tested, the alpha-pyridones, N-methylcytisine and cytisine, showed the highest affinities at the nicotinic receptor, while several quinolizidine alkaloid types were especially active at the muscarinic receptor.

  9. Effect of nicotine on cariogenic virulence of Streptococcus mutans.

    PubMed

    Li, Mingyun; Huang, Ruijie; Zhou, Xuedong; Qiu, Wei; Xu, Xin; Gregory, Richard L

    2016-11-01

    Nicotine has well-documented effects on the growth and colonization of Streptococcus mutans. This study attempts to investigate the effects of nicotine on pathogenic factors of S. mutans, such as the effect on biofilm formation and viability, expression of pathogenic genes, and metabolites of S. mutans. The results demonstrated that addition of nicotine did not significantly influence the viability of S. mutans cells. The biofilms became increasingly compact as the concentrations of nicotine increased. The expression of virulence genes, such as ldh and phosphotransferase system (PTS)-associated genes, was upregulated, and nlmC was upregulated significantly, while ftf was downregulated. The lactate concentration of S. mutans grown in 1 mg/mL of nicotine was increased up to twofold over either biofilm or planktonic cells grown without nicotine. Changes in the metabolites involved in central carbon metabolism from sucrose indicated that most selected metabolites were detectable and influenced by increased concentrations of nicotine. This study demonstrated that nicotine can influence the pathogenicity of S. mutans and may lead to increased dental caries through the production of more lactate and the upregulation of virulence genes.

  10. 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.

  11. Baclofen interactions with nicotine in rats: effects on memory.

    PubMed

    Levin, Edward D; Weber, Elyssa; Icenogle, Laura

    2004-10-01

    Nicotine has been shown in numerous previous studies to significantly improve memory on the radial-arm maze, yet the critical mechanisms underlying this effect are not fully characterized. Nicotine stimulates the release of a number of neurotransmitters important for memory function including (gamma-aminobutyric acid) GABA. The importance of nicotinic-GABA interactions regarding memory is currently unknown. The purpose of the current study was to determine the interactive effects of nicotine and the GABA agonist baclofen on working memory function as measured by choice accuracy in the radial-arm maze. Female Sprague-Dawley rats trained to asymptotic performance levels on a win-shift eight-arm radial maze task were used for assessment of nicotine-baclofen interactions. Low doses of baclofen improved memory performance while higher doses impaired it. Nicotine, as seen before, improved memory performance. Nicotine also significantly reversed the higher dose baclofen-induced deficit. These data show the importance of both nicotinic and GABA systems in working memory function and the interactions between these two transmitter receptor systems. This not only provides information concerning the neural bases of cognitive performance, it also lends insight into new combination treatments for memory impairment.

  12. Temporal Rewiring of Striatal Circuits Initiated by Nicotine

    PubMed Central

    Adermark, Louise; Morud, Julia; Lotfi, Amir; Danielsson, Klara; Ulenius, Lisa; Söderpalm, Bo; Ericson, Mia

    2016-01-01

    Drug addiction has been conceptualized as maladaptive recruitment of integrative circuits coursing through the striatum, facilitating drug-seeking and drug-taking behavior. The aim of this study was to define temporal neuroadaptations in striatal subregions initiated by 3 weeks of intermittent nicotine exposure followed by protracted abstinence. Enhanced rearing activity was assessed in motor activity boxes as a measurement of behavioral change induced by nicotine (0.36 mg/kg), whereas electrophysiological field potential recordings were performed to evaluate treatment effects on neuronal activity. Dopamine receptor mRNA expression was quantified by qPCR, and nicotine-induced dopamine release was measured in striatal subregions using in vivo microdialysis. Golgi staining was performed to assess nicotine-induced changes in spine density of medium spiny neurons. The data presented here show that a brief period of nicotine exposure followed by abstinence leads to temporal changes in synaptic efficacy, dopamine receptor expression, and spine density in a subregion-specific manner. Nicotine may thus initiate a reorganization of striatal circuits that continues to develop despite protracted abstinence. We also show that the response to nicotine is modulated in previously exposed rats even after 6 months of abstinence. The data presented here suggests that, even though not self-administered, nicotine may produce progressive neuronal alterations in brain regions associated with goal-directed and habitual performance, which might contribute to the development of compulsive drug seeking and the increased vulnerability to relapse, which are hallmarks of drug addiction. PMID:27388328

  13. Uncoupled angiogenesis and osteogenesis in nicotine-compromised bone healing.

    PubMed

    Ma, Li; Zheng, Li Wu; Sham, Mai Har; Cheung, Lim Kwong

    2010-06-01

    Nicotine is the main chemical component responsible for tobacco addiction. This study aimed to evaluate the influence of nicotine on angiogenesis and osteogenesis and the associated expression of angiogenic and osteogenic mediators during bone healing. Forty-eight adult New Zealand White rabbits were randomly assigned to a nicotine group and a control group. Nicotine pellets (1.5 g, 60-day time release) or placebo pellets were implanted in the neck subcutaneous tissue. The nicotine or placebo exposure time for all the animals was 7 weeks. Unilateral mandibular distraction osteogenesis was performed. Eight animals in each group were euthanized on day 5, day 11 of active distraction, and week 1 of consolidation, respectively. The mandibular samples were subjected to radiographic, histologic, immunohistochemical, and real-time reverse-transcriptase polymerase chain reaction examinations. Nicotine exposure upregulated the expression of hypoxia inducible factor 1alpha and vascular endothelial growth factor and enhanced angiogenesis but inhibited the expression of bone morphogenetic protein 2 and impaired bone healing. The results indicate that nicotine decouples angiogenesis and osteogenesis in this rabbit model of distraction osteogenesis, and the enhanced angiogenesis cannot compensate for the adverse effects of nicotine on bone healing.

  14. Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis

    PubMed Central

    Singh, Sandeep; Pillai, Smitha; Chellappan, Srikumar

    2011-01-01

    Cigarette smoking is highly correlated with the onset of a variety of human cancers, and continued smoking is known to abrogate the beneficial effects of cancer therapy. While tobacco smoke contains hundreds of molecules that are known carcinogens, nicotine, the main addictive component of tobacco smoke, is not carcinogenic. At the same time, nicotine has been shown to promote cell proliferation, angiogenesis, and epithelial-mesenchymal transition, leading to enhanced tumor growth and metastasis. These effects of nicotine are mediated through the nicotinic acetylcholine receptors that are expressed on a variety of neuronal and nonneuronal cells. Specific signal transduction cascades that emanate from different nAChR subunits or subunit combinations facilitate the proliferative and prosurvival functions of nicotine. Nicotinic acetylcholine receptors appear to stimulate many downstream signaling cascades induced by growth factors and mitogens. It has been suggested that antagonists of nAChR signaling might have antitumor effects and might open new avenues for combating tobacco-related cancer. This paper examines the historical data connecting nicotine tumor progression and the recent efforts to target the nicotinic acetylcholine receptors to combat cancer. PMID:21541211

  15. 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…

  16. Can nicotine be used medicinally in Parkinson's disease?

    PubMed

    Thiriez, Claire; Villafane, Gabriel; Grapin, Frédérique; Fenelon, Gilles; Remy, Philippe; Cesaro, Pierre

    2011-07-01

    The risk of Parkinson's disease is reduced by cigarette smoking, which raises some unanswered questions. Nicotine, a major component of tobacco smoke, could exert either nonreceptor-mediated biological effects or, more importantly, act on the different subtypes of nicotinic brain receptors, in particular those associated with the nigrostriatal dopaminergic pathway. There is now robust experimental evidence for a neuroprotective effect of nicotine upon dopaminergic neurons. By contrast, in animal models of Parkinson's disease, nicotine alone has slight or no motor effects. However, nicotine may modulate dopamine transmission and has clear motor effects when associated with L-DOPA, reducing L-DOPA-induced dyskinesias. Clinical trials have yielded inconclusive results thus far and are hampered by different designs and small cohorts. Ongoing studies address either symptomatic motor or nonmotor symptoms, or neuroprotection. There is still no agreement on the daily dosage of nicotine or the method of administration. Together, these data suggest that nicotine or nicotinic receptor drugs have therapeutic potential for Parkinson's disease, although the specific treatment regimens remain to be determined.

  17. 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.

  18. 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.

  19. Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure.

    PubMed

    Maouche, Kamel; Medjber, Kahina; Zahm, Jean-Marie; Delavoie, Franck; Terryn, Christine; Coraux, Christelle; Pons, Stéphanie; Cloëz-Tayarani, Isabelle; Maskos, Uwe; Birembaut, Philippe; Tournier, Jean-Marie

    2013-03-05

    Loss or dysfunction of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) leads to impairment of airway mucus transport and to chronic lung diseases resulting in progressive respiratory failure. Nicotinic acetylcholine receptors (nAChRs) bind nicotine and nicotine-derived nitrosamines and thus mediate many of the tobacco-related deleterious effects in the lung. Here we identify α7 nAChR as a key regulator of CFTR in the airways. The airway epithelium in α7 knockout mice is characterized by a higher transepithelial potential difference, an increase of amiloride-sensitive apical Na(+) absorption, a defective cAMP-dependent Cl(-) conductance, higher concentrations of Na(+), Cl(-), K(+), and Ca(2+) in secretions, and a decreased mucus transport, all relevant to a deficient CFTR activity. Moreover, prolonged nicotine exposure mimics the absence of α7 nAChR in mice or its inactivation in vitro in human airway epithelial cell cultures. The functional coupling of α7 nAChR to CFTR occurs through Ca(2+) entry and activation of adenylyl cyclases, protein kinase A, and PKC. α7 nAChR, CFTR, and adenylyl cyclase-1 are physically and functionally associated in a macromolecular complex within lipid rafts at the apical membrane of surface and glandular airway epithelium. This study establishes the potential role of α7 nAChR in the regulation of CFTR function and in the pathogenesis of smoking-related chronic lung diseases.

  20. Tachyphylaxis and sensitization to nicotine-induced tachycardiac and pressor effects after nicotine infusions.

    PubMed

    Cruz, S L; Vidrio, H

    1997-01-01

    This work examined the effects of nicotine on mean arterial pressure and heart rate in non-anesthetized spinal rats. Nicotine (200 mg/kg) was administered as a single bolus, as infusions lasting 7.5, 15 or 30 min, and as a post-infusion bolus. A nicotine bolus increased pressure and rate. These effects were less marked as the rate of infusion decreased. The infusions affected differentially the effects of a subsequent bolus. Thus, while tachycardia was decreased, the blood pressure rise was increased. An initial transient bradycardia was observed after bolus administration, but not during infusions; this effect was unchanged after post-infusion boluses. Pharmacological analysis indicated that tachycardia and bradycardia were predominantly due to ganglionic stimulation, while adrenal and sympathetic nerve catecholamine release played a major role in the pressor response. These results indicate that slow nicotine infusions do not induce tachyphylaxis for all of the cardiovascular effects of a subsequent bolus, and that development of acute tolerance appears to depend on the mechanism of action of the response.

  1. Development of a novel prolonged-release nicotine transdermal patch.

    PubMed

    Davaran, Soodabeh; Rashidi, Mohammad R; Khandaghi, Reza; Hashemi, Mahdi

    2005-03-01

    A transdermal patch for delivering nicotine for periods of 12-48h was designed. An inclusion complex formed between the nicotine and beta-cyclodextrine (beta-CD) was used in drug depot. The usefulness of a specially cross-linked polyvinyl alcohol (cross-PVA) membrane was investigated as a rate controlling membrane. The influence of carbopol polymers, type C-934P and C-940 and propylene glycol on transdermal permeation of nicotine through the rat skin was investigated. The results indicated a maximum flux of 42 microgcm(-2)h(-1) after 48 h from the patches made from C-934P when the propylene glycol concentration was 15% and the nicotine-beta-CD mole ratio in the inclusion complex was 3:1. These nicotine transdermal patches can be fabricated to obtain a controlled release, zero order systems.

  2. Effect of exogenous selenium on nicotine induced hyperlipidemia in rats.

    PubMed

    Sreekala, S; Indira, M

    2008-01-01

    The effect of two different doses (1 microg Se/Kg and 50 microg Se/Kg Body wt) of selenium on nicotine induced hyperlipidemia was investigated in rats. Results revealed that nicotine intake caused an increase in concentration of cholesterol, triglycerides, free fatty acids, phospholipids and low density lipoprotein compared to control group. Coadministration of selenium along with nicotine reduced the levels of lipids compared to nicotine group. This reduction was due to reduction in the biosynthesis of lipids as evidenced by the reduced activity of HMGCoA reductase and lipogenic enzymes. Nicotine intake also reduced the absorption of selenium in the intestine. Histopathological studies revealed that selenium at a dose of 1 microg was more effective in reducing lipid levels and higher dose of selenium was toxic.

  3. Targeting glutamate homeostasis for potential treatment of nicotine dependence

    PubMed Central

    Alasmari, Fawaz; Al-Rejaie, Salim S.; AlSharari, Shakir D.; Sari, Youssef

    2015-01-01

    Several studies demonstrated that impairment in glutamatergic neurotransmission is linked to drug dependence and drug-seeking behavior. Increased extracellular glutamate concentration in mesocorticolimbic regions has been observed in animals developing nicotine dependence. Changes in glutamate release might be associated with stimulatory effect of nicotinic acetylcholine receptors (nAChRs) via nicotine exposure. We and others have shown increased extracellular glutamate concentration, which was associated with downregulation of the major glutamate transporter, glutamate transporter 1 (GLT-1), in brain reward regions of animals exposed to drug abuse, including nicotine and ethanol. Importantly, studies from our laboratory and others showed that upregulation of GLT-1 expression in the mesocorticolimbic brain regions may have potential therapeutic effects in drug dependence. In this review article, we discussed the effect of antagonizing presynaptic nAChRs in glutamate release, the upregulatory effect in GLT-1 expression and the role of glutamate receptors antagonists in the treatment of nicotine dependence. PMID:26589642

  4. 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.

  5. 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.

  6. Baclofen-induced antinociception and nicotinic receptor mechanism(s).

    PubMed

    Sabetkasai, M; Ahang, S; Shafaghi, B; Zarrindast, M R

    1999-11-01

    In this study, the influences of nicotinic receptor agents on baclofen-induced antinociception in the tail-flick test have been studied. Intraperitoneal administration of baclofen (2.5, 5 and 10 mg/kg) to mice induced a dose-dependent antinociception in the tail-flick test. Subcutaneous injection of nicotine (0.5-2.5 mg/kg) also caused a dose-dependent antinociceptive response. Intracerebral (10 and 20 microg/mouse) but not intraperitoneal administration of hexamethonium (5 and 10 mg/kg) to mice decreased the response of both nicotine and baclofen. However, administration of the GABA(B) antagonist CGP 35348 (100 and 200 mg/kg) decreased the response induced by baclofen but not by nicotine. It is concluded that at least part of the baclofen-induced antinociception may be mediated through a nicotinic mechanism.

  7. 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

  8. Nicotine effects on general semantic priming in Parkinson's disease.

    PubMed

    Holmes, Anna D; Copland, David A; Silburn, Peter A; Chenery, Helen J

    2011-06-01

    In young healthy nonsmokers, effects of nicotine on semantic processing have been observed under strategy-based priming procedures but not under more general priming procedures (Holmes, Chenery, & Copland, 2008; Holmes, Chenery, & Copland, 2010). Effects of nicotine under general priming procedures, however, may be mediated by baseline priming levels that are below optimum such as when compromised by disease. Nicotinic mechanisms may be involved in the cognitive sequalae of Parkinson's disease (PD). Evidence suggests that semantic processing may be compromised in PD but the potential benefit of nicotinic stimulation is unknown. This study investigated the effects of nicotine on semantic processing in nonsmokers with PD (n = 12) and nonsmoking matched controls (n = 17) using general priming procedures. Specifically, an automatic priming task (0.15 relatedness proportion, RP, and 200 ms stimulus onset asynchrony, SOA) and a controlled priming task (0.8 RP and 1000 ms SOA) were used. Prime-target category relation (category related, noncategory related) was also manipulated. Transdermal nicotine patches (7 mg/24 h) were administered in a double-blind, placebo-controlled, crossover design. For the automatic task, nicotine did not influence priming effects for PD. Unexpectedly, compromised automatic priming for controls was ameliorated. For the controlled task, nicotine influenced priming effects for PD but not controls. The patterns of priming and nicotine effects across the tasks suggest an age-related slowing of the rate of semantic activation for controls, which may be exacerbated in PD. Overall, the findings indicate that nicotine can improve compromised semantic processing in PD, and also influence semantic processing in healthy older individuals.

  9. Nicotine reduces antipsychotic-induced orofacial dyskinesia in rats.

    PubMed

    Bordia, Tanuja; McIntosh, J Michael; Quik, Maryka

    2012-03-01

    Antipsychotics are an important class of drugs for the management of schizophrenia and other psychotic disorders. They act by blocking dopamine receptors; however, because these receptors are present throughout the brain, prolonged antipsychotic use also leads to serious side effects. These include tardive dyskinesia, repetitive abnormal involuntary movements of the face and limbs for which there is little treatment. In this study, we investigated whether nicotine administration could reduce tardive dyskinesia because nicotine attenuates other drug-induced abnormal movements. We used a well established model of tardive dyskinesia in which rats injected with the commonly used antipsychotic haloperidol develop vacuous chewing movements (VCMs) that resemble human orofacial dyskinesias. Rats were first administered nicotine (minipump; 2 mg/kg per day). Two weeks later, they were given haloperidol (1 mg/kg s.c.) once daily. Nicotine treatment reduced haloperidol-induced VCMs by ∼20% after 5 weeks, with a significant ∼60% decline after 13 weeks. There was no worsening of haloperidol-induced catalepsy. To understand the molecular basis for this improvement, we measured the striatal dopamine transporter and nicotinic acetylcholine receptors (nAChRs). Both haloperidol and nicotine treatment decreased the transporter and α6β2* nAChRs (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex) when given alone, with no further decline with combined drug treatment. By contrast, nicotine alone increased, while haloperidol reduced α4β2* nAChRs in both vehicle and haloperidol-treated rats. These data suggest that molecular mechanisms other than those directly linked to the transporter and nAChRs underlie the nicotine-mediated improvement in haloperidol-induced VCMs in rats. The present results are the first to suggest that nicotine may be useful for improving the tardive dyskinesia associated with antipsychotic use.

  10. Dimethylsulfoxide-soluble smoking particles and nicotine affect vascular contractibility.

    PubMed

    Zhang, Jin-Yan; Cao, Lei; Zheng, Xiao-Hui; Xu, Cang-Bao; Cao, Yong-Xiao

    2009-10-01

    The aim is to study the effect of dimethylsulfoxide-soluble smoking particles (DSP) and nicotine on the contractility of rat mesenteric artery. The superior mesenteric artery segments were cultured with DSP or nicotine for 24 h. The vascular contractibility was recorded with myograph system. DSP 0.4 mL/L and nicotine 0.48 and 0.96 mg/L shifted the concentration-contractile curves induced by sarafotoxin 6c, a selective agonist for ET(B) receptor toward the left with increased E(max). DSP 0.4 mL/L and nicotine 0.96 mg/L shifted ET(A) receptor-mediated the concentration-contractile curves toward the left with increased E(max). However, nicotine 0.06 mg/L which is the equivalent concentration of nicotine in DSP 0.4 mL/L did not affect the curves and the E(max) mediated with ET(A) receptor and ET(B) receptor. DSP 0.2 and 0.4 mL/L shifted the concentration-contractile curves induced by noradrenaline toward the right with decreased E(max). Neither did nicotine 0.06 and 0.96 mg/L. Both DSP and nicotine shifted the concentration-contractile curves induced by 5-hydroxytryptamine (5-HT) toward the right parallely. DSP changed the phenotypes towards an increased efficacy of ET(A) receptor and ET(B) receptor, and a reduced efficacy of 5-HT receptor and alpha-adrenocceptor. The effects of DSP on ET(B) receptor, ET(A) receptor and alpha-adrenocceptor were independent of nicotine. The effect on 5-HT receptor was responsible to nicotine.

  11. Effect of nicotine on in vitro maturation of bovine oocytes.

    PubMed

    Liu, Ying; Li, Guang-Peng; Rickords, Lee F; White, Kenneth L; Sessions, Benjamin R; Aston, Kenneth I; Bunch, Thomas D

    2008-01-15

    The putative effect of nicotine on maturation and the chromosomal complement of bovine oocytes were investigated in the present study. Cumulus-enclosed oocytes were incubated in maturation medium with 0, 0.5, 1.0, 2.5, 5.0, and 10.0 mmol concentrations of nicotine. The results indicated that: (1) nicotine affected cumulus cell expansion in a dose-dependent manner and the perivitelline space failed to form when concentrations were equal to or greater than 5.0 mmol; (2) oocytes treated with 0.5 and 1.0 mmol nicotine concentrations resulted in maturation rates (83.3% and 85.9%, respectively) which was similar to the control (86.2%), whereas treatment with 2.5 and 5.0 mmol concentrations significantly decreased maturation rates to 70.2% and 26.7%, respectively; (3) nicotine at or over 2.5 mmol caused extremely irregular meiotic spindles and interrupted microfilament organization; (4) chromosomal analyses of oocytes with PB1 showed that oocytes derived from 0.5 and 1.0 mmol nicotine groups had haploid complements similar to the control (87-90%), but when the concentrations were increased to 2.5 and 5.0 mmol the haploid state was significantly reduced to around 70%; (5) oocytes at GVBD (germinal vesicle breakdown) and metaphase I stages were less affected by nicotine at 5.0 and 10.0 mmol concentrations than GV-stage oocytes; (6) maturation rates of the short-term nicotine-treated oocytes could be improved when subsequently incubated in normal maturation medium. Prolonged culture of nicotine-pretreated oocytes resulted in self-activation and some oocytes formed 1 or 2 pronuclei. In conclusion, nicotine affects bovine oocyte cumulus cell expansion, maturation rate, and chromosomal complement in a dose-dependent and an oocyte-stage-dependent manner.

  12. 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

  13. 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.

  14. 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...

  15. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs

    PubMed Central

    Saccone, Scott F.; Hinrichs, Anthony L.; Saccone, Nancy L.; Chase, Gary A.; Konvicka, Karel; Madden, Pamela A.F.; Breslau, Naomi; Johnson, Eric O.; Hatsukami, Dorothy; Pomerleau, Ovide; Swan, Gary E.; Goate, Alison M.; Rutter, Joni; Bertelsen, Sarah; Fox, Louis; Fugman, Douglas; Martin, Nicholas G.; Montgomery, Grant W.; Wang, Jen C.; Ballinger, Dennis G.; Rice, John P.; Bierut, Laura Jean

    2007-01-01

    Nicotine dependence is one of the world’s leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the β3 nicotinic receptor subunit gene (P = 9.4 × 10−5). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the α5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 × 10−4). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies. PMID:17135278

  16. 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.

  17. Crystal structure of human nicotinic acid phosphoribosyltransferase

    PubMed Central

    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

  18. Influence of the heat treatment condition of alloy AlCu4Mg1 on the microstructure and properties of anodic oxide layers

    NASA Astrophysics Data System (ADS)

    Morgenstern, R.; Dietrich, D.; Sieber, M.; Lampke, T.

    2017-03-01

    Due to their outstanding specific mechanical properties, high-strength, age-hardenable aluminum alloys offer a high potential for lightweight security-related applications. However, the use of copper-alloyed aluminum is limited because of their susceptibility to selective corrosion and their low wear resistance. These restrictions can be overcome and new applications can be opened up by the generation of protective anodic aluminum oxide layers. In contrast to the anodic oxidation of unalloyed aluminum, oxide layers produced on copper-rich alloys exhibit a significantly more complex pore structure. It is the aim of the investigation to identify the influence of microstructural parameters such as size and distribution of the strengthening precipitations on the coating microstructure. The aluminum alloy EN AW-2024 (AlCu4Mg1) in different heat treatment conditions serves as substrate material. The influence of the strengthening precipitations’ size and distribution on the development of the pore structure is investigated by the use of high-resolution scanning electron microscopy. Integral coating properties are characterized by non-destructive and light-microscopic thickness measurements and instrumented indentation tests.

  19. Genetic and pharmacokinetic determinants of response to transdermal nicotine in white, black, and Asian nonsmokers.

    PubMed

    Dempsey, D A; St Helen, G; Jacob, P; Tyndale, R F; Benowitz, N L

    2013-12-01

    The aim of the study was to examine genetic, pharmacokinetic, and demographic factors that influence sensitivity to nicotine in never-smokers. Sixty never-smokers, balanced for gender and race (white, black, and Asian), wore 7-mg nicotine skin patches for up to 8 h. Serial plasma nicotine concentrations and subjective and cardiovascular effects were measured, and genetic variation in the CYP2A6 gene, encoding the primary enzyme responsible for nicotine metabolism, was assessed. Nicotine toxicity requiring patch removal developed in nine subjects and was strongly associated with rate of increase and peak concentrations of plasma nicotine. Toxicity and subjective and cardiovascular effects of nicotine were associated with the presence of reduced-function CYP2A6 alleles, presumably reflecting slow nicotine metabolic inactivation. This study has implications for understanding individual differences in responses to nicotine medications, particularly when they are used for treating medical conditions in nonsmokers, and possibly in vulnerability to developing nicotine dependence.

  20. A C. elegans model of nicotine-dependent behavior: regulation by TRP family channels

    PubMed Central

    Feng, Zhaoyang; Li, Wei; Ward, Alex; Piggott, Beverly J.; Larkspur, Erin R.; Sternberg, Paul W.; Shawn Xu, X. Z.

    2010-01-01

    Summary 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 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. PMID:17081982

  1. Adolescent nicotine exposure produces less affective measures of withdrawal relative to adult nicotine exposure in male rats

    PubMed Central

    O’Dell, Laura E.; Torres, Oscar V.; Natividad, Luis A.; Tejeda, Hugo A.

    2012-01-01

    Vulnerability to nicotine addiction is significantly increased in individuals who begin smoking during adolescence; however, the underlying mechanisms of this phenomenon remain unclear. This study examined the motivational effects of nicotine withdrawal in adolescent (PND 27–42) and adult (PND 60–75) rats using the conditioned place aversion paradigm. Male Wistar rats were tested for their initial preference for either of two distinct compartments of our conditioning apparatus. Rats were then implanted with subcutaneous (sc) pumps that produce equivalent blood plasma levels of nicotine for 14 days. Conditioning was conducted over the last 8 days of nicotine exposure. Rats received the nicotinic antagonist mecamylamine (1.5 or 3.0 mg/kg, sc) to precipitate withdrawal in their initially preferred compartment, and on alternate days they received saline in their non-preferred compartment. Following conditioning, rats were re-tested for their preference for each compartment. A subsequent study was conducted to examine potential developmental differences in learning place aversion produced by another aversive stimulus, lithium chloride (LiCl). Rats received LiCl (0, 10, 30, or 100 mg/kg, sc) in their initially preferred side using similar conditioning procedures. Adults displayed robust place aversion produced by nicotine withdrawal. This effect was lower in adolescent rats even in a group of young rats that received 7 additional days of nicotine exposure prior to conditioning. This developmental difference was specific to nicotine withdrawal since there were no differences between adolescents and adults in learning place aversion with LiCl. Our findings demonstrating reduced effects of nicotine withdrawal constitute a powerful basis for the increased vulnerability to nicotine dependence during adolescence. PMID:17184972

  2. Upregulation of surface alpha4beta2 nicotinic receptors is initiated by receptor desensitization after chronic exposure to nicotine.

    PubMed

    Fenster, C P; Whitworth, T L; Sheffield, E B; Quick, M W; Lester, R A

    1999-06-15

    It is hypothesized that desensitization of neuronal nicotinic acetylcholine receptors (nAChRs) induced by chronic exposure to nicotine initiates upregulation of nAChR number. To test this hypothesis directly, oocytes expressing alpha4beta2 receptors were chronically incubated (24-48 hr) in nicotine, and the resulting changes in specific [3H]nicotine binding to surface receptors on intact oocytes were compared with functional receptor desensitization. Four lines of evidence strongly support the hypothesis. (1) The half-maximal nicotine concentration necessary to produce desensitization (9.7 nM) was the same as that needed to induce upregulation (9.9 nM). (2) The concentration of [3H]nicotine for half-maximal binding to surface nAChRs on intact oocytes was also similar (11.1 nM), as predicted from cyclical desensitization models. (3) Functional desensitization of alpha3beta4 receptors required 10-fold higher nicotine concentrations, and this was mirrored by a 10-fold shift in concentrations necessary for upregulation. (4) Mutant alpha4beta2 receptors that do not recover fully from desensitization, but not wild-type channels, were upregulated after acute (1 hr) applications of nicotine. Interestingly, the nicotine concentration required for half-maximal binding of alpha4beta2 receptors in total cell membrane homogenates was 20-fold lower than that measured for surface nAChRs in intact oocytes. These data suggest that cell homogenate binding assays may not accurately reflect the in vivo desensitization affinity of surface nAChRs and may account for some of the previously reported differences in the efficacy of nicotine for inducing nAChR desensitization and upregulation.

  3. 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.

  4. Cholinergic transmission during nicotine withdrawal is influenced by age and pre-exposure to nicotine: Implications for teenage smoking

    PubMed Central

    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 as compared to 1) adolescents and 2) adults that were pre-exposed to nicotine during adolescence. The first study compared extracellular levels of acetylcholine (ACh) in the nucleus accumbens (NAcc) during nicotine exposure and precipitated withdrawal using microdialysis procedures. Adolescent (PND 28–42) and adult rats (PND 60–74) were prepared with osmotic pumps that delivered nicotine for 14 days (4.7 mg/kg/day adolescents; 3.2 mg/kg/day adults). 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, rats were implanted with microdialysis probes in the NAcc. The following day, dialysis samples were collected during baseline and following systemic administration of the nicotinic-receptor antagonist mecamylamine (1.5 mg/kg and 3.0 mg/kg, IP) 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 NAcc 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 nicotine withdrawal, ACh levels in

  5. 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

  6. 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

    2014-04-05

    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.

  7. The pharmacological actions of nicotine on the gastrointestinal tract.

    PubMed

    Wu, William K K; Cho, Chi Hin

    2004-04-01

    Increasing use of tobacco and its related health problems are a great concern in the world. Recent epidemiological findings have demonstrated the positive association between cigarette smoking and several gastrointestinal (GI) diseases, including peptic ulcer and cancers. Interestingly, smoking also modifies the disease course of ulcerative colitis (UC). Nicotine, a major component of cigarette smoke, seems to mediate some of the actions of cigarette smoking on the pathogenesis of GI disorders. Nicotine worsens the detrimental effects of aggressive factors and attenuates the protective actions of defensive factors in the processes of development and repair of gastric ulceration. Nicotine also takes part in the initiation and promotion of carcinogenesis in the GI tract. In this regard, nicotine and its metabolites are found to be mutagenic and have the ability to modulate cell proliferation, apoptosis, and angiogenesis during tumoriogenesis through specific receptors and signalling pathways. However, to elucidate this complex pathogenic mechanism, further study at the molecular level is warranted. In contrast, findings of clinical trials give promising results on the use of nicotine as an adjuvant therapy for UC. The beneficial effect of nicotine on UC seems to be mediated through multiple mechanisms. More clinical studies are needed to establish the therapeutic value of nicotine in this disease.

  8. Nicotine: therapeutic potential for the treatment of ulcerative colitis.

    PubMed

    Green, J T; Thomas, G A; Rhodes, J

    1997-01-01

    Ulcerative colitis (UC) is predominantly a disease of non-smokers, and nicotine may be the agent responsible for this association. Transdermal nicotine has been shown to improve disease activity and sigmoidoscopic appearance in the active disease but in one study had no effect on maintenance of remission. Since side-effects with nicotine patches occur in up to two thirds of patients, attempts to reduce systemic levels and improve drug tolerance have been developed with colonic delivery systems of nicotine. Preliminary observations with nicotine enemas in UC have shown clinical benefit, but controlled trials are needed. Mechanisms responsible for the association of smoking with colitis and for the therapeutic effect of nicotine remain an enigma; possibilities include: modulation of the immune response, alterations of colonic mucus and eicosanoid production, changes in rectal blood flow, decreased intestinal permeability and the release of endogenous glucocorticoids. With current treatment for UC limited to corticosteroids and formulations of 5-aminosalicylic acid, alternative treatments are required and nicotine may fulfil this role.

  9. 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'.

  10. Nicotine dependence and problem behaviors among urban South African adolescents.

    PubMed

    Pahl, Kerstin; Brook, David W; Morojele, Neo K; Brook, Judith S

    2010-04-01

    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.

  11. Evaluating nicotine dependence levels in e-cigarette users.

    PubMed

    González Roz, Alba; Secades Villa, Roberto; Weidberg, Sara

    2017-01-11

    Despite the fact that electronic cigarettes (e-cigarettes) are rapidly growing in popularity and use worldwide, there is scarce scientific data on abuse liability among e-cigarette users, and about whether e-cigarette use is related to nicotine dependence or not. The aim of this study is to explore nicotine dependence levels in a sample of experienced e-cigarette users (n= 39) and to compare them with current tobacco cigarette smokers (n=42). We conducted several face-to-face interviews in order to assess sociodemographic and dependence related characteristics in both e-cigarette users and in smokers. Adapted versions of both the Fagerström test for nicotine dependence (FTND) and the nicotine dependence syndrome scale (NDSS) were used to analyze nicotine dependence in each of the groups. Biochemical markers of carbon monoxide and urinary cotinine analysis were also collected. Results showed that e-cigarette users scored lower than cigarette smokers in both FTND and all NDSS subscales. Our findings extend previous research on e-cigarette use and nicotine addiction and suggest that e-cigarette users are less dependent on nicotine than current tobacco cigarette smokers. Further prospective studies are needed to better ascertain their addictiveness potential, comparing those smokers who switched to e-cigarettes from smoking cigarettes, and those who had never been tobacco cigarette smokers.

  12. Bupropion for the treatment of nicotine withdrawal and craving.

    PubMed

    Mooney, Marc E; Sofuoglu, Mehmet

    2006-07-01

    Over the past decade, bupropion has become a major pharmacotherapy for smoking cessation in the Western world. Unlike other smoking cessation pharmacotherapies, bupropion is a non-nicotine treatment. Compared with a placebo control, bupropion approximately doubles smoking quit rates. Most smoking cessation pharmacotherapies are thought to work, in part, by reducing nicotine withdrawal and craving. This article reviews preclinical, human laboratory and clinical trial studies of the effect of bupropion on nicotine withdrawal and craving. Preclinical studies demonstrate that in rats undergoing nicotine withdrawal, bupropion can dose-dependently lower changes in brain-reward threshold and somatic signs of nicotine withdrawal. Human laboratory studies have demonstrated that bupropion can alleviate some nicotine withdrawal symptoms, including depressed mood, irritability, difficulty concentrating and increased appetite. Moreover, bupropion has shown some efficacy in alleviating craving to smoke. Clinical trials of bupropion have offered mixed support of its ability to reduce nicotine withdrawal, weight gain during treatment and craving. Strong mediational evidence of bupropion's action through relief of withdrawal and craving in smoking cessation is growing. Greater understanding of the psychological mechanisms of bupropion action will likely be obtained through advances in the conceptualization and measurement of withdrawal and craving. Improvements in the efficacy of bupropion may be achieved through pharmacogenetic studies, with particular emphasis on its metabolites. Ultimately, the efficacy of bupropion may be augmented by combination with other agents that target withdrawal and craving through complementary neurobiological processes.

  13. Chronic caffeine exposure potentiates nicotine self-administration in rats.

    PubMed

    Shoaib, M; Swanner, L S; Yasar, S; Goldberg, S R

    1999-03-01

    The prevalence of tobacco smoking and coffee drinking place nicotine and caffeine among the most used licit drugs in many societies and their consumption is often characterised by concurrent use. The pharmacological basis for any putative interaction between these drugs remains unclear. Epidemiological reports support anecdotal evidence, which suggests that smokers consume caffeine to enhance the euphoric effects of nicotine. The aim of the present experiment was to examine effects of chronic exposure to caffeine on responding maintained by nicotine. Sprague-Dawley rats consuming caffeine (approximately 150-180 mg/kg per day) in their drinking water for 7 days prior to the beginning and throughout behavioural testing acquired intravenous nicotine self-administration (0.03 mg/kg per infusion) more rapidly than did controls. In a cross-over design, exclusion of caffeine brought levels of nicotine self-administration back to baseline, while adding caffeine to the drinking water of control rats increased responding maintained by nicotine over 90%. These findings strongly suggest that caffeine can potentiate the reinforcing properties of nicotine, thus highlighting the importance of environmental factors in shaping and maintaining tobacco smoking.

  14. Inactivation gating determines nicotine blockade of human HERG channels.

    PubMed

    Wang, H Z; Shi, H; Liao, S J; Wang, Z

    1999-09-01

    We have previously found that nicotine blocked multiple K+ currents, including the rapid component of delayed rectifier K+ currents (IKr), by interacting directly with the channels. To shed some light on the mechanisms of interaction between nicotine and channels, we performed detailed analysis on the human ether-à-go-go-related gene (HERG) channels, which are believed to be equivalent to the native I(Kr) when expressed in Xenopus oocytes. Nicotine suppressed the HERG channels in a concentration-dependent manner with greater potency with voltage protocols, which favor channel inactivation. Nicotine caused dramatic shifts of the voltage-dependent inactivation curve to more negative potentials and accelerated the inactivation process. Conversely, maneuvers that weakened the channel inactivation gating considerably relieved the blockade. Elevating the extracellular K+ concentration from 5 to 20 mM increased the nicotine concentration (by approximately 100-fold) needed to achieve the same degree of inhibition. Moreover, nicotine lost its ability to block the HERG channels when a single mutation was introduced to a residue located after transmembrane domain 6 (S631A) to remove the rapid channel inactivation. Our data suggest that the inactivation gating determines nicotine blockade of the HERG channels.

  15. Adenosine strongly potentiates pressor responses to nicotine in rats.

    PubMed Central

    von Borstel, R W; Renshaw, A A; Wurtman, R J

    1984-01-01

    Intravenous infusion of subhypotensive doses of adenosine strongly potentiates the pressor response of anesthetized rats to nicotine. A dose of nicotine (40 micrograms/kg, i.v.), which, given alone, elicits a peak increase in diastolic pressure of approximately equal to 15 mm Hg, increases pressure by approximately equal to 70 mm Hg when arterial plasma adenosine levels have been increased to 2 microM from a basal concentration of approximately equal to 1 microM. The pressor response to cigarette smoke applied to the lungs is also strongly potentiated during infusion of adenosine. Slightly higher adenosine concentrations (approximately equal to 4 microM) attenuate pressor responses to electrical stimulation of preganglionic sympathetic nerves, or to injections of the alpha-adrenergic agonist phenylephrine, but continue to potentiate pressor responses to nicotine. Low doses (0.25-5 micrograms/kg) of the synthetic adenosine receptor agonists 5'-N-cyclopropylcarboxamidoadenosine, 2-chloroadenosine, and N6-L-phenylisopropyladenosine also potentiate pressor responses to nicotine. Caffeine and theophylline (10 mg/kg) block the potentiating effect of adenosine, and also decrease basal responses to nicotine, suggesting that endogenous adenosine might normally potentiate some nicotine responses. The synergism between nicotine and adenosine appears to take place within sympathetic ganglia. PMID:6591207

  16. Nicotine Enhances Interspecies Relationship between Streptococcus mutans and Candida albicans.

    PubMed

    Liu, Shiyu; Qiu, Wei; Zhang, Keke; Zhou, Xuedong; Ren, Biao; He, Jinzhi; Xu, Xin; Cheng, Lei; Li, Mingyun

    2017-01-01

    Streptococcus mutans and Candida albicans are common microorganisms in the human oral cavity. The synergistic relationship between these two species has been deeply explored in many studies. In the present study, the effect of alkaloid nicotine on the interspecies between S. mutans and C. albicans is explored. We developed a dual-species biofilm model and studied biofilm biomass, biofilm structure, synthesis of extracellular polysaccharides (EPS), and expression of glucosyltransferases (Gtfs). Biofilm formation and bacterial and fungal cell numbers in dual-species biofilms increased in the presence of nicotine. More C. albicans cells were present in the dual-species biofilms in the nicotine-treated groups as determined by scanning electron microscopy. The synthesis of EPS was increased by 1 mg/ml of nicotine as detected by confocal laser scanning microscopy. The result of qRT-PCR showed gtfs expression was upregulated when 1 mg/ml of nicotine was used. We speculate that nicotine promoted the growth of S. mutans, and more S. mutans cells attracted more C. albicans cells due to the interaction between two species. Since S. mutans and C. albicans are putative pathogens for dental caries, the enhancement of the synergistic relationship by nicotine may contribute to caries development in smokers.

  17. Menthol's potential effects on nicotine dependence: a tobacco industry perspective

    PubMed Central

    2011-01-01

    Objective To examine what the tobacco industry knows about the potential effects menthol may have on nicotine dependence. Methods A snowball strategy was used to systematically search the Legacy Tobacco Documents Library (http://legacy.library.ucsf.edu/) between 22 February and 29 April, 2010. Of the approximately 11 million documents available in the Legacy Tobacco Documents Library, the iterative searches returned tens of thousands of results. We qualitatively analysed a final collection of 309 documents relevant the effects of menthol on nicotine dependence. Results The tobacco industry knows that menthol overrides the harsh taste of tobacco and alleviates nicotine's irritating effects, synergistically interacts with nicotine, stimulates the trigeminal nerve to elicit a ‘liking’ response for a tobacco product, and makes low tar, low nicotine tobacco products more acceptable to smokers than non-mentholated low delivery products. Conclusion Menthol is not only used in cigarettes as a flavour additive; tobacco companies know that menthol also has sensory effects and interacts with nicotine to produce tobacco products that are easier to smoke, thereby making it easier to expose smokers, especially those who are new and uninitiated, to the addictive power of nicotine. PMID:21504929

  18. Nicotine Enhances Interspecies Relationship between Streptococcus mutans and Candida albicans

    PubMed Central

    Qiu, Wei; Zhang, Keke; Zhou, Xuedong; Ren, Biao; He, Jinzhi; Xu, Xin

    2017-01-01

    Streptococcus mutans and Candida albicans are common microorganisms in the human oral cavity. The synergistic relationship between these two species has been deeply explored in many studies. In the present study, the effect of alkaloid nicotine on the interspecies between S. mutans and C. albicans is explored. We developed a dual-species biofilm model and studied biofilm biomass, biofilm structure, synthesis of extracellular polysaccharides (EPS), and expression of glucosyltransferases (Gtfs). Biofilm formation and bacterial and fungal cell numbers in dual-species biofilms increased in the presence of nicotine. More C. albicans cells were present in the dual-species biofilms in the nicotine-treated groups as determined by scanning electron microscopy. The synthesis of EPS was increased by 1 mg/ml of nicotine as detected by confocal laser scanning microscopy. The result of qRT-PCR showed gtfs expression was upregulated when 1 mg/ml of nicotine was used. We speculate that nicotine promoted the growth of S. mutans, and more S. mutans cells attracted more C. albicans cells due to the interaction between two species. Since S. mutans and C. albicans are putative pathogens for dental caries, the enhancement of the synergistic relationship by nicotine may contribute to caries development in smokers. PMID:28280743

  19. 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.

  20. Nicotinic acetylcholine receptor from chick optic lobe.

    PubMed Central

    Norman, R I; Mehraban, F; Barnard, E A; Dolly, J O

    1982-01-01

    An alpha-bungarotoxin-sensitive nicotinic cholinergic receptor from chick optic lobe has been completely purified. Its standard sedimentation coefficient is 9.1 S. The value near 12 S reported for the related component from other brain regions can be reproduced when the initial extraction is by Triton X-100 (rather than Lubrol PX), but other protein is then complexed with it. A single subunit of apparent molecular weight 54,000 is detected, and this subunit is specifically labeled by bromo-[3H]acetylcholine, but only after disulfide reduction. The same size subunit likewise is labeled in the protein (purified similarly) from the rest of the chick brain which can also bind alpha-bungarotoxin and nicotinic ligands. Immunological crossreactivity is demonstrated between both of these proteins with an antiserum to pure acetylcholine receptor from skeletal muscle. The acetylcholine receptor from chick optic lobe and the alpha-bungarotoxin-binding protein from the rest of the brain appear similar or identical by a series of criteria and are related to (but with differences from) peripheral acetylcholine receptors. Images PMID:6175967

  1. Structural Studies of Nicotinoids: Cotinine versus Nicotine.

    PubMed

    Uriarte, Iciar; Pérez, Cristóbal; Caballero-Mancebo, Elena; Basterretxea, Francisco J; Lesarri, Alberto; Fernández, José A; Cocinero, Emilio J

    2017-02-17

    Nicotinoids are agonists of the acetylcholine receptor (nAChR) and play important biochemical and pharmacological roles. Herein, we report on the structure and conformation of cotinine, and compare its molecular properties with the nicotine prototype, from which it only differs in the addition of a carbonyl group. This investigation included a theoretical survey of the effects of rotamerization of the pyridine moiety, the puckering of the pyrrolidinone ring and the internal rotation of the methyl group. The experimental work examined the rotational spectrum of the molecule in a supersonic expansion, using both broadband chirped-pulse excitation techniques and cavity microwave spectrometers. Two conformers were observed for cotinine, and the fine and hyperfine structures arising from the two quadrupolar (14) N nuclei and the methyl internal rotor were fully analyzed. The two observed conformers share the same twisted conformation of the five-membered ring, but differ in a roughly 180° rotamerization around the C-C bond connecting the two rings. The energy barriers for the internal rotation of the methyl group in cotinine (4.55(4) and 4.64(3) kJ mol(-1) , respectively) are much lower than in nicotine (estimated in 16.5 kJ mol(-1) ). The combination of different intramolecular electronic effects, hydrogen bonding and possible binding differences to receptor molecules arising from the carbonyl group could explain the lower affinity of cotinine for nAChRs.

  2. 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

  3. Electronic nicotine delivery systems: a research agenda.

    PubMed

    Etter, Jean-François; Bullen, Chris; Flouris, Andreas D; Laugesen, Murray; Eissenberg, Thomas

    2011-05-01

    Electronic nicotine delivery systems (ENDS, also called electronic cigarettes or e-cigarettes) are marketed to deliver nicotine and sometimes other substances by inhalation. Some tobacco smokers report that they used ENDS as a smoking cessation aid. Whether sold as tobacco products or drug delivery devices, these products need to be regulated, and thus far, across countries and states, there has been a wide range of regulatory responses ranging from no regulation to complete bans. The empirical basis for these regulatory decisions is uncertain, and more research on ENDS must be conducted in order to ensure that the decisions of regulators, health care providers and consumers are based on science. However, there is a dearth of scientific research on these products, including safety, abuse liability and efficacy for smoking cessation. The authors, who cover a broad range of scientific expertise, from basic science to public health, suggest research priorities for non-clinical, clinical and public health studies. They conclude that the first priority is to characterize the safety profile of these products, including in long-term users. If these products are demonstrated to be safe, their efficacy as smoking cessation aids should then be tested in appropriately designed trials. Until these studies are conducted, continued marketing constitutes an uncontrolled experiment and the primary outcome measure, poorly assessed, is user health. Potentially, this research effort, contributing to the safety and efficacy of new smoking cessation devices and to the withdrawal of dangerous products, could save many lives.

  4. Electronic nicotine delivery systems: a research agenda

    PubMed Central

    Etter, Jean-François; Bullen, Chris; Flouris, Andreas D; Laugesen, Murray; Eissenberg, Thomas

    2011-01-01

    Electronic nicotine delivery systems (ENDS, also called electronic cigarettes or e-cigarettes) are marketed to deliver nicotine and sometimes other substances by inhalation. Some tobacco smokers report that they used ENDS as a smoking cessation aid. Whether sold as tobacco products or drug delivery devices, these products need to be regulated, and thus far, across countries and states, there has been a wide range of regulatory responses ranging from no regulation to complete bans. The empirical basis for these regulatory decisions is uncertain, and more research on ENDS must be conducted in order to ensure that the decisions of regulators, health care providers and consumers are based on science. However, there is a dearth of scientific research on these products, including safety, abuse liability and efficacy for smoking cessation. The authors, who cover a broad range of scientific expertise, from basic science to public health, suggest research priorities for non-clinical, clinical and public health studies. They conclude that the first priority is to characterize the safety profile of these products, including in long-term users. If these products are demonstrated to be safe, their efficacy as smoking cessation aids should then be tested in appropriately designed trials. Until these studies are conducted, continued marketing constitutes an uncontrolled experiment and the primary outcome measure, poorly assessed, is user health. Potentially, this research effort, contributing to the safety and efficacy of new smoking cessation devices and to the withdrawal of dangerous products, could save many lives. PMID:21415064

  5. Nicotinic excitation of rat hypoglossal motoneurons.

    PubMed

    Chamberlin, N L; Bocchiaro, C M; Greene, R W; Feldman, J L

    2002-01-01

    Hypoglossal motoneurons (HMNs), which innervate the tongue muscles, are involved in several important physiological functions, including the maintenance of upper airway patency. The neural mechanisms that affect HMN excitability are therefore important determinants of effective breathing. Obstructive sleep apnea is a disorder characterized by recurrent collapse of the upper airway that is likely due to decline of pharyngeal motoneuron activity during sleep. Because cholinergic neuronal activity is closely coupled to wake and sleep states, we tested the effects and pharmacology of nicotinic acetylcholine receptor (nAChR) activation on HMNs. We made intracellular recordings from HMNs in medullary slices from neonatal rats and found that local application of the nicotinic agonist, 1,1-dimethyl-4-phenylpiperazinium iodide, excited HMNs by a Ca(2+)-sensitive, and TTX-insensitive inward current that was blocked by dihydro-beta-erythroidine (IC(50): 19+/-3 nM), methyllycaconitine (IC(50): 32+/-7 nM), and mecamylamine (IC(50): 88+/-11 nM), but not by alpha-bungarotoxin (10 nM). This is consistent with responses being mediated by postsynaptic nAChRs that do not contain the alpha7 subunit. These results suggest that nAChR activation may contribute to central maintenance of upper airway patency and that the decline in firing rate of cholinergic neurons during sleep could potentially disfacilitate airway dilator muscle activity, contributing to airway obstruction.

  6. Effects of nicotine on response inhibition and interference control.

    PubMed

    Ettinger, Ulrich; Faiola, Eliana; Kasparbauer, Anna-Maria; Petrovsky, Nadine; Chan, Raymond C K; Liepelt, Roman; Kumari, Veena

    2017-04-01

    Nicotine is a cholinergic agonist with known pro-cognitive effects in the domains of alerting and orienting attention. However, its effects on attentional top-down functions such as response inhibition and interference control are less well characterised. Here, we investigated the effects of 7 mg transdermal nicotine on performance on a battery of response inhibition and interference control tasks. A sample of N = 44 healthy adult non-smokers performed antisaccade, stop signal, Stroop, go/no-go, flanker, shape matching and Simon tasks, as well as the attentional network test (ANT) and a continuous performance task (CPT). Nicotine was administered in a within-subjects, double-blind, placebo-controlled design, with order of drug administration counterbalanced. Relative to placebo, nicotine led to significantly shorter reaction times on a prosaccade task and on CPT hits but did not significantly improve inhibitory or interference control performance on any task. Instead, nicotine had a negative influence in increasing the interference effect on the Simon task. Nicotine did not alter inter-individual associations between reaction times on congruent trials and error rates on incongruent trials on any task. Finally, there were effects involving order of drug administration, suggesting practice effects but also beneficial nicotine effects when the compound was administered first. Overall, our findings support previous studies showing positive effects of nicotine on basic attentional functions but do not provide direct evidence for an improvement of top-down cognitive control through acute administration of nicotine at this dose in healthy non-smokers.

  7. Carbon Disulfide Mediates Socially-Acquired Nicotine Self-Administration

    PubMed Central

    Wang, Tengfei; Chen, Hao

    2014-01-01

    The social environment plays a critical role in smoking initiation as well as relapse. We previously reported that rats acquired nicotine self-administration with an olfactogustatory cue only when another rat consuming the same cue was present during self-administration. Because carbon disulfide (CS2) mediates social learning of food preference in rodents, we hypothesized that socially acquired nicotine self-administration is also mediated by CS2. We tested this hypothesis by placing female adolescent Sprague-Dawley rats in operant chambers equipped with two lickometers. Licking on the active spout meeting a fixed-ratio 10 schedule triggered the concurrent delivery of an i.v. infusion (saline, or 30 µg/kg nicotine, free base) and an appetitive olfactogustatory cue containing CS2 (0–500 ppm). Rats that self-administered nicotine with the olfactogustatory cue alone licked less on the active spout than on the inactive spout. Adding CS2 to the olfactogustatory cue reversed the preference for the spouts. The group that received 500 ppm CS2 and the olfactogustatory cue obtained a significantly greater number of nicotine infusions than other groups. After extinction training, the original self-administration context reinstated nicotine-seeking behavior in all nicotine groups. In addition, in rats that received the olfactogustatory cue and 500 ppm CS2 during SA, a social environment where the nicotine-associated olfactory cue is present, induced much stronger drug-seeking behavior compared to a social environment lacking the olfactogustatory cue. These data established that CS2 is a critical signal that mediates social learning of nicotine self-administration with olfactogustatory cues in rodents. Additionally, these data showed that the social context can further enhance the drug-seeking behavior induced by the drug-taking environment. PMID:25532105

  8. Direct block of inward rectifier potassium channels by nicotine.

    PubMed

    Wang, H; Yang, B; Zhang, L; Xu, D; Wang, Z

    2000-04-01

    Nicotine has been shown to depolarize membrane potential and to lengthen action potential duration in isolated cardiac preparations. To investigate whether this is a consequence of direct interaction of nicotine with inward rectifier K(+) channels which are a key determinant of membrane potentials, we assessed the effects of nicotine on two cloned human inward rectifier K(+) channels, Kir2.1 and Kir2.2, expressed in Xenopus oocytes and the native inward rectifier K(+) current I(K1) in canine ventricular myocytes. Nicotine suppressed Kir2.1-expressed currents at varying potentials negative to -20 mV, with more pronounced effects on the outward current between -70 and -20 mV relative to the inward current at hyperpolarized potentials (below -70 mV). The inhibition was concentration dependent. For the outward currents recorded at -50 mV, the IC50 was 165 +/- 18 microM. Similar effects of nicotine were observed for Kir2.2. A more potent effect was seen with I(K1) in canine myocytes. Significant blockade ( approximately 60%) was found at a concentration as low as 0.5 microM and the IC50 was 4.0 +/- 0.4 microM. The effects in both oocytes and myocytes were partially reversible upon washout of nicotine. Antagonists of nicotinic receptors (mecamylamine, 100 microM), muscarinic receptors (atropine, 1 microM), and beta-adrenergic receptors (propranolol, 1 microM) all failed to restore the depressed currents, suggesting that nicotine acted directly on Kir channels, independent of catecholamine release. This property of nicotine may explain its membrane-depolarizing and action potential duration-prolonging effects in cardiac cells and may contribute in part to its ability to promote propensity for cardiac arrhythmias.

  9. 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 (0, 0.25, 0.5 and 1 mg) by indicating how similar each sample was to the training dose. Generalization took place in the presence of either EL or DE music. Nicotine-appropriate responding during generalization was linearly related to dose, with subjects being able to distinguish 0.5mg of nicotine from placebo. Nicotine-appropriate responding at generalization was higher when the context (type of music) was the same as the one employed during discrimination training when nicotine was administered (i.e. a context-dependent generalization effect was present). In addition, it was shown that the context-dependent effect was due to the properties of the EL music. These data provide the first evidence that extrinsic context can facilitate nicotine discrimination in humans. In addition, the findings suggest that this facilitatory effect is not a general effect but is sensitive to specific attributes of the context.

  10. Nicotine inhibits potassium currents in Aplysia bag cell neurons.

    PubMed

    White, Sean H; Sturgeon, Raymond M; Magoski, Neil S

    2016-06-01

    Acetylcholine and the archetypal cholinergic agonist, nicotine, are typically associated with the opening of ionotropic receptors. In the bag cell neurons, which govern the reproductive behavior of the marine snail, Aplysia californica, there are two cholinergic responses: a relatively large acetylcholine-induced current and a relatively small nicotine-induced current. Both currents are readily apparent at resting membrane potential and result from the opening of distinct ionotropic receptors. We now report a separate current response elicited by applying nicotine to cultured bag cell neurons under whole cell voltage-clamp. This current was ostensibly inward, best resolved at depolarized voltages, presented a noncooperative dose-response with a half-maximal concentration near 1.5 mM, and associated with a decrease in membrane conductance. The unique nicotine-evoked response was not altered by intracellular perfusion with the G protein blocker GDPβS or exposure to classical nicotinic antagonists but was occluded by replacing intracellular K(+) with Cs(+) Consistent with an underlying mechanism of direct inhibition of one or more K(+) channels, nicotine was found to rapidly reduce the fast-inactivating A-type K(+) current as well as both components of the delayed-rectifier K(+) current. Finally, nicotine increased bag cell neuron excitability, which manifested as reduction in spike threshold, greater action potential height and width, and markedly more spiking to continuous depolarizing current injection. In contrast to conventional transient activation of nicotinic ionotropic receptors, block of K(+) channels could represent a nonstandard means for nicotine to profoundly alter the electrical properties of neurons over prolonged periods of time.

  11. Relationships between trait urgency, smoking reinforcement expectancies, and nicotine dependence.

    PubMed

    Pang, Raina D; Hom, Marianne S; Geary, Bree A; Doran, Neal; Spillane, Nichea S; Guillot, Casey R; Leventhal, Adam M

    2014-01-01

    Urgency (i.e., the tendency to act rashly during negative/positive affect) may increase vulnerability to a variety of risky behaviors. This cross-sectional study of nontreatment-seeking smokers examined the relationship between urgency, level of nicotine dependence, and smoking reinforcement expectancies. Both positive and negative urgency were associated with nicotine dependence. Mediational analyses illustrated that smoking reinforcement expectancies significantly accounted for urgency-dependence relations, with negative reinforcement expectancies displaying incremental mediational effects. If replicated and extended, these findings may support the use of treatments that modify beliefs regarding smoking reinforcement outcomes as a means of buffering the risk of nicotine dependence carried by urgency.

  12. Counteractive effects of cannabinoid and nicotine-addictive behavior.

    PubMed

    Han, Jing; Liu, Zhiqiang; Ren, Wei; Zhang, Xia

    2011-03-09

    Our recent results suggest that cannabinoid exposure induces conditioned place preference (CPP) through facilitated induction of synaptic long-term depression at dopamine circuitry of the midbrain ventral tegmental area (VTA). Here, we show that chronic nicotine exposure also induces CPP, but facilitates the induction of synaptic long-term potentiation in the VTA. Coadministration of cannabinoid and nicotine leads to a blockade of facilitated long-term depression and long-term potentiation induction in these neurons and elimination of CPP. These findings point to counteractive effects of cannabinoid and nicotine-addictive behavior through opposite changes in synaptic plasticity of dopamine circuitry of the VTA.

  13. A vaccine for nicotine dependence: targeting the drug rather than the brain.

    PubMed

    Pentel, Paul; Malin, David

    2002-01-01

    Nicotine is the principal addictive component of tobacco. Vaccination of rats against nicotine elicits the production of nicotine-specific antibodies which can bind and sequester nicotine in serum and extracellular fluid, reduce nicotine distribution to brain, and reduce many of nicotine's physiologic and behavioral effects. Vaccination reduces the distribution to brain of both a single nicotine dose and chronic nicotine infusion at rates approximating cigarette smoking. The passive transfer of nicotine-specific antibodies (from vaccinated rabbits) into rats attenuates numerous actions of nicotine: increases in blood pressure and locomotor activity, the induction of nicotine dependence, the relief of nicotine withdrawal by subsequent nicotine and the stimulus properties that allow rats to discriminate a nicotine from a saline injection. Vaccination of rats against nicotine also reduces nicotine-induced dopamine release in the reward pathway of the brain and the reinstatement of nicotine responding, a model for relapse. Because nicotine vaccines target the drug rather than the brain, and the antibodies themselves do not cross the blood-brain barrier, immunization should circumvent the central nervous system side effects that limit the usable dosage of other medications for tobacco dependence. Nicotine vaccines have not yet been tested in humans. The effects of these vaccines in rats are highly dependent upon the concentration of antibody in serum, and are more often partial than complete. If effective for treating tobacco dependence in humans, vaccination will likely benefit from concurrent use of counseling (as is the case with other medications for smoking cessation) and perhaps from its combination with other medications that act via different mechanisms.

  14. Surveillance of moist snuff: total nicotine, moisture, pH, un-ionized nicotine, and tobacco-specific nitrosamines.

    PubMed

    Richter, Patricia; Hodge, Knachelle; Stanfill, Stephen; Zhang, Liqin; Watson, Clifford

    2008-11-01

    In 2005, approximately 2.3% of U.S. adults used smokeless tobacco. Moist snuff leads all types of smokeless tobacco in revenues and marketing expenditures. The U.S. Surgeon General has concluded that smokeless tobacco use can lead to nicotine addiction. The National Toxicology Program of the National Institutes of Health has classified smokeless tobacco as a human carcinogen. Tobacco-specific nitrosamines (TSNAs) are potent carcinogens in smokeless tobacco products, and the pH of the product influences the content of un-ionized nicotine which is the form of nicotine most rapidly absorbed in the mouth. The Centers for Disease Control and Prevention analyzed 40 top-selling brands of moist snuff to measure nicotine, moisture, pH, un-ionized nicotine, and TSNAs, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). The study findings indicate that moist snuff brands varied widely in content of rapidly absorbed, addictive un-ionized nicotine (500-fold range) and of carcinogenic TSNAs (18-fold range). Product characteristics such as packaging and moisture content appeared to be correlated with concentrations of un-ionized nicotine, and flavor characteristics of low-priced brands may correlate with TSNA concentrations. These findings warrant further study in light of (a) the marketing of smokeless tobacco for use in places where smoking is prohibited, (b) the promotion of smokeless tobacco as a harm-reduction product, and (c) the ever-expanding number of highly flavored smokeless varieties brought to the market.

  15. The pharmacological activity of nicotine and nornicotine on nAChRs subtypes: relevance to nicotine dependence and drug discovery.

    PubMed

    Papke, Roger L; Dwoskin, Linda P; Crooks, Peter A

    2007-04-01

    Cigarette smoking and other forms of tobacco use deliver an array of pharmacologically active alkaloids, including nicotine and ultimately various metabolites of these substances. While nornicotine is a significant component in tobacco as well as a minor systemic metabolite of nicotine, nornicotine appears to be N-demethylated locally in the brain where it accumulates at relatively high levels after chronic nicotine administration. We have now examined the effects of nornicotine on specific combinations of neuronal nicotinic acetylcholine receptor (nAChR) subunits expressed in Xenopus oocytes and compared these responses to those evoked by acetylcholine and nicotine. Of the nAChR subtypes studied, we have found that alpha7 receptors are very responsive to nornicotine (EC50 approximately 17 micromol/L I(max) 50%, compared with acetylcholine (ACh)). nAChRs containing the ligand-binding domain of the alpha6 subunits (in the form of an alpha6/alpha3 chimera) are also strongly responsive to nornicotine (EC50 approximately 4 micromol/L I(max) 50%, compared with ACh). Alpha7-type nAChRs have been suggested to be potential therapeutic targets for Alzheimer's disease, schizophrenia and possibly other pathologies. nAChRs containing alpha6 subunits have been suggested to have a role in nicotine-evoked dopamine release. Thus, understanding the actions of nornicotine in the brain may have significance for both emerging therapeutics and the management of nicotine dependence.

  16. Effects of nicotinic and NMDA receptor channel blockers on intravenous cocaine and nicotine self-administration in mice.

    PubMed

    Blokhina, Elena A; Kashkin, Vladimir A; Zvartau, Edwin E; Danysz, Wojciech; Bespalov, Anton Y

    2005-03-01

    Previous studies have indicated that blockade of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors prevents acquisition of instrumental behaviors reinforced by food and drugs such as morphine and cocaine. The present study aimed to extend this evidence by testing whether NMDA receptor channel blocker, memantine, would exert similar effects on acquisition of cocaine and nicotine self-administration in mice. Inasmuch as memantine also acts as nicotinic receptor channel blocker, this study assessed the effects of mecamylamine and MRZ 2/621 that are more selective nicotinic blockers. Adult male Swiss mice were allowed to self-administer cocaine (0.8-2.4 microg/infusion) or nicotine (0.08-0.32 microg/infusion) during the 30-min test. Pretreatment with memantine (0.1-10 mg/kg) prevented acquisition of nicotine but not cocaine self-administration. Pretreatment with mecamylamine (0.3-3 mg/kg) and MRZ 2/621 (0.3-10 mg/kg) produced dose-dependent suppression of both cocaine and nicotine self-administration. Taken together with the previous reports, these results indicate that nicotinic receptor blockers antagonize acute reinforcing effects of cocaine while NMDA receptor blockade may have limited effectiveness.

  17. CHRNA5/A3/B4 Variant rs3743078 and Nicotine-Related Phenotypes: Indirect Effects Through Nicotine Craving

    PubMed Central

    Shmulewitz, Dvora; Meyers, Jacquelyn L.; Wall, Melanie M.; Aharonovich, Efrat; Frisch, Amos; Spivak, Baruch; Weizman, Abraham; Edenberg, Howard J.; Gelernter, Joel; hasin, Deborah S.

    2016-01-01

    Objective: Nicotine craving is considered an important element in the persistence of cigarette smoking, but little is known about the role of craving in the widely recognized association between variants mapped to the neuronal nicotinic acetylcholine receptor (CHRN) genes on chromosome 15 and nicotine phenotypes. Method: The associations between CHRNA5–CHRNA3–CHRNB4 variants and cigarettes per day (CPD), the Fagerström Test for Nicotine Dependence (FTND), and craving were analyzed in data from 662 lifetime smokers from an Israeli adult Jewish household sample. Indirect effects of genotype on nicotine phenotypes through craving were formally tested using regression and bootstrapping procedures. Results: At CHRNA3, allele G of rs3743078 was associated with increased craving, CPD, and FTND scores: Participants with one or two copies of the G allele had, on average, higher scores on the craving scale (p = .0025), more cigarettes smoked (p = .0057), and higher scores on the FTND (p = .0024). With craving in the model, variant rs3743078 showed a significant indirect effect through craving on CPD (p = .0026) and on FTND score (p = .0024). A sizeable proportion of the total rs3743078 effect on CPD (56.4%) and FTND (65.2%) was indirect through craving. Conclusions: These results suggest that nicotine craving may play a central role in nicotine use disorders and may have utility as a therapeutic target. PMID:26997181

  18. Effects of nicotine-specific antibodies, Nic311 and Nic-IgG, on the transfer of nicotine across the human placenta.

    PubMed

    Nekhayeva, Ilona A; Nanovskaya, Tatiana N; Pentel, Paul R; Keyler, Dan E; Hankins, Gary D V; Ahmed, Mahmoud S

    2005-11-25

    The adverse effects of smoking during pregnancy on fetal development are, in part, due to nicotine. These effects may be due to the actions of nicotine in fetal circulation or on placental functions. In pregnant rats, vaccination with a nicotine immunogen reduces the transfer of nicotine from the maternal to fetal circulation. However, extrapolation of these results to pregnant women might not be valid due to the well-recognized differences between human and rat placentas. In the current investigation, the effects of nicotine-specific antibodies on the transfer of nicotine from the maternal to fetal circuit of the dually perfused human placental lobule were determined. Two types of nicotine-specific antibodies were investigated; nicotine-specific mouse monoclonal antibody (Nic311, K(d) for nicotine 60nM) and IgG from rabbits vaccinated with a nicotine immunogen (Nic-IgG, K(d) 1.6nM). Transfer of the antibodies from maternal to fetal circuits was negligible. Both rabbit Nic-IgG and, to a lesser extent, mouse monoclonal Nic311 significantly reduced nicotine transfer from the maternal to fetal circuit as well as the retention of the drug by placental tissue. These effects were mediated by a substantial increase in the protein binding of nicotine and a reduction in the unbound nicotine concentration. Therefore, the data cited in this report suggest that the use of nicotine-specific antibodies might reduce fetal exposure to the drug, and that antibody affinity for nicotine is a key determinant of the extent of nicotine transfer.

  19. Nicotinic Acetylcholine Receptor (nAChR) Dependent Chorda Tympani Taste Nerve Responses to Nicotine, Ethanol and Acetylcholine.

    PubMed

    Ren, Zuo Jun; Mummalaneni, Shobha; Qian, Jie; Baumgarten, Clive M; DeSimone, John A; Lyall, Vijay

    2015-01-01

    Nicotine elicits bitter taste by activating TRPM5-dependent and TRPM5-independent but neuronal nAChR-dependent pathways. The nAChRs represent common targets at which acetylcholine, nicotine and ethanol functionally interact in the central nervous system. Here, we investigated if the nAChRs also represent a common pathway through which the bitter taste of nicotine, ethanol and acetylcholine is transduced. To this end, chorda tympani (CT) taste nerve responses were monitored in rats, wild-type mice and TRPM5 knockout (KO) mice following lingual stimulation with nicotine free base, ethanol, and acetylcholine, in the absence and presence of nAChR agonists and antagonists. The nAChR modulators: mecamylamine, dihydro-β-erythroidine, and CP-601932 (a partial agonist of the α3β4* nAChR), inhibited CT responses to nicotine, ethanol, and acetylcholine. CT responses to nicotine and ethanol were also inhibited by topical lingual application of 8-chlorophenylthio (CPT)-cAMP and loading taste cells with [Ca2+]i by topical lingual application of ionomycin + CaCl2. In contrast, CT responses to nicotine were enhanced when TRC [Ca2+]i was reduced by topical lingual application of BAPTA-AM. In patch-clamp experiments, only a subset of isolated rat fungiform taste cells exposed to nicotine responded with an increase in mecamylamine-sensitive inward currents. We conclude that nAChRs expressed in a subset of taste cells serve as common receptors for the detection of the TRPM5-independent bitter taste of nicotine, acetylcholine and ethanol.

  20. Nicotinic Acetylcholine Receptor (nAChR) Dependent Chorda Tympani Taste Nerve Responses to Nicotine, Ethanol and Acetylcholine

    PubMed Central

    Ren, Zuo Jun; Mummalaneni, Shobha; Qian, Jie; Baumgarten, Clive M.; DeSimone, John A.; Lyall, Vijay

    2015-01-01

    Nicotine elicits bitter taste by activating TRPM5-dependent and TRPM5-independent but neuronal nAChR-dependent pathways. The nAChRs represent common targets at which acetylcholine, nicotine and ethanol functionally interact in the central nervous system. Here, we investigated if the nAChRs also represent a common pathway through which the bitter taste of nicotine, ethanol and acetylcholine is transduced. To this end, chorda tympani (CT) taste nerve responses were monitored in rats, wild-type mice and TRPM5 knockout (KO) mice following lingual stimulation with nicotine free base, ethanol, and acetylcholine, in the absence and presence of nAChR agonists and antagonists. The nAChR modulators: mecamylamine, dihydro-β-erythroidine, and CP-601932 (a partial agonist of the α3β4* nAChR), inhibited CT responses to nicotine, ethanol, and acetylcholine. CT responses to nicotine and ethanol were also inhibited by topical lingual application of 8-chlorophenylthio (CPT)-cAMP and loading taste cells with [Ca2+]i by topical lingual application of ionomycin + CaCl2. In contrast, CT responses to nicotine were enhanced when TRC [Ca2+]i was reduced by topical lingual application of BAPTA-AM. In patch-clamp experiments, only a subset of isolated rat fungiform taste cells exposed to nicotine responded with an increase in mecamylamine-sensitive inward currents. We conclude that nAChRs expressed in a subset of taste cells serve as common receptors for the detection of the TRPM5-independent bitter taste of nicotine, acetylcholine and ethanol. PMID:26039516

  1. Chronic Exposure to Nicotine Enhances Insulin Sensitivity through α7 Nicotinic Acetylcholine Receptor-STAT3 Pathway

    PubMed Central

    Wang, Pei; Song, Jie; Le, Ying-Ying; Viollet, Benoit; Miao, Chao-Yu

    2012-01-01

    This study was to investigate the effect of nicotine on insulin sensitivity and explore the underlying mechanisms. Treatment of Sprague-Dawley rats with nicotine (3 mg/kg/day) for 6 weeks reduced 43% body weight gain and 65% blood insulin level, but had no effect on blood glucose level. Both insulin tolerance test and glucose tolerance test demonstrated that nicotine treatment enhanced insulin sensitivity. Pretreatment of rats with hexamethonium (20 mg/kg/day) to antagonize peripheral nicotinic receptors except for α7 nicotinic acetylcholine receptor (α7-nAChR) had no effect on the insulin sensitizing effect of nicotine. However, the insulin sensitizing effect but not the bodyweight reducing effect of nicotine was abrogated in α7-nAChR knockout mice. Further, chronic treatment with PNU-282987 (0.53 mg/kg/day), a selective α7-nAChR agonist, significantly enhanced insulin sensitivity without apparently modifying bodyweight not only in normal mice but also in AMP-activated kinase-α2 knockout mice, an animal model of insulin resistance with no sign of inflammation. Moreover, PNU-282987 treatment enhanced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in skeletal muscle, adipose tissue and liver in normal mice. PNU-282987 treatment also increased glucose uptake by 25% in C2C12 myotubes and this effect was total abrogated by STAT3 inhibitor, S3I-201. All together, these findings demonstrated that nicotine enhanced insulin sensitivity in animals with or without insulin resistance, at least in part via stimulating α7-nAChR-STAT3 pathway independent of inflammation. Our results contribute not only to the understanding of the pharmacological effects of nicotine, but also to the identifying of new therapeutic targets against insulin resistance. PMID:23251458

  2. Brain regions mediating α3β4 nicotinic antagonist effects of 18-MC on nicotine self-administration.

    PubMed

    Glick, Stanley D; Sell, Elizabeth M; McCallum, Sarah E; Maisonneuve, Isabelle M

    2011-11-01

    18-Methoxycoronaridine (18-MC), a putative anti-addictive agent, has been shown to decrease the self-administration of several drugs of abuse in rats. 18-MC is a potent antagonist at α3β4 nicotinic receptors. Consistent with high densities of α3β4 nicotinic receptors being located in the medial habenula and the interpeduncular nucleus, 18-MC has been shown to act in these regions to decrease both morphine and methamphetamine self-administration. The present study was conducted to determine if 18-MC's effect on nicotine self-administration is mediated by acting in these same brain regions. Because moderate densities of α3β4 receptors occur in the dorsolateral tegmentum, ventral tegmental area, and basolateral amygdala, these brain areas were also examined as potential sites of action of 18-MC. Local administration of 18-MC into either the medial habenula, the basolateral amygdala or the dorsolateral tegmentum decreased nicotine self-administration. Surprisingly, local administration of 18-MC into the interpeduncular nucleus increased nicotine self-administration while local administration of 18-MC into the ventral tegmental area had no effect on nicotine self-administration. Similar effects were produced by local administration of either mecamylamine or conotoxin AuIB. These data are consistent with the hypothesis that 18-MC decreases nicotine self-administration by indirectly modulating the dopaminergic mesolimbic pathway via blockade of α3β4 nicotinic receptors in the medial habenula, basolateral amygdala, and dorsolateral tegmentum. The data also suggest that an action of 18-MC in the interpeduncular nucleus may attenuate aversive and/or depressive effects of nicotine.

  3. Neuronal Nicotinic Acetylcholine Receptor Structure and Function and Response to Nicotine.

    PubMed

    Dani, John A

    2015-01-01

    Nicotinic acetylcholine receptors (nAChRs) belong to the "Cys-loop" superfamily of ligand-gated ion channels that includes GABAA, glycine, and serotonin (5-HT3) receptors. There are 16 homologous mammalian nAChR subunits encoded by a multigene family. These subunits combine to form many different nAChR subtypes with various expression patterns, diverse functional properties, and differing pharmacological characteristics. Because cholinergic innervation is pervasive and nAChR expression is extremely broad, practically every area of the brain is impinged upon by nicotinic mechanisms. This review briefly examines the structural and functional properties of the receptor/channel complex itself. The review also summarizes activation and desensitization of nAChRs by the low nicotine concentrations obtained from tobacco. Knowledge of the three-dimensional structure and the structural characteristics of channel gating has reached an advanced stage. Likewise, the basic functional properties of the channel also are reasonably well understood. It is these receptor/channel properties that underlie the participation of nAChRs in nearly every anatomical region of the mammalian brain.

  4. The role of nicotinic acetylcholine receptors in the primary reinforcing and reinforcement-enhancing effects of nicotine.

    PubMed

    Palmatier, Matthew I; Liu, Xiu; Caggiula, Anthony R; Donny, Eric C; Sved, Alan F

    2007-05-01

    The primary reinforcing effects of nicotine are mediated by the drugs action at central nervous system nicotinic acetylcholine receptors (nAChRs). Although previous studies have demonstrated that nicotine potently enhances responding for non-pharmacological stimuli, the role of nAChRs in this reinforcement-enhancing effect is not known. The two reinforcement-related effects of nicotine can be dissociated in a paradigm that provides concurrent access to drug infusions and a non-pharmacological visual stimulus (VS). The present study characterized the role of nAChRs in the primary reinforcing effect of nicotine and the reinforcement-enhancing effect of nicotine. For rats with access to VS (VS-Only), nicotine (NIC-Only), both reinforcers contingent upon one response (NIC+VS) or both reinforcers contingent upon separate responses (2-Lever), unit dose-response relationships (0, 30, 60, or 90 microg/kg/infusion, free base) were determined over a 22-day acquisition period. Expression of the two reinforcement-related effects of nicotine was manipulated by pharmacological antagonism of nAChRs (1 mg/kg mecamylamine, subcutaneous, 5-min before the session) or by substituting saline for nicotine infusions (ie extinction) over a series of seven test sessions. Unit dose manipulations yielded an inverse dose-response relationship for active lever responding in the NIC+VS group. The dose-response relationships for rats with independent access to each reinforcer (2-Lever group) were relatively flat. For the 2-Lever group, acute mecamylamine challenge blocked the reinforcement-enhancing effects of nicotine, VS-lever responding decreased to basal levels on the first day of mecamylamine treatment or saline substitution (to the level of the VS-Only group). In contrast, nicotine-lever responding decreased gradually over the 7-day testing period (similar to saline extinction). The two reinforcement-related effects of nicotine are mediated by nAChRs but can be dissociated by acute and

  5. Animal Models of Nicotine Exposure: Relevance to Second-Hand Smoking, Electronic Cigarette Use, and Compulsive Smoking

    PubMed Central

    Cohen, Ami; George, Olivier

    2013-01-01

    Much evidence indicates that individuals use tobacco primarily to experience the psychopharmacological properties of nicotine and that a large proportion of smokers eventually become dependent on nicotine. In humans, nicotine acutely produces positive reinforcing effects, including mild euphoria, whereas a nicotine abstinence syndrome with both somatic and affective components is observed after chronic nicotine exposure. Animal models of nicotine self-administration and chronic exposure to nicotine have been critical in unveiling the neurobiological substrates that mediate the acute reinforcing effects of nicotine and emergence of a withdrawal syndrome during abstinence. However, important aspects of the transition from nicotine abuse to nicotine dependence, such as the emergence of increased motivation and compulsive nicotine intake following repeated exposure to the drug, have only recently begun to be modeled in animals. Thus, the neurobiological mechanisms that are involved in these important aspects of nicotine addiction remain largely unknown. In this review, we describe the different animal models available to date and discuss recent advances in animal models of nicotine exposure and nicotine dependence. This review demonstrates that novel animal models of nicotine vapor exposure and escalation of nicotine intake provide a unique opportunity to investigate the neurobiological effects of second-hand nicotine exposure, electronic cigarette use, and the mechanisms that underlie the transition from nicotine use to compulsive nicotine intake. PMID:23761766

  6. Use of caffeine and nicotine in people with schizophrenia.

    PubMed

    Williams, Jill M; Gandhi, Kunal K

    2008-06-01

    There are numerous reports of increased use of both caffeine and nicotine in schizophrenia. Clinical effects of these substances are important and may complicate the interpretation of schizophrenia symptoms and antipsychotic medication side effects. Use of caffeine and nicotine is often linked, with smokers using more caffeine due to interacting metabolic effects. Studies of neurobiology reveal evidence of specific brain changes in schizophrenia that are impacted by nicotine and caffeine and suggest self-medication effects. Interestingly both substances are linked to altered inhibitory mechanisms in brain functioning. Few studies have examined both simultaneously which is critical given their metabolic and symptomatic interactions. This paper reviews use of caffeine and nicotine in people with schizophrenia and gives recommendations for their further study.

  7. Brain imaging and the effects of caffeine and nicotine.

    PubMed

    Dager, S R; Friedman, S D

    2000-12-01

    Caffeine and nicotine are the most common psychostimulant drugs used worldwide. Structural neuroimaging findings associated with caffeine and nicotine consumption are limited and primarily reflect the putative relationship between smoking and white matter hyperintensities (WMH), a finding that warrants further appraisal of its clinical implications. The application of newer brain imaging modalities that measure subtle haemodynamic changes or tissue-based chemistry in order to better elucidate brain functional processes, including mechanisms underlying addiction to nicotine and caffeine and the brain functional consequences, provide intriguing findings. Potential influences of caffeine and nicotine on the functional contrast, or metabolic response, to neural activation also necessitates the careful appraisal of the effects that these commonly used drugs may have on the results of functional imaging.

  8. [Sialadenosis of the parotid gland after chronic nicotine use].

    PubMed

    Maier, H; Mall, G; Born, I A

    1991-04-01

    The effect of chronic nicotine consumption on the morphology of the rat parotid gland was investigated. After nicotine-loading for 90 days with an average serum nicotine concentration of 78 +/- 10 ng/ml a significant increase of acinar cell volume was observed. The acinar cells contained an increased number of enlarged light, immature secretory granules. These findings were confirmed by morphometric analysis. Further an increase of the granular endoplasmatic reticulum, an enlargement of the Golgi complexes and an oedematous swelling of intraglandular autonomous nerves were found. Similar findings have been observed in the parotid gland of animals and also of humans chronically treated with the beta-adrenergic drugs aludrin and isoproterenol, and have been termed "sialadenosis". It seems likely that the observed morphological alterations are caused by a stimulation of glandular beta-adrenoceptors via a nicotine-induced release of catecholamines from the adrenals.

  9. Rapid Sensitization of Physiological, Neuronal, and Locomotor Effects of Nicotine: Critical Role of Peripheral Drug Actions

    PubMed Central

    Lenoir, Magalie; Tang, Jeremy S.; Woods, Amina S.

    2013-01-01

    Repeated exposure to nicotine and other psychostimulant drugs produces persistent increases in their psychomotor and physiological effects (sensitization), a phenomenon related to the drugs' reinforcing properties and abuse potential. Here we examined the role of peripheral actions of nicotine in nicotine-induced sensitization of centrally mediated physiological parameters (brain, muscle, and skin temperatures), cortical and VTA EEG, neck EMG activity, and locomotion in freely moving rats. Repeated injections of intravenous nicotine (30 μg/kg) induced sensitization of the drug's effects on all these measures. In contrast, repeated injections of the peripherally acting analog of nicotine, nicotine pyrrolidine methiodide (nicotinePM, 30 μg/kg, i.v.) resulted in habituation (tolerance) of the same physiological, neuronal, and behavioral measures. However, after repeated nicotine exposure, acute nicotinePM injections induced nicotine-like physiological responses: powerful cortical and VTA EEG desynchronization, EMG activation, a large brain temperature increase, but weaker hyperlocomotion. Additionally, both the acute locomotor response to nicotine and nicotine-induced locomotor sensitization were attenuated by blockade of peripheral nicotinic receptors by hexamethonium (3 mg/kg, i.v.). These data suggest that the peripheral actions of nicotine, which precede its direct central actions, serve as a conditioned interoceptive cue capable of eliciting nicotine-like physiological and neural responses after repeated nicotine exposure. Thus, by providing a neural signal to the CNS that is repeatedly paired with the direct central effects of nicotine, the drug's peripheral actions play a critical role in the development of nicotine-induced physiological, neural, and behavioral sensitization. PMID:23761889

  10. Pharmacologic characterization of a nicotine-discriminative stimulus in rhesus monkeys.

    PubMed

    Cunningham, Colin S; Javors, Martin A; McMahon, Lance R

    2012-06-01

    This study examined mechanisms by which nicotine (1.78 mg/kg base s.c.) produces discriminative stimulus effects in rhesus monkeys. In addition to nicotine, various test compounds were studied including other nicotinic acetylcholine receptor agonists (varenicline and cytisine), antagonists [mecamylamine and the α4β2 receptor-selective antagonist dihydro-β-erythroidine (DHβE)], a nicotinic acetylcholine receptor antagonist/indirect-acting catecholamine agonist (bupropion), and non-nicotinics (cocaine and midazolam). Nicotine, varenicline, and cytisine dose-dependently increased drug-lever responding; the ED(50) values were 0.47, 0.53, and 39 mg/kg, respectively. Bupropion and cocaine produced 100% nicotine-lever responding in a subset of monkeys, whereas mecamylamine, DHβE, and midazolam produced predominantly vehicle-lever responding. The training dose of nicotine resulted in 1128 ng/ml cotinine in saliva. Mecamylamine antagonized the discriminative stimulus effects of nicotine and varenicline, whereas DHβE was much less effective. Nicotine and varenicline had synergistic discriminative stimulus effects. In monkeys responding predominantly on the vehicle lever after a test compound (bupropion, cocaine, and midazolam), that test compound blocked the nicotine-discriminative stimulus, perhaps reflecting a perceptual-masking phenomenon. These results show that nicotine, varenicline, and cytisine produce discriminative stimulus effects through mecamylamine-sensitive receptors (i.e., nicotinic acetylcholine) in primates, whereas the involvement of DHβE-sensitive receptors (i.e., α4β2) is unclear. The current nicotine-discrimination assay did not detect a difference in agonist efficacy between nicotine, varenicline, and cytisine, but did show evidence of involvement of dopamine. The control that nicotine has over choice behavior can be disrupted by non-nicotinic compounds, suggesting that non-nicotinics could be exploited to decrease the control that tobacco has

  11. Megakaryocytes and platelets express nicotinic acetylcholine receptors but nicotine does not affect megakaryopoiesis or platelet function.

    PubMed

    Schedel, Angelika; Kaiser, Kerstin; Uhlig, Stefanie; Lorenz, Florian; Sarin, Anip; Starigk, Julian; Hassmann, Dennis; Bieback, Karen; Bugert, Peter

    2016-01-01

    In our previous investigations we have shown that platelets and their precursors express nicotinic α7 acetylcholine receptors (nAChRα7) that are involved in platelet function and in vitro differentiation of the megakaryoblastic cell line MEG-01. In this study, we were interested in the expression analysis of additional nAChR and the effects of nicotine in an ex vivo model using megakaryocytic cells differentiated from cord blood derived CD34(+) cells (CBMK) and an in vivo model using blood samples from smokers. CBMK were differentiated with thrombopoietin (TPO) for up to 17 days. Quantitative real-time PCR (QRT-PCR), Western blot analysis and flow cytometry were used to investigate nAChR expression (nAChRα7, nAChRα4, nAChRβ2) and nicotine effects. In blood samples of 15 nonsmokers and 16 smokers platelet parameters (count, mean platelet volume--MPV and platelet distribution width--PDW) were determined as indicators for changes of in vivo megakaryopoiesis. Platelet function was determined by the use of whole blood aggregometry and flow cytometry. The functional role of nAChR was evaluated using specific antagonists in aggregometry. CHRNA7, CHRNA4 and CHRNB2 gene transcripts and the corresponding proteins could be identified in CBMK during all stages of differentiation. Platelets contain nAChRα7 and nAChRβ2 but not nAChRα4. Nicotine had no effect on TPO-induced differentiation of CBMK. There was no significant difference in all platelet parameters of the smokers compared to the nonsmokers. In line with this, cholinergic gene transcripts as well as the encoded proteins were equally expressed in both the study groups. Despite our observation of nAChR expression in megakaryopoiesis and platelets, we were not able to detect effects of nicotine in our ex vivo and in vivo models. Thus, the functional role of the nAChR in these cells remains open.

  12. Impulsive behavior and nicotinic acetylcholine receptors.

    PubMed

    Ohmura, Yu; Tsutsui-Kimura, Iku; Yoshioka, Mitsuhiro

    2012-01-01

    Higher impulsivity is thought to be a risk factor for drug addiction, criminal involvement, and suicide. Excessive levels of impulsivity are often observed in several psychiatric disorders including attention-deficit/hyperactivity disorder and schizophrenia. Previous studies have demonstrated that nicotinic acetylcholine receptors (nAChRs) are involved in impulsive behavior. Here, we introduce recent advances in this field and describe the role of the following nAChR-related brain mechanisms in modulating impulsive behavior: dopamine release in the ventral striatum; α4β2 nAChRs in the infralimbic cortex, which is a ventral part of the medial prefrontal cortex (mPFC); and dopamine release in the mPFC. We also suggest several potential therapeutic drugs to address these mechanisms in impulsivity-related disorders and explore future directions to further elucidate the roles of central nAChRs in impulsive behavior.

  13. Progesterone Modulates a Neuronal Nicotinic Acetylcholine Receptor

    NASA Astrophysics Data System (ADS)

    Valera, S.; Ballivet, M.; Bertrand, D.

    1992-10-01

    The major brain nicotinic acetylcholine receptor is assembled from two subunits termed α 4 and nα 1. When expressed in Xenopus oocytes, these subunits reconstitute a functional acetylcholine receptor that is inhibited by progesterone levels similar to those found in serum. In this report, we show that the steroid interacts with a site located on the extracellular part of the protein, thus confirming that inhibition by progesterone is not due to a nonspecific perturbation of the membrane bilayer or to the activation of second messengers. Because inhibition by progesterone does not require the presence of agonist, is voltage-independent, and does not alter receptor desensitization, we conclude that the steroid is not an open channel blocker. In addition, we show that progesterone is not a competitive inhibitor but may interact with the acetylcholine binding site and that its effect is independent of the ionic permeability of the receptor.

  14. Conotoxins Targeting Nicotinic Acetylcholine Receptors: An Overview

    PubMed Central

    Lebbe, Eline K. M.; Peigneur, Steve; Wijesekara, Isuru; Tytgat, Jan

    2014-01-01

    Marine snails of the genus Conus are a large family of predatory gastropods with an unparalleled molecular diversity of pharmacologically active compounds in their venom. Cone snail venom comprises of a rich and diverse cocktail of peptide toxins which act on a wide variety of ion channels such as voltage-gated sodium- (NaV), potassium- (KV), and calcium- (CaV) channels as well as nicotinic acetylcholine receptors (nAChRs) which are classified as ligand-gated ion channels. The mode of action of several conotoxins has been the subject of investigation, while for many others this remains unknown. This review aims to give an overview of the knowledge we have today on the molecular pharmacology of conotoxins specifically interacting with nAChRs along with the structure–function relationship data. PMID:24857959

  15. [Desensitization of the nicotinic acetylcholine receptor].

    PubMed

    Quiñonez, M; Rojas, L

    1994-01-01

    In biological membranes, ionic channels act speeding up ion movements. Each ionic channel is excited by a specific stimulus (i.e. electric, mechanical, chemical, etc.). Chemically activated ionic channels (CAIC), such as the nicotinic acetylcholine receptor (nAChR), suffer desensitization when the receptor site is still occupied by the agonist molecule. The desensitized CAIC is a non functional channel state regarded as a particular case of receptors rundown. CAIC desensitization only involve reduced activity and not their membrane elimination. Desensitization is important to control synaptic transmission and the development of the nervous system. In this review we discuss results related to its production, modulation and some aspects associated to models that consider it. Finally, an approach combining molecular biology and electrophysiology techniques to understand desensitization and its importance in biological systems is presented.

  16. Binding of HIV-1 gp120 to the nicotinic receptor.

    PubMed

    Bracci, L; Lozzi, L; Rustici, M; Neri, P

    1992-10-19

    We previously described a significant sequence homology between HIV-1 gp120 and the functional sites responsible for the specific binding of snake curare-mimetic neurotoxins and rabies virus glycoprotein to the nicotinic acetylcholine receptor. Here we report findings about the existence of a mechanism of functional molecular mimicry which could enable the binding of HIV-1 gp120 to nicotinic acetylcholine receptors in muscle cells and neurons.

  17. Is nicotine protective against Parkinson's disease? An experimental analysis.

    PubMed

    García-Montes, José-Rubén; Boronat-García, Alejandra; López-Colomé, Ana-María; Bargas, José; Guerra-Crespo, Magdalena; Drucker-Colín, René

    2012-11-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and its projections. Reports show a lower incidence of PD in smokers compared to nonsmokers. Nicotine reduce motor symptoms of patients already diagnosed with PD. However, the mechanisms underlying the effects of nicotine in the dopamine (DA) depleted striatum remain elusive. This study evaluates the effects of chronic nicotine administration on PD motor symptoms in an attempt to mimic the chronic self-administration of nicotine in smokers. To achieve this, we used the 6-OHDA hemiparkinson rat model evaluating the amphetamine/apomorphine induced circling behavior, in rats whose daily water intake included nicotine. We found that chronic nicotine reduced amphetamine (AMPH) induced circling behavior by 40%, whereas apomorphine (APO) increased this behavior by 230%. High-performance liquid chromatography (HPLC) revealed that AMPH produced a 50% decrease of DA release in the intact hemisphere, while on the striatum of the lesioned side, receptor binding assays showed an increased affinity to D1 receptors and a concurrent decrease in D2 receptors. c-Fos activity showed through double labeling, that cell types involved in nicotine action were low threshold (LTS) and fast spiking (FS) inter-neurons, which increased in the DA-depleted striatum. We also observed an increase in the activity of D1 medium spiny neurons (D1 MSN), a striatal population with a major role in motor control. Our results show that chronic nicotine does not specifically protect against degeneration, but rather modifies DA receptor dynamics, suggesting that it could be used as a therapeutic element in PD pathology.

  18. Effects of oxytocin on nicotine withdrawal in rats.

    PubMed

    Manbeck, Katherine E; Shelley, David; Schmidt, Clare E; Harris, Andrew C

    2014-01-01

    Development of medications that attenuate symptoms of nicotine withdrawal may be useful for facilitating smoking cessation. The neuropeptide oxytocin (OXY) decreases withdrawal signs and other addiction-related effects of several drugs of abuse in animals, but has not been examined in a preclinical model of nicotine addiction. The goal of this study was to examine the effects of OXY on nicotine withdrawal in rats, measured as increases in somatic signs and elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior) during antagonist-precipitated withdrawal from a chronic nicotine infusion. Effects of OXY on baseline ICSS thresholds in non-dependent rats were also evaluated. OXY (0.06 - 1.0mg/kg, i.p.) blocked withdrawal-induced elevations in somatic signs in nicotine-dependent rats without affecting somatic signs in non-dependent rats. In contrast, OXY did not affect nicotine withdrawal-induced elevations in ICSS thresholds. Relatively high doses of OXY (0.75 or 2.0mg/kg) elevated baseline ICSS thresholds in non-dependent rats. These findings demonstrate that OXY blocks somatic signs but not elevations in ICSS thresholds during antagonist-precipitated nicotine withdrawal. The ability of higher OXY doses to elevate baseline ICSS thresholds in non-dependent rats may reflect an aversive and/or motoric effect. These data suggest that OXY-based medications may be useful for treating the somatic component of the nicotine withdrawal syndrome, but may not be effective in attenuating withdrawal-induced anhedonia.

  19. Differences between nicotine and cocaine-induced conditioned place preferences.

    PubMed

    Sershen, H; Hashim, A; Lajtha, A

    2010-01-15

    In previous studies, we found differences between nicotine and cocaine-induced changes in the levels of neurotransmitters in various brain areas, which suggested differences in their reward - preference mechanisms. The present study was based on the idea that drug preference is modulated by a number of different factors, among them several neurotransmitters and their receptors, and antagonists of specific receptors will influence preference. We also assumed that the factors (components of reward mechanisms) involved are different in the case of different drugs. We compared the inhibition of nicotine preference with cocaine preference. We assayed preference as conditioned place preference (CPP) and measured CPP inhibition by receptor subtype antagonists using mice. In general, induced CPP of cocaine was stronger than of nicotine as shown by more time spent in the nonpreferred area after conditioning with cocaine. We measured inhibition by four antagonists: mecamylamine, atropine, SCH23390, and phentolamine: antagonists respectively of nicotinic, and muscarinic acetylcholine, dopamine D1, and alpha noradrenergic receptors. The inhibition by the antagonists of cocaine CPP was lower in most instances than that of nicotine CPP. Atropine and SCH23390 inhibited nicotine and cocaine CPP approximately to the same degree, while the inhibition by mecamylamine and phentolamine of nicotine CPP was 100%; that of cocaine was 20% and 0, respectively. We conclude that several receptor systems and transmitters play a role in drug preference, some represent essential elements or circuits, some may be only required partially or their role can be partially substituted. The composition of such systems is different for different drugs - in the present study, some of the components influencing CPP are different for nicotine as opposed to cocaine.

  20. Epigenetics of nicotine: another nail in the coughing.

    PubMed

    Volkow, Nora D

    2011-11-02

    In a mouse model, chronic nicotine exposure before cocaine use exacerbated the epigenetic, gene-expression, electrophysiological, and behavioral effects that occur during the transition from acute to chronic responses to cocaine that have been linked with the addictive process. Nicotine enhancement of the effects can be mimicked with an inhibitor of chromatin-modifying enzymes (class I and II histone deacetylases). These findings may spur the discovery of therapeutics for the treatment of addiction.

  1. Effects of Nicotine Withdrawal in Adult Male and Female Rats

    DTIC Science & Technology

    2008-01-01

    differences in withdrawal symptomatology (e.g., Svikis, Hatsumaki, Hughes, Caroll, & Pickins, 1986 ), and other research reporting more nicotine...relapse (e.g. Covey, Glassman & Stetner, 1990; Gritz, Carr, & Marcus, 1991; Gunn, 1986 ). Patten and Martin concluded that overall, the results of the...self- reported withdrawal symptomatology (e.g., Svikis, et aI., 1986 ; Hughes, 1992), and other researchers finding more self-reported nicotine

  2. [Cigarette and coffee--pharmacokinetics interaction between nicotine and caffeine].

    PubMed

    Florek, Ewa; Enko, Jolanta; Piekoszewski, Wojciech

    2009-01-01

    Coffee drinking and tobacco smoking stand nicotine and caffeine the number one licit psychoactive substances. Many people inseparably combine a cup of coffee with cigarette. The two most important compounds in these products, nicotine and caffeine can influence on there concentration and pharmacodynamics activity in the body. The changes of the level of these compounds can be caused by changes of the pharmacokinetics on the way of enzyme induction by other chemical individuals content in the coffee and tobacco smoke.

  3. Nicotine delivery, retention, and pharmacokinetics from various electronic cigarettes

    PubMed Central

    St. Helen, Gideon; Havel, Christopher; Dempsey, Delia; Jacob, Peyton; Benowitz, Neal L.

    2015-01-01

    Aims To measure the systemic retention of nicotine, propylene glycol (PG), and vegetable glycerin (VG) in electronic cigarette (e-cigarette) users, and assess the abuse liability of e-cigarettes by characterizing nicotine pharmacokinetics. Design E-cigarette users recruited over the Internet participated in a 1-day research ward study. Subjects took 15 puffs from their usual brand of e-cigarette. Exhaled breath was trapped in gas-washing bottles and blood was sampled before and several time after use. Setting San Francisco, California, USA. Participants Thirteen healthy, experienced adult e-cigarette users (6 females and 7 males). Measurements Plasma nicotine was analyzed by GC-MS/MS, and nicotine, VG, and PG in e-liquids and gas traps were analyzed by LC-MS/MS. Heart rate changes and subjective effects were assessed. Findings E-cigarettes delivered an average of 1.3 (0.9–1.8) mg (mean and 95% CI) of nicotine and 94% of the inhaled dose, 1.2 (0.8–1.7), was systemically retained. Average maximum plasma nicotine concentration (Cmax) was 8.4 (5.4–11.5) ng/mL and time of maximal concentration (Tmax) was 2 to 5 minutes; one participant had Tmax of 30 minutes. 89% and 92% of VG and PG, respectively, was systemically retained. Heart rate increased by an average of 8.0 bpm after 5 minutes. Withdrawal and urge to smoke decreased and the e-cigarettes were described as satisfying. Conclusions E-cigarettes can deliver levels of nicotine that are comparable to or higher than typical tobacco cigarettes, with similar systemic retention. Although the average maximum plasma nicotine concentration in experienced e-cigarettes users appears to be generally lower than what has been reported from tobacco cigarette use, the shape of the pharmacokinetic curve is similar, suggesting addictive potential. PMID:26430813

  4. Nicotine elicits prolonged calcium signaling along ventral hippocampal axons.

    PubMed

    Zhong, Chongbo; Talmage, David A; Role, Lorna W

    2013-01-01

    Presynaptic nicotinic acetylcholine receptors (nAChRs) have long been implicated in the modulation of CNS circuits. We previously reported that brief exposure to low concentrations of nicotine induced sustained potentiation of glutamatergic transmission at ventral hippocampal (vHipp)-striatal synapses. Here, we exploited nAChR subtype-selective antagonists and agonists and α7*nAChR knockout mutant mice (α7-/-) to elucidate the signaling mechanisms underlying nAChR-mediated modulation of synaptic transmission. Using a combination of micro-slices culture from WT and α7-/-mice, calcium imaging, and immuno-histochemical techniques, we found that nicotine elicits localized and oscillatory increases in intracellular Ca(2+) along vHipp axons that persists for up to 30 minutes. The sustained phase of the nicotine-induced Ca(2+) response was blocked by α-BgTx but not by DHβE and was mimicked by α7*nAChR agonists but not by non-α7*nAChR agonists. In vHipp slices from α7-/- mice, nicotine elicited only transient increases of axonal Ca(2+) signals and did not activate CaMKII. The sustained phase of the nicotine-induced Ca(2+) response required localized activation of CaMKII, phospholipase C, and IP3 receptor mediated Ca(2+)-induced Ca(2+) release (CICR). In conclusion, activation of presynaptic nAChRs by nicotine elicits Ca(2+) influx into the presynaptic axons, the sustained phase of the nicotine-induced Ca(2+) response requires that axonal α7*nAChR activate a downstream signaling network in the vHipp axons.

  5. NMDA receptors regulate nicotine-enhanced brain reward function and intravenous nicotine self-administration: Role of the ventral tegmental area and central nucleus of the amygdala

    PubMed Central

    Kenny, Paul J.; Chartoff, Elena; Roberto, Marisa; Carlezon, William A.; Markou, Athina

    2009-01-01

    Nicotine is considered an important component of tobacco responsible for the smoking habit in humans. Nicotine increases glutamate-mediated transmission throughout brain reward circuitries. This action of nicotine could potentially contribute to its intrinsic rewarding and reward-enhancing properties, which motivate consumption of the drug. Here we show that the competitive N-methyl-D-aspartate (NMDA) receptor antagonist LY235959 (0.5–2.5 mg/kg) abolished nicotine-enhanced brain reward function, reflected in blockade of the lowering of intracranial self-stimulation (ICSS) thresholds usually observed after experimenter-administered (0.25 mg/kg) or intravenously self-administered (0.03 mg/kg/infusion) nicotine injections. The highest LY235959 dose (5 mg/kg) tested reversed the hedonic valence of nicotine from positive to negative, reflected in nicotine-induced elevations of ICSS thresholds. LY235959 doses that reversed nicotine-induced lowering of ICSS thresholds also markedly decreased nicotine self-administration without altering responding for food reinforcement, whereas the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist NBQX had no effects on nicotine intake. In addition, nicotine self-administration upregulated NMDA receptor subunit expression in the central nucleus of the amygdala (CeA) and ventral tegmental area (VTA), suggesting important interactions between nicotine and the NMDA receptor. Furthermore, nicotine (1 μM) increased NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) in rat CeA slices, similar to its previously described effects in the VTA. Finally, infusion of LY235959 (0.1–10 ng/side) into the CeA or VTA decreased nicotine self-administration. Taken together, these data suggest that NMDA receptors, including those in the CeA and VTA, gate the magnitude and valence of the effects of nicotine on brain reward systems, thereby regulating motivation to consume the drug. PMID:18418357

  6. Early postnatal nicotine exposure causes hippocampus-dependent memory impairments in adolescent mice: Association with altered nicotinic cholinergic modulation of LTP, but not impaired LTP.

    PubMed

    Nakauchi, Sakura; Malvaez, Melissa; Su, Hailing; Kleeman, Elise; Dang, Richard; Wood, Marcelo A; Sumikawa, Katumi

    2015-02-01

    Fetal nicotine exposure from smoking during pregnancy causes long-lasting cognitive impairments in offspring, yet little is known about the mechanisms that underlie this effect. Here we demonstrate that early postnatal exposure of mouse pups to nicotine via maternal milk impairs long-term, but not short-term, hippocampus-dependent memory during adolescence. At the Schaffer collateral (SC) pathway, the most widely studied synapses for a cellular correlate of hippocampus-dependent memory, the induction of N-methyl-D-aspartate receptor-dependent transient long-term potentiation (LTP) and protein synthesis-dependent long-lasting LTP are not diminished by nicotine exposure, but rather unexpectedly the threshold for LTP induction becomes lower after nicotine treatment. Using voltage sensitive dye to visualize hippocampal activity, we found that early postnatal nicotine exposure also results in enhanced CA1 depolarization and hyperpolarization after SC stimulation. Furthermore, we show that postnatal nicotine exposure induces pervasive changes to the nicotinic modulation of CA1 activity: activation of nicotinic receptors no longer increases CA1 network depolarization, acute nicotine inhibits rather than facilitates the induction of LTP at the SC pathway by recruiting an additional nicotinic receptor subtype, and acute nicotine no longer blocks LTP induction at the temporoammonic pathway. These findings reflect the pervasive impact of nicotine exposure during hippocampal development, and demonstrate an association of hippocampal memory impairments with altered nicotinic cholinergic modulation of LTP, but not impaired LTP. The implication of our results is that nicotinic cholinergic-dependent plasticity is required for long-term memory formation and that postnatal nicotine exposure disrupts this form of plasticity.

  7. Actions of octocoral and tobacco cembranoids on nicotinic receptors.

    PubMed

    Ferchmin, P A; Pagán, Oné R; Ulrich, Henning; Szeto, Ada C; Hann, Richard M; Eterović, Vesna A

    2009-12-15

    Nicotinic acetylcholine receptors (AChRs) are pentameric proteins that form agonist-gated cation channels through the plasma membrane. AChR agonists and antagonists are potential candidates for the treatment of neurodegenerative diseases. Cembranoids are naturally occurring diterpenoids that contain a 14-carbon ring. These diterpenoids interact with AChRs in complex ways: as irreversible inhibitors at the agonist sites, as noncompetitive inhibitors, or as positive modulators, but no cembranoid was ever shown to have agonistic activity on AChRs. The cembranoid eupalmerin acetate displays positive modulation of agonist-induced currents in the muscle-type AChR and in the related gamma-aminobutyric acid (GABA) type A receptor. Moreover, cembranoids display important biological effects, many of them mediated by nicotinic receptors. Cembranoids from tobacco are neuroprotective through a nicotinic anti-apoptotic mechanism preventing excitotoxic neuronal death which in part could result from anti-inflammatory properties of cembranoids. Moreover, tobacco cembranoids also have anti-inflammatory properties which could enhance their neuroprotective properties. Cembranoids from tobacco affect nicotine-related behavior: they increase the transient initial ataxia caused by first nicotine injection into naive rats and inhibit the expression of locomotor sensitization to repeated injections of nicotine. In addition, cembranoids are known to act as anti-tumor compounds. In conclusion, cembranoids provide a promising source of lead drugs for many clinical areas, including neuroprotection, smoking-cessation, and anti-cancer therapies.

  8. Concentration of Nicotine and Glycols in 27 Electronic Cigarette Formulations.

    PubMed

    Peace, Michelle R; Baird, Tyson R; Smith, Nathaniel; Wolf, Carl E; Poklis, Justin L; Poklis, Alphonse

    2016-07-01

    Personal battery-powered vaporizers or electronic cigarettes were developed to deliver a nicotine vapor such that smokers could simulate smoking tobacco without the inherent pathology of inhaled tobacco smoke. Electronic cigarettes and their e-cigarette liquid formulations are virtually unregulated. These formulations are typically composed of propylene glycol and/or glycerin, flavoring components and an active drug, such as nicotine. Twenty-seven e-cigarette liquid formulations that contain nicotine between 6 and 22 mg/L were acquired within the USA and analyzed by various methods to determine their contents. They were screened by Direct Analysis in Real Time™ Mass Spectrometry (DART-MS). Nicotine was confirmed and quantitated by high-performance liquid chromatography-tandem mass spectrometry, and the glycol composition was confirmed and quantitated by gas chromatography-mass spectrometry. The DART-MS screening method was able to consistently identify the exact mass peaks resulting from the protonated molecular ion of nicotine, glycol and a number of flavor additives within 5 mmu. Nicotine concentrations were determined to range from 45 to 131% of the stated label concentration, with 18 of the 27 have >10% variance. Glycol composition was generally accurate to the product description, with only one exception where the propylene glycol to glycerin percentage ratio was stated as 50:50 and the determined concentration of propylene glycol to glycerin was 81:19 (% v/v). No unlabeled glycols were detected in these formulations.

  9. Neuronal effects of nicotine during auditory selective attention in schizophrenia.

    PubMed

    Smucny, Jason; Olincy, Ann; Rojas, Donald C; Tregellas, Jason R

    2016-01-01

    Although nicotine has been shown to improve attention deficits in schizophrenia, the neurobiological mechanisms underlying this effect are poorly understood. We hypothesized that nicotine would modulate attention-associated neuronal response in schizophrenia patients in the ventral parietal cortex (VPC), hippocampus, and anterior cingulate based on previous findings in control subjects. To test this hypothesis, the present study examined response in these regions in a cohort of nonsmoking patients and healthy control subjects using an auditory selective attention task with environmental noise distractors during placebo and nicotine administration. In agreement with our hypothesis, significant diagnosis (Control vs. Patient) X drug (Placebo vs. Nicotine) interactions were observed in the VPC and hippocampus. The interaction was driven by task-associated hyperactivity in patients (relative to healthy controls) during placebo administration, and decreased hyperactivity in patients after nicotine administration (relative to placebo). No significant interaction was observed in the anterior cingulate. Task-associated hyperactivity of the VPC predicted poor task performance in patients during placebo. Poor task performance also predicted symptoms in patients as measured by the Brief Psychiatric Rating Scale. These results are the first to suggest that nicotine may modulate brain activity in a selective attention-dependent manner in schizophrenia.

  10. Nicotine effect on cardiovascular system and ion channels.

    PubMed

    Hanna, Salma Toma

    2006-03-01

    Smoking is a leading cause of cardiovascular disease, hypertension, myocardial infarction, and stroke. Nicotine is one of the components of cigarette smoke. Nicotine effects on the cardiovascular system reflect the activity of the nicotine receptors centrally and on peripheral autonomic ganglia. It has been found that cigarette smoke extract-induced contraction of porcine coronary arteries is related to superoxide anion-mediated degradation of nitric oxide. Treatment of rabbit aortas with an oxygen free radicals scavenger attenuated cigarette smoke impairment of arterial relaxation. Treatment of smokers with vitamin C, an antioxidant, improved impaired endothelium-dependent reactivity of large peripheral arteries. Thus it appears that chronic smoking and acute exposure to cigarette smoke extract may alter endothelium-dependent reactivity via the production of oxygen derived free radicals. This review discusses the effects of nicotine on resistance arterioles, compliance arteries, smooth muscle cells, and ion channels in the cardiovascular system. We discuss studies performed on humans, nicotine-exposed animals, and cell cultures yielding varying and inconsistent results that may be due to differences in experimental design, species, and the dose of exposure. Nicotine exposure appears to induce a combination of free radical production, vascular wall adhesion, and a reduction of fibrinolytic activity in the plasma.

  11. [Development of analytical method for determination nicotine metabolites in urine].

    PubMed

    Piekoszewski, Wojciech; Florek, Ewa; Kulza, Maksymilian; Wilimowska, Jolanta; Loba, Urszula

    2009-01-01

    The assay of biomarkers in biological material is the most popular and reliable method in estimate exposure to tobacco smoke. Nicotine and its metabolites qualify to the most specific biomarkers for tobacco smoke. Currently the most often used are cotinine and trans-3'-hydroxycotinine. The aim of this study was development of easy and quick method of determining nicotine and its main metabolites with high performance liquid chromatography--available in most laboratories. Nicotine and its metabolites in urine (cotinine, trans-3'-hydroxycotinine, nornicotine and nicotine N-oxide) was determined by means of high performance liquid chromatography with spectrometry detection (HPLC-UV). The determined compounds were extracted from urine by means of the liquid-liquid technique, before analysed by the HPLC method. Developed technique of high performance liquid chromatography proved to be useful to assessment nicotine and its four metabolites in smokers, though further research are necessary. The further modification of procedure is required, because of the interferences of cotinine N-oxide with matrix, which prevent determination. Increasing the efficiency of extraction nicotine and nornicotine could enable the determination in people exposed on environmental tobacco smoke (ETS). This study confirm other authors' observations that 3'-hydroxycotinine might be equivalent with cotinine predictor of tobacco smoke exposure, however further studies are required.

  12. Is low-nicotine Marlboro snus really snus?

    PubMed

    Foulds, Jonathan; Furberg, Helena

    2008-02-27

    Swedish snus is a medium/high nicotine delivery, low-nitrosamine moist smokeless tobacco product that has been estimated to be at least 90% less harmful than smoked tobacco. More men use snus than smoke cigarettes in Sweden, and a quarter of male former smokers quit by switching to snus. Leading multinational cigarette manufacturers have begun test-marketing snus-like products in the United States and other countries. The version of Philip Morris' Marlboro snus currently being marketed in the United States differs from Swedish snus in many ways; it has lower moisture content and pH, but most puzzling is its very low nicotine delivery. Philip Morris, the market-leader in United States cigarette sales, may have designed the product so that it does not satisfy nicotine cravings and fails to enable smokers to switch. In this paper we compare and contrast Swedish snus and Marlboro snus, and speculate as to why Philip Morris may have intentionally designed a product that delivers very low levels of nicotine. We recommend that Philip Morris cease using the term "snus" to refer to dry tobacco products with low nicotine delivery, so that the term be reserved for moist, low-toxin, medium/high nicotine delivery smokeless tobacco products that are qualitatively similar to the leading brands in Sweden.

  13. Ryanodine receptor-2 upregulation and nicotine-mediated plasticity.

    PubMed

    Ziviani, Elena; Lippi, Giordano; Bano, Daniele; Munarriz, Eliana; Guiducci, Stefania; Zoli, Michele; Young, Kenneth W; Nicotera, Pierluigi

    2011-01-05

    Nicotine, the major psychoactive component of cigarette smoke, modulates neuronal activity to produce Ca2+-dependent changes in gene transcription. However, the downstream targets that underlie the long-term effects of nicotine on neuronal function, and hence behaviour, remain to be elucidated. Here, we demonstrate that nicotine administration to mice upregulates levels of the type 2 ryanodine receptor (RyR2), a Ca2+-release channel present on the endoplasmic reticulum, in a number of brain areas associated with cognition and addiction, notably the cortex and ventral midbrain. Nicotine-mediated RyR2 upregulation was driven by CREB, and caused a long-lasting reinforcement of Ca2+ signalling via the process of Ca2+-induced Ca2+ release. RyR2 upregulation was itself required for long-term phosphorylation of CREB in a positive-feedback signalling loop. We further demonstrate that inhibition of RyR-activation in vivo abolishes sensitization to nicotine-induced habituated locomotion, a well-characterised model for onset of drug dependence. Our findings, therefore, indicate that gene-dependent reprogramming of Ca2+ signalling is involved in nicotine-induced behavioural changes.

  14. Nicotine dependance among adult male smokers in rural Egypt.

    PubMed

    Gad, Rita R; El-Setouhy, Maged; Haroun, Amany; Gadalla, Shahinaz; Abdel-Aziz, Fatma; Aboul-Fotouh, Aisha; Mohamed, Mostafa K; Mikhail, Nabiel; Israel, Ebenezer

    2003-12-01

    Nicotine dependence is a significant public health problem. This study describes the nicotine dependence status among male adults in rural communities in Egypt. A survey was carried out in five rural villages in Egypt to study the smoking prevalence. A total of 938 current smokers were identified and their nicotine dependence status was studied. About 9% of all smokers in the studied villages were found to have heavy dependence to nicotine. Heavy dependence was associated with younger age of smoking initiation (p<0.05) and more smoking in the first hours of the day (p<0.001). Heavy dependent smokers are less likely to quit smoking (p<0.001), lack the confidence to quit by themselves (p<0.001) and less likely to have tried to quit earlier (p<0.001). Dependent smokers are more likely to smoke in the presence of their children (p<0.001). Reasons for smoking included the habit of smoking helping them to keep them going when tired, to make them alert and not knowing what to do with their hands without a cigarette. The main reasons they identified for restarting smoking after quitting were the signs of withdrawal namely headaches, irritability and difficulty in concentration. Nicotine dependence status and attributes were comparable to studies reported in other countries around the world. Enhanced behavioral and medical intervention strategies are needed to motivate helping both low and heavy nicotine dependent smokers to increase the number and effectiveness of quit attempts.

  15. Associations between nicotine dependence, anhedonia, urgency and smoking motives.

    PubMed

    Roys, Melanie; Weed, Keri; Carrigan, Maureen; MacKillop, James

    2016-11-01

    Models of nicotine dependence have suggested that the association between urgency, a subconstruct of impulsivity, and smoking behaviors may be mediated by motivations. Motives that are driven by expectations that smoking will relieve negative affect or increase positive affect may be especially salient in persons who have depression symptoms such as anhedonia. Support for associations between symptoms of depression, urgency, and addiction has been found for alcohol dependence, but empirical analysis is lacking for an interactive effect of urgency and depression symptoms on nicotine dependence. The current study investigated relationships among the urgency facet of impulsivity, anhedonia, smoking motives, and nicotine dependence with secondary analyses of a sample of 1084 daily smokers using simultaneous moderation and multiple mediation analyses. The moderation analysis revealed that although urgency was significantly associated with smoking at average or higher levels of anhedonia, it was unrelated to smoking when few anhedonia symptoms were endorsed. Further, multiple mediation analyses revealed that the smoking motives of craving, cue exposure, positive reinforcement, and tolerance significantly mediated the relationship between urgency and nicotine dependence. Results suggest that models of alcohol addiction that include an interactive effect of urgency and certain symptoms of depression may be applied to nicotine dependence. Examination of the multiple mediational pathways between urgency and nicotine dependence suggests directions for intervention efforts.

  16. Validation of a GC-FID method for rapid quantification of nicotine in fermented extracts prepared from Nicotiana tabacum fresh leaves and studies of nicotine metabolites.

    PubMed

    Millet, Agnès; Stintzing, Florian; Merfort, Irmgard

    2009-07-12

    A new GC-FID method, which allows rapid and reliable quantitation of nicotine in tobacco leaf extracts, was developed and validated. To avoid nicotine adsorption on the column, an amine-deactivated capillary column was used. The method developed was applied to study the degradation of nicotine in a fermented aqueous extract, and a loss of nearly 20% of nicotine over 12 months was observed. Careful inspection of GC-MS runs from concentrated samples of the same extract revealed the presence of nicotine metabolites such as nornicotine, anatabine, myosmine, 2,3'-bipyridyl, and 2-pyrrolidinone.

  17. Nicotine at concentrations found in cigarette smokers activates and desensitizes nicotinic acetylcholine receptors in CA1 interneurons of rat hippocampus.

    PubMed

    Alkondon, M; Pereira, E F; Almeida, L E; Randall, W R; Albuquerque, E X

    2000-10-01

    Behavioral effects of cigarette smoking are attributed to the interactions of nicotine with brain nicotinic acetylcholine receptors (nAChRs). However, the mechanisms by which nAChR function in developing and mature brain is affected by a smoker's level of nicotine (50-500 nM) remain unclear. Thus, the objective of this study was to determine the concentration- and time-dependent effects of nicotine on alpha7 and alpha4beta2 nAChRs, the two major brain subtypes, natively expressed in CA1 interneurons of rat hippocampal slices. Only at concentrations > or =5 microM did nicotine (applied for 6-60 s) elicit action potentials or measurable whole-cell currents (EC(50)=158 microM) in stratum radiatum interneurons that express alpha7 nAChRs. Continuous exposure for 10-15 min of the neurons to nicotine (0.5-2.5 microM) inhibited alpha7 nAChR-mediated currents (IC(50)=640 nM) evoked by choline (10 mM). Nicotine (> or =0.125 microM) applied to the neurons for 1-5 min induced slowly desensitizing whole-cell currents (EC(50)=3.2 microM) in stratum lacunosum moleculare interneurons; this effect was mediated by alpha4beta2 nAChRs. Also via activation of alpha4beta2 nAChRs, nicotine (0.125-0.5 microM) increased the frequency and amplitude of GABAergic postsynaptic currents (PSCs) in stratum radiatum interneurons. However, exposure of the neurons for 10-15 min to nicotine (0.25-0.5 microM) resulted in desensitization of alpha4beta2 nAChRs. It is suggested that nanomolar concentrations of nicotine after acute intake suppress inhibitory inputs to pyramidal cells through a disinhibitory mechanism involving activation of alpha4beta2 nAChRs and desensitization of alpha7 nAChRs, and after chronic intake leads to up-regulation of both receptor subtypes via desensitization. These findings have direct implications to the actions of nicotine in cigarette smokers.

  18. Nicotine Dehydrogenase Complexed with 6-Hydroxypseudooxynicotine Oxidase Involved in the Hybrid Nicotine-Degrading Pathway in Agrobacterium tumefaciens S33

    PubMed Central

    Li, Huili; Xie, Kebo; Yu, Wenjun; Hu, Liejie; Huang, Haiyan; Xie, Huijun

    2016-01-01

    Nicotine, a major toxic alkaloid in tobacco wastes, is degraded by bacteria, mainly via pyridine and pyrrolidine pathways. Previously, we discovered a new hybrid of the pyridine and pyrrolidine pathways in Agrobacterium tumefaciens S33 and characterized its key enzyme 6-hydroxy-3-succinoylpyridine (HSP) hydroxylase. Here, we purified the nicotine dehydrogenase initializing the nicotine degradation from the strain and found that it forms a complex with a novel 6-hydroxypseudooxynicotine oxidase. The purified complex is composed of three different subunits encoded by ndhAB and pno, where ndhA and ndhB overlap by 4 bp and are ∼26 kb away from pno. As predicted from the gene sequences and from chemical analyses, NdhA (82.4 kDa) and NdhB (17.1 kDa) harbor a molybdopterin cofactor and two [2Fe-2S] clusters, respectively, whereas Pno (73.3 kDa) harbors an flavin mononucleotide and a [4Fe-4S] cluster. Mutants with disrupted ndhA or ndhB genes did not grow on nicotine but grew well on 6-hydroxynicotine and HSP, whereas the pno mutant did not grow on nicotine or 6-hydroxynicotine but grew well on HSP, indicating that NdhA and NdhB are responsible for initialization of nicotine oxidation. We successfully expressed pno in Escherichia coli and found that the recombinant Pno presented 2,6-dichlorophenolindophenol reduction activity when it was coupled with 6-hydroxynicotine oxidation. The determination of reaction products catalyzed by the purified enzymes or mutants indicated that NdhAB catalyzed nicotine oxidation to 6-hydroxynicotine, whereas Pno oxidized 6-hydroxypseudooxynicotine to 6-hydroxy-3-succinoylsemialdehyde pyridine. These results provide new insights into this novel hybrid pathway of nicotine degradation in A. tumefaciens S33. PMID:26729714

  19. Nicotine Dehydrogenase Complexed with 6-Hydroxypseudooxynicotine Oxidase Involved in the Hybrid Nicotine-Degrading Pathway in Agrobacterium tumefaciens S33.

    PubMed

    Li, Huili; Xie, Kebo; Yu, Wenjun; Hu, Liejie; Huang, Haiyan; Xie, Huijun; Wang, Shuning

    2016-01-04

    Nicotine, a major toxic alkaloid in tobacco wastes, is degraded by bacteria, mainly via pyridine and pyrrolidine pathways. Previously, we discovered a new hybrid of the pyridine and pyrrolidine pathways in Agrobacterium tumefaciens S33 and characterized its key enzyme 6-hydroxy-3-succinoylpyridine (HSP) hydroxylase. Here, we purified the nicotine dehydrogenase initializing the nicotine degradation from the strain and found that it forms a complex with a novel 6-hydroxypseudooxynicotine oxidase. The purified complex is composed of three different subunits encoded by ndhAB and pno, where ndhA and ndhB overlap by 4 bp and are ∼26 kb away from pno. As predicted from the gene sequences and from chemical analyses, NdhA (82.4 kDa) and NdhB (17.1 kDa) harbor a molybdopterin cofactor and two [2Fe-2S] clusters, respectively, whereas Pno (73.3 kDa) harbors an flavin mononucleotide and a [4Fe-4S] cluster. Mutants with disrupted ndhA or ndhB genes did not grow on nicotine but grew well on 6-hydroxynicotine and HSP, whereas the pno mutant did not grow on nicotine or 6-hydroxynicotine but grew well on HSP, indicating that NdhA and NdhB are responsible for initialization of nicotine oxidation. We successfully expressed pno in Escherichia coli and found that the recombinant Pno presented 2,6-dichlorophenolindophenol reduction activity when it was coupled with 6-hydroxynicotine oxidation. The determination of reaction products catalyzed by the purified enzymes or mutants indicated that NdhAB catalyzed nicotine oxidation to 6-hydroxynicotine, whereas Pno oxidized 6-hydroxypseudooxynicotine to 6-hydroxy-3-succinoylsemialdehyde pyridine. These results provide new insights into this novel hybrid pathway of nicotine degradation in A. tumefaciens S33.

  20. Transdermal nicotine maintenance attenuates the subjective and reinforcing effects of intravenous nicotine, but not cocaine or caffeine, in cigarette-smoking stimulant abusers.

    PubMed

    Sobel, Bai-Fang X; Sigmon, Stacey C; Griffiths, Roland R

    2004-05-01

    The effects of transdermal nicotine maintenance on the subjective, reinforcing, and cardiovascular effects of intravenously administered cocaine, caffeine, and nicotine were examined using double-blind procedures in nine volunteers with histories of using tobacco, caffeine, and cocaine. Each participant was exposed to two chronic drug maintenance phases (21 mg/day nicotine transdermal patch and placebo transdermal patch). Within each drug phase, the participant received intravenous injections of placebo, cocaine (15 and 30 mg/70 kg), caffeine (200 and 400 mg/70 kg), and nicotine (1.0 and 2.0 mg/70 kg) in mixed order across days. Subjective and cardiovascular data were collected before and repeatedly after drug or placebo injection. Reinforcing effects were also assessed after each injection with a Drug vs Money Multiple-Choice Form. Intravenous cocaine produced robust dose-related increases in subjective and reinforcing effects; these effects were not altered by nicotine maintenance. Intravenous caffeine produced elevations on several subjective ratings; nicotine maintenance did not affect these ratings. Under the placebo maintenance condition, intravenous nicotine produced robust dose-related subjective effects, with maximal increases similar to the high dose of cocaine; nicotine maintenance significantly decreased the subjective and reinforcing effects of intravenous nicotine. The results of the present study demonstrate that chronic nicotine maintenance produces tolerance to the effects of intravenous nicotine, but does not affect the subjective or reinforcing effects of cocaine or caffeine.

  1. Nicotine administration in adolescence reprograms the subsequent response to nicotine treatment and withdrawal in adulthood: sex-selective effects on cerebrocortical serotonergic function.

    PubMed

    Slotkin, Theodore A; Card, Jennifer; Seidler, Frederic J

    2014-03-01

    Nicotine exposure in adolescence produces lasting changes in subsequent behavioral responses to addictive agents. We gave nicotine to adolescent rats (postnatal days PN30-47), simulating plasma levels in smokers, and then examined the subsequent effects of nicotine given again in adulthood (PN90-107), focusing on cerebrocortical serotonin levels and utilization (turnover) as an index of presynaptic activity of circuits involved in emotional state. Our evaluations encompassed responses during the period of adult nicotine treatment (PN105) and withdrawal (PN110, PN120, PN130), as well as long-term changes (PN180). In males, prior exposure to nicotine in adolescence greatly augmented the increase in serotonin turnover evoked by nicotine given in adulthood, an interaction that was further exacerbated during withdrawal. The effect was sufficiently large that it led to significant depletion of serotonin stores, an effect that was not seen with nicotine given alone in either adolescence or adulthood. In females, adolescent nicotine exposure blunted or delayed the spike in serotonin turnover evoked by withdrawal from adult nicotine treatment, a totally different effect from the interaction seen in males. Combined with earlier work showing persistent dysregulation of serotonin receptor expression and receptor coupling, the present results indicate that adolescent nicotine exposure reprograms future responses of 5HT systems to nicotine, changes that may contribute to life-long vulnerability to relapse and re-addiction.

  2. PRENATAL NICOTINE EXPOSURE SELECTIVELY AFFECTS NICOTINIC RECEPTOR EXPRESSION IN PRIMARY AND ASSOCIATIVE VISUAL CORTICES OF THE FETAL BABOON

    PubMed Central

    Duncan, Jhodie R.; Garland, Marianne; Stark, Raymond I.; Myers, Michael M.; Fifer, William P.; Mokler, David J.; Kinney, Hannah C.

    2014-01-01

    Exposure to nicotine during pregnancy via maternal cigarette smoking is associated with visual deficits in children. This is possibly due to activation of nicotinic acetylcholine receptors (nAChRs) in the occipital cortex which are important in the development of visual mapping. Using a baboon model we explored the effects of prenatal nicotine on parameters in the primary and associated visual cortices. Pregnant baboons were infused with nicotine (0.5 mg/hr, i.v.) or saline from 86 days gestation. At 161 days gestation fetal brains were collected (n=5/group) and the occipital lobe assessed for nAChRs and markers of the serotonergic and catecholaminergic systems using tissue autoradiography and/or high performance liquid chromatography. Neuronal nAChRs and serotonergic markers were expressed in a region and subunit dependent manner. Prenatal nicotine exposure was associated with increased binding for 3H-epibatidine sensitive nAChRs in the primary visual cortex (BA 17) and BA 18, but not BA 19, of the associative visual cortex (p<0.05). Markers of the serotonergic or catecholaminergic systems were not significantly altered. Thus, prenatal nicotine exposure is associated with alterations in the cholinergic system in the occipital lobe which may aid in the explanation of the appearance of visual deficits in children from mothers who smoke during pregnancy. PMID:24903536

  3. Prenatal nicotine exposure selectively affects nicotinic receptor expression in primary and associative visual cortices of the fetal baboon.

    PubMed

    Duncan, Jhodie R; Garland, Marianne; Stark, Raymond I; Myers, Michael M; Fifer, William P; Mokler, David J; Kinney, Hannah C

    2015-03-01

    Exposure to nicotine during pregnancy via maternal cigarette smoking is associated with visual deficits in children. This is possibly due to the activation of nicotinic acetylcholine receptors (nAChRs) in the occipital cortex, which are important in the development of visual mapping. Using a baboon model, we explored the effects of prenatal nicotine on parameters in the primary and associated visual cortices. Pregnant baboons were infused with nicotine (0.5 mg/h, intravenous) or saline from 86 days gestation. At 161 days gestation, fetal brains were collected (n = 5 per group) and the occipital lobe assessed for nAChRs and markers of the serotonergic and catecholaminergic systems using tissue autoradiography and/or high-performance liquid chromatography. Neuronal nAChRs and serotonergic markers were expressed in a region- and subunit-dependent manner. Prenatal nicotine exposure was associated with increased binding for (3) H-epibatidine sensitive nAChRs in the primary visual cortex [Brodmann areas (BA) 17] and BA 18, but not BA 19, of the associative visual cortex (P < 0.05). Markers of the serotonergic or catecholaminergic systems were not significantly altered. Thus, prenatal nicotine exposure is associated with alterations in the cholinergic system in the occipital lobe, which may aid in the explanation of the appearance of visual deficits in children from mothers who smoke during pregnancy.

  4. Nicotine enhances the cyclic AMP-dependent protein kinase-mediated phosphorylation of alpha4 subunits of neuronal nicotinic receptors.

    PubMed

    Hsu, Y N; Edwards, S C; Wecker, L

    1997-12-01

    Studies determined whether alpha4beta2 or alpha3beta2 neuronal nicotinic receptors expressed in Xenopus oocytes are substrates for cyclic AMP-dependent protein kinase (PKA) and whether nicotine affects receptor phosphorylation. The cRNAs for the subunits were coinjected into oocytes, and cells were incubated for 24 h in the absence or presence of nicotine (50 nM for alpha4beta2 and 500 nM for alpha3beta2 receptors). Nicotine did not interfere with the isolation of the receptors. When receptors isolated from oocytes expressing alpha4beta2 receptors were incubated with [gamma-32P]ATP and the catalytic subunit of PKA, separated by electrophoresis, and visualized by autoradiography, a labeled phosphoprotein with the predicted molecular size of the alpha4 subunit was present. Phosphorylation of alpha4 subunits of alpha4beta2 receptors increased within the first 5 min of incubation with nicotine and persisted for 24 h. In contrast, receptors isolated from oocytes expressing alpha3beta2 receptors did not exhibit a labeled phosphoprotein corresponding to the size of the alpha3 subunit. Results suggest that the PKA-mediated phosphorylation of alpha4 and not alpha3 subunits may explain the differential inactivation by nicotine of these receptor subtypes expressed in oocytes.

  5. Effect of dextrometorphan and dextrorphan on nicotine and neuronal nicotinic receptors: in vitro and in vivo selectivity.

    PubMed

    Damaj, M I; Flood, P; Ho, K K; May, E L; Martin, B R

    2005-02-01

    The effects of dextrometorphan and its metabolite dextrorphan on nicotine-induced antinociception in two acute thermal pain assays after systematic administration were evaluated in mice and compared with that of mecamylamine. Dextrometorphan and dextrorphan were found to block nicotine's antinociception in the tail-flick and hot-plate tests with different potencies (dextrometorphan is 10 times more potent than its metabolite). This blockade was not due to antagonism of N-methyl-d-aspartate receptors and/or interaction with opiate receptors, since selective drugs of these receptors failed to block nicotine's analgesic effects. Our results with the tail-flick and hot-plate tests showed an interesting in vivo functional selectivity for dextrometorphan over dextrorphan. In oocytes expressing various neuronal acetylcholine nicotinic receptors (nAChR), dextrometorphan and dextrorphan blocked nicotine activation of expressed alpha(3)beta(4), alpha(4)beta(2), and alpha(7) subtypes with a small degree of selectivity. However, the in vivo antagonistic potency of dextrometorphan and dextrorphan in the pain tests does not correlate well with their in vitro blockade potency at expressed nAChR subtypes. Furthermore, the apparent in vivo selectivity of dextrometorphan over dextrorphan is not related to its in vitro potency and does suggest the involvement of other mechanisms. In that respect, dextrometorphan seems to behave as another mecamylamine, a noncompetitive nicotinic receptor antagonist with a preferential activity to alpha(3)beta(4)(*) neuronal nAChR subtypes.

  6. Nicotine versus 6-hydroxy-l-nicotine against chlorisondamine induced memory impairment and oxidative stress in the rat hippocampus.

    PubMed

    Hritcu, Lucian; Ionita, Radu; Motei, Diana Elena; Babii, Cornelia; Stefan, Marius; Mihasan, Marius

    2017-02-01

    6-Hydroxy-l-nicotine (6HLN), a nicotine derivative from nicotine degradation by Arthrobacter nicotinovorans pAO1 strain was found to improve behavioral deficits and to reverse oxidative stress in the rat hippocampus. Rats were given CHL (10mg/kg, i.p.) were used as an Alzheimer's disease-like model. The nicotine (0.3mg/kg) and 6HLN (0.3mg/kg) were administered alone or in combination in the CHL-treated rats. Memory-related behaviors were evaluated using Y-maze and radial arm-maze tests. The antioxidant enzymes activity and the levels of the biomarkers of oxidative stress were measured in the hippocampus. Statistical analyses were performed using two-way ANOVA and Tukey's post hoc test. F values for which p<0.05 were regarded as statistically significant. CHL-caused memory deficits and oxidative stress enhancing were observed. Both nicotine and 6HLN administration attenuated the cognitive deficits and recovered the antioxidant capacity in the rat hippocampus of the CHL rat model. Our results suggest that 6HLN versus nicotine confers anti-amnesic properties in the CHL-induced a rat model of memory impairment via reversing cholinergic function and decreasing brain oxidative stress, suggesting the use of this compound as an alternative agent in AD treatment.

  7. Beta3 subunits promote expression and nicotine-induced up-regulation of human nicotinic alpha6* nicotinic acetylcholine receptors expressed in transfected cell lines.

    PubMed

    Tumkosit, Prem; Kuryatov, Alexander; Luo, Jie; Lindstrom, Jon

    2006-10-01

    Nicotinic acetylcholine receptors (AChRs) containing alpha6 subunits are typically found at aminergic nerve endings where they play important roles in nicotine addiction and Parkinson's disease. alpha6* AChRs usually contain beta3 subunits. beta3 subunits are presumed to assemble only in the accessory subunit position within AChRs where they do not participate in forming acetylcholine binding sites. Assembly of subunits in the accessory position may be a critical final step in assembly of mature AChRs. Human alpha6 AChRs subtypes were permanently transfected into human tsA201 human embryonic kidney (HEK) cell lines. alpha6beta2beta3 and alpha6beta4beta3 cell lines were found to express much larger amounts of AChRs and were more sensitive to nicotine-induced increase in the amount of AChRs than were alpha6beta2 or alpha6beta4 cell lines. The increased sensitivity to nicotine-induced up-regulation was due not to a beta3-induced increase in affinity for nicotine but probably to a direct effect on assembly of AChR subunits. HEK cells express only a small amount of mature alpha6beta2 AChRs, but many of these subunits are on the cell surface. This contrasts with Xenopus laevis oocytes, which express a large amount of incorrectly assembled alpha6beta2 subunits that bind cholinergic ligands but form large amorphous intracellular aggregates. Monoclonal antibodies (mAbs) were made to the alpha6 and beta3 subunits to aid in the characterization of these AChRs. The alpha6 mAbs bind to epitopes C-terminal of the extracellular domain. These data demonstrate that both cell type and the accessory subunit beta3 can play important roles in alpha6* AChR expression, stability, and up-regulation by nicotine.

  8. Motoneuron axon pathfinding errors in zebrafish: Differential effects related to concentration and timing of nicotine exposure

    SciTech Connect

    Menelaou, Evdokia; Paul, Latoya T.; Perera, Surangi N.; Svoboda, Kurt R.

    2015-04-01

    Nicotine exposure during embryonic stages of development can affect many neurodevelopmental processes. In the developing zebrafish, exposure to nicotine was reported to cause axonal pathfinding errors in the later born secondary motoneurons (SMNs). These alterations in SMN axon morphology coincided with muscle degeneration at high nicotine concentrations (15–30 μM). Previous work showed that the paralytic mutant zebrafish known as sofa potato exhibited nicotine-induced effects onto SMN axons at these high concentrations but in the absence of any muscle deficits, indicating that pathfinding errors could occur independent of muscle effects. In this study, we used varying concentrations of nicotine at different developmental windows of exposure to specifically isolate its effects onto subpopulations of motoneuron axons. We found that nicotine exposure can affect SMN axon morphology in a dose-dependent manner. At low concentrations of nicotine, SMN axons exhibited pathfinding errors, in the absence of any nicotine-induced muscle abnormalities. Moreover, the nicotine exposure paradigms used affected the 3 subpopulations of SMN axons differently, but the dorsal projecting SMN axons were primarily affected. We then identified morphologically distinct pathfinding errors that best described the nicotine-induced effects on dorsal projecting SMN axons. To test whether SMN pathfinding was potentially influenced by alterations in the early born primary motoneuron (PMN), we performed dual labeling studies, where both PMN and SMN axons were simultaneously labeled with antibodies. We show that only a subset of the SMN axon pathfinding errors coincided with abnormal PMN axonal targeting in nicotine-exposed zebrafish. We conclude that nicotine exposure can exert differential effects depending on the levels of nicotine and developmental exposure window. - Highlights: • Embryonic nicotine exposure can specifically affect secondary motoneuron axons in a dose-dependent manner.

  9. Modulation of Hippocampus-Dependent Learning and Synaptic Plasticity by Nicotine

    PubMed Central

    Kenney, Justin W.; Gould, Thomas J.

    2009-01-01

    A long-standing relationship between nicotinic acetylcholine receptors (nAChRs) and cognition exists. Drugs that act at nAChRs can have cognitive-enhancing effects and diseases that disrupt cognition such as Alzheimer’s disease and schizophrenia are associated with altered nAChR function. Specifically, hippocampus-dependent learning is particularly sensitive to the effects of nicotine. However, the effects of nicotine on hippocampus-dependent learning vary not only with the doses of nicotine used and whether nicotine is administered acutely, chronically, or withdrawn after chronic nicotine treatment but also vary across different hippocampus-dependent tasks such as the Morris water maze, the radial arm maze, and contextual fear conditioning. In addition, nicotine has variable effects across different types of hippocampal long-term potentiation (LTP). Because different types of hippocampus-dependent learning and LTP involve different neural and molecular substrates, comparing the effects of nicotine across these paradigms can yield insights into the mechanisms that may underlie the effects of nicotine on learning and memory and aid in understanding the variable effects of nicotine on cognitive processes. This review compares and contrasts the effects of nicotine on hippocampus-dependent learning and LTP and briefly discusses how the effects of nicotine on learning could contribute to nicotine addiction. PMID:18690555

  10. Discriminative stimulus properties of nicotine at low doses: the effects of caffeine preload.

    PubMed

    Duka, T; Tasker, R; Russell, K; Stephens, D N

    1998-05-01

    Discriminative stimulus properties of low nicotine doses administered in the form of chewing gum in combination with caffeine have been evaluated in humans, using established behavioural drug discrimination procedures. Twenty-one smokers who were also regular coffee drinkers were trained to discriminate 0 versus 1 mg nicotine chewing gum. Twenty subjects (11 men and nine women) were able to reach criterion performance (at least 80% correct). Generalization of responding across nicotine doses of 0, 0.25, 0.5 and 1 mg was then examined. Subjects were randomly allocated to receive either 50 mg caffeine or placebo before testing. Nicotine-appropriate responding was linearly related to dose, demonstrating that smokers can accurately discriminate nicotine from placebo and between relatively small doses of nicotine. Nicotine-appropriate responding was high at the 0 mg nicotine dose in the caffeine group demonstrating a partial generalization. Subjective effects assessed concurrently with behavioural discrimination revealed that nicotine discrimination was guided by the interoceptive cues of 'sensations in mouth', 'taste', 'heart rate', 'stimulated', 'alert' 'jittery' and 'nausea'. Caffeine increased self-ratings of 'stimulated' and 'alert' (at the 0 mg nicotine dose) and 'jittery' at the 0.5 and 1.0 mg nicotine dose. Relationships between nicotine-appropriate responding and subjective feelings induced by caffeine suggested that feelings of 'stimulated' and 'alert' were guiding discrimination behaviour. These data are discussed in terms of interoceptive nicotine cues and their importance at different doses and after caffeine preload.

  11. Chronic nicotine administration in the drinking water affects the striatal dopamine in mice.

    PubMed

    Pietilä, K; Ahtee, L

    2000-05-01

    Although tobacco contains a large variety of substances, its addictive properties are most probably due to the reinforcing actions of nicotine that motivates continued tobacco use. Animals and humans self-administer nicotine, a response that appears to involve the mesolimbic dopamine system and to be common to other abused drugs. The present article reviews animal models to administer nicotine chronically. We also describe a new animal model in which nicotine is given to mice in drinking water as their sole source of fluid. This treatment produced nicotine plasma concentrations comparable to or above those found in smokers. We found that mice withdrawn from nicotine were tolerant to the effects of nicotine challenge on striatal dopamine metabolism as well as on body temperature and locomotor activity. Furthermore, 3H-nicotine binding in the cortex and midbrain was significantly increased in mice withdrawn from nicotine. The last part of the article will focus on the effects of this chronic nicotine treatment on striatal dopamine. Dopamine and its metabolites and locomotor activity were increased in the forenoon in mice still drinking nicotine solutions. We also report recent data in which chronic nicotine administration in the drinking water enhanced the effect of dopamine receptor agonist, quinpirole, on striatal metabolism. The animal model described appears to be a relevant method for studying the mechanisms that are thought to be involved in nicotine dependence.

  12. CHARACTERIZATION OF NICOTINE ACETYLCHOLINE RECEPTOR SUBUNITS IN THE COCKROACH Periplaneta americana MUSHROOM BODIES REVEALS A STRONG EXPRESSION OF β1 SUBUNIT: INVOLVEMENT IN NICOTINE-INDUCED CURRENTS.

    PubMed

    Taillebois, Emiliane; Thany, Steeve H

    2016-09-01

    Nicotinic acetylcholine receptors are ligand-gated ion channels expressed in many insect structures, such as mushroom bodies, in which they play a central role. We have recently demonstrated using electrophysiological recordings that different native nicotinic receptors are expressed in cockroach mushroom bodies Kenyon cells. In the present study, we demonstrated that eight genes coding for cockroach nicotinic acetylcholine receptor subunits are expressed in the mushroom bodies. Quantitative real-time polymerase chain reaction (PCR) experiments demonstrated that β1 subunit was the most expressed in the mushroom bodies. Moreover, antisense oligonucleotides performed against β1 subunit revealed that inhibition of β1 expression strongly decreases nicotine-induced currents amplitudes. Moreover, co-application with 0.5 μM α-bungarotoxin completely inhibited nicotine currents whereas 10 μM d-tubocurarine had a partial effect demonstrating that β1-containing neuronal nicotinic acetylcholine receptor subtypes could be sensitive to the nicotinic acetylcholine receptor antagonist α-bungarotoxin.

  13. Differences in Nicotine Metabolism of Two Nicotiana attenuata Herbivores Render Them Differentially Susceptible to a Common Native Predator

    PubMed Central

    Kumar, Pavan; Rathi, Preeti; Schöttner, Matthias; Baldwin, Ian T.; Pandit, Sagar

    2014-01-01

    Background Nicotiana attenuata is attacked by larvae of both specialist (Manduca sexta) and generalist (Spodoptera exigua) lepidopteran herbivores in its native habitat. Nicotine is one of N. attenuata's important defenses. M. sexta is highly nicotine tolerant; whether cytochrome P450 (CYP)-mediated oxidative detoxification and/or rapid excretion is responsible for its exceptional tolerance remains unknown despite five decades of study. Recently, we demonstrated that M. sexta uses its nicotine-induced CYP6B46 to efflux midgut-nicotine into the hemolymph, facilitating nicotine exhalation that deters predatory wolf spiders (Camptocosa parallela). S. exigua's nicotine metabolism is uninvestigated. Methodology/Principal Findings We compared the ability of these two herbivores to metabolize, tolerate and co-opt ingested nicotine for defense against the wolf spider. In addition, we analyzed the spider's excretion to gain insights into its nicotine metabolism. Contrary to previous reports, we found that M. sexta larvae neither accumulate the common nicotine oxides (cotinine, cotinine N-oxide and nicotine N-oxide) nor excrete them faster than nicotine. In M. sexta larvae, ingestion of nicotine as well as its oxides increases the accumulation of CYP6B46 transcripts. In contrast, S. exigua accumulates nicotine oxides and exhales less (66%) nicotine than does M. sexta. Spiders prefer nicotine-fed S. exigua over M. sexta, a preference reversed by topical or headspace nicotine supplementation, but not ingested or topically-coated nicotine oxides, suggesting that externalized nicotine but not the nicotine detoxification products deter spider predation. The spiders also do not accumulate nicotine oxides. Conclusions Nicotine oxidation reduces S. exigua's headspace-nicotine and renders it more susceptible to predation by spiders than M. sexta, which exhales unmetabolized nicotine. These results are consistent with the hypothesis that generalist herbivores incur costs of

  14. In vivo interactions between α7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α: Implication for nicotine dependence.

    PubMed

    Jackson, Asti; Bagdas, Deniz; Muldoon, Pretal P; Lichtman, Aron H; Carroll, F Ivy; Greenwald, Mark; Miles, Michael F; Damaj, M Imad

    2017-03-07

    Chronic tobacco use dramatically increases health burdens and financial costs. Limitations of current smoking cessation therapies indicate the need for improved molecular targets. The main addictive component of tobacco, nicotine, exerts its dependency effects via nicotinic acetylcholine receptors (nAChRs). Activation of the homomeric α7 nAChR reduces nicotine's rewarding properties in conditioned place preference (CPP) test and i.v. self-administration models, but the mechanism underlying these effects is unknown. Recently, the nuclear receptor peroxisome proliferator-activated receptor type-α (PPARα) has been implicated as a downstream signaling target of the α7 nAChR in ventral tegmental area dopamine cells. The present study investigated PPARα as a possible mediator of the effect of α7 nAChR activation in nicotine dependence. Our results demonstrate the PPARα antagonist GW6471 blocks actions of the α7 nAChR agonist PNU282987 on nicotine reward in an unbiased CPP test in male ICR adult mice. These findings suggests that α7 nAChR activation attenuates nicotine CPP in a PPARα-dependent manner. To evaluate PPARα activation in nicotine dependence we used the selective and potent PPARα agonist, WY-14643 and the clinically used PPARα activator, fenofibrate, in nicotine CPP and we observed attenuation of nicotine preference, but fenofibrate was less potent. We also studied PPARα in nicotine dependence by evaluating its activation in nicotine withdrawal. WY-14643 reversed nicotine withdrawal signs whereas fenofibrate had modest efficacy. This suggests that PPARα plays a role in nicotine reward and withdrawal and that further studies are warranted to elucidate its function in mediating the effects of α7 nAChRs in nicotine dependence.

  15. Effects of nicotine in combination with drugs described as positive allosteric nicotinic acetylcholine receptor modulators in vitro: discriminative stimulus and hypothermic effects in mice.

    PubMed

    Moerke, Megan J; de Moura, Fernando B; Koek, Wouter; McMahon, Lance R

    2016-09-05

    Some drugs that are positive allosteric nAChR modulators in vitro, desformylflustrabromine (dFBr), PNU-120596 and LY 2087101, have not been fully characterized in vivo. These drugs were examined for their capacity to share or modify the hypothermic and discriminative stimulus effects of nicotine (1mg/kg s.c.) in male C57Bl/6J mice. Nicotine, dFBr, and PNU-120596 produced significant hypothermia, whereas LY 2087101 (up to 100mg/kg) did not. Nicotine dose-dependently increased nicotine-appropriate responding and decreased response rate; the respective ED50 values were 0.56mg/kg and 0.91mg/kg. The modulators produced no more than 38% nicotine-appropriate responding up to doses that disrupted operant responding. Rank order potency was the same for hypothermia and rate-decreasing effects: nicotine>dFBr>PNU-120596=LY 2087101. Mecamylamine and the α4β2 nAChR antagonist dihydro-β-erythroidine, but not the α7 antagonist methyllycaconitine, antagonized the hypothermic effects of nicotine. In contrast, mecamylamine did not antagonize the hypothermic effects of the modulators. The combined discriminative stimulus effects of DFBr and nicotine were synergistic, whereas the combined hypothermic effects of nicotine with either dFBr or PNU-120596 were infra-additive. PNU-120596 did not modify the nicotine discriminative stimulus, and LY 2087101 did not significantly modify either effect of nicotine. Positive modulation of nicotine at nAChRs by PNU-120596 and LY 2087101 in vitro does not appear to confer enhancement of the nAChR-mediated hypothermic or discriminative stimulus effects of nicotine. However, dFBr appears to be a positive allosteric modulator of some behavioral effects of nicotine at doses of dFBr smaller than the doses producing unwanted effects (e.g. hypothermia) through non-nAChR mechanisms.

  16. Inflammatory Response to Burn Trauma: Nicotine Attenuates Proinflammatory Cytokine Levels

    PubMed Central

    Papst, S.; Reimers, K.; Stukenborg-Colsman, C.; Steinstraesser, L.; Vogt, P. M.; Kraft, T.; Niederbichler, A. D.

    2014-01-01

    Objective: The immune response to an inflammatory stimulus is balanced and orchestrated by stimulatory and inhibitory factors. After a thermal trauma, this balance is disturbed and an excessive immune reaction with increased production and release of proinflammatory cytokines results. The nicotine-stimulated anti-inflammatory reflex offsets this. The goal of this study was to verify that transdermal administration of nicotine downregulates proinflammatory cytokine release after burn trauma. Methods: A 30% total body surface area full-thickness rat burn model was used in Sprague Dawley rats (n = 35, male). The experimental animals were divided into a control group, a burn trauma group, a burn trauma group with additional nicotine treatment, and a sham + nicotine group with 5 experimental animals per group. The last 2 groups received a transdermal nicotine administration of 1.75 mg. The concentrations of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 were determined in homogenates of hearts, livers, and spleens 12 or 24 hours after burn trauma. Results: Experimental burn trauma resulted in a significant increase in cytokine levels in hearts, livers, and spleens. Nicotine treatment led to a decrease of the effect of the burn trauma with significantly lower concentrations of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 compared to the trauma group. Conclusions: This study confirms in a standardized burn model that stimulation of the nicotinic acetylcholine receptor is involved in the regulation of effectory molecules of the immune response. Looking at the results of our study, further experiments designed to explore and evaluate the potency and mechanisms of the immunomodulating effects of this receptor system are warranted. PMID:25671045

  17. Prolonged exposure to denicotinized cigarettes with or without transdermal nicotine.

    PubMed

    Donny, Eric C; Jones, Melissa

    2009-09-01

    Sensorimotor smoking stimuli are important determinants of cigarette use. The present study aimed to determine whether denicotinized cigarettes lose their reinforcing and/or subjective effects over a 9-day outpatient period when they are smoked with or without concurrent transdermal nicotine. After a preferred brand baseline, 68 participants were randomized into one of four conditions based on the dose (mg) of transdermal nicotine and the type of cigarettes (dose/cigarette): 0/nicotine, 0/denicotinized, 7/denicotinized, and 21/denicotinized. Under placebo patch conditions, participants smoked a similar number of nicotine and denicotinized cigarettes and no group differences emerged over repeated testing. The total volume of smoke inhaled was lower in the denicotinized group, although this decrease dissipated over time. Denicotinized cigarettes were rated as having low positive and high negative subjective effects. Compared to placebo, transdermal nicotine decreased the number of denicotinized cigarette smoked, produced a lasting decrease in the total volume of denicotinized cigarette smoke inhaled, but had little effect on the subjective effects of denicotinized cigarettes. Transdermal nicotine attenuated withdrawal during initial smoking abstinence; however, once participants were allowed to smoke withdrawal symptoms were relatively low regardless of patch condition. The persistent use of denicotinized cigarettes may result from the presence of nicotine withdrawal and/or the degree to which smoking becomes somewhat independent of the outcome of the behavior (i.e., habit learning). Additional studies would be useful to determine what factors drive continued use of denicotinized cigarettes, whether their use subsides as withdrawal dissipates, and whether they address motives for smoking distinct from current pharmacotherapy.

  18. Sorption, desorption, and surface oxidative fate of nicotine.

    PubMed

    Petrick, Lauren; Destaillats, Hugo; Zouev, Irena; Sabach, Sara; Dubowski, Yael

    2010-09-21

    Nicotine dynamics in an indoor environment can be greatly affected by building parameters (e.g. relative humidity (RH), air exchange rate (AER), and presence of ozone), as well as surface parameters (e.g. surface area (SA) and polarity). To better understand the indoor fate of nicotine, these parameter effects on its sorption, desorption, and oxidation rates were investigated on model indoor surfaces that included fabrics, wallboard paper, and wood materials. Nicotine sorption under dry conditions was enhanced by higher SA and higher polarity of the substrate. Interestingly, nicotine sorption to cotton and nylon was facilitated by increased RH, while sorption to polyester was hindered by it. Desorption was affected by RH, AER, and surface type. Heterogeneous nicotine-ozone reaction was investigated by Fourier transform infrared spectrometry with attenuated total reflection (FTIR-ATR), and revealed a pseudo first-order surface reaction rate of 0.035 +/- 0.015 min(-1) (at [O(3)] = 6 +/- 0.3 x 10(15) molecules cm(-3)) that was partially inhibited at high RH. Extrapolation to a lower ozone level ([O(3)] = 42 ppb) showed oxidation on the order of 10(-5) min(-1) corresponding to a half-life of 1 week. In addition, similar surface products were identified in dry and high RH using gas chromatography-mass spectrometry (GC-MS). However, FTIR analysis revealed different product spectra for these conditions, suggesting additional unidentified products and association with surface water. Knowing the indoor fate of condensed and gas phase nicotine and its oxidation products will provide a better understanding of nicotine's impact on personal exposures as well as overall indoor air quality.

  19. The effects of acute nicotine on contextual safety discrimination.

    PubMed

    Kutlu, Munir G; Oliver, Chicora; Gould, Thomas J

    2014-11-01

    Anxiety disorders, such as post-traumatic stress disorder (PTSD), may be related to an inability to distinguish safe versus threatening environments and to extinguish fear memories. Given the high rate of cigarette smoking in patients with PTSD, as well as the recent finding that an acute dose of nicotine impairs extinction of contextual fear memory, we conducted a series of experiments to investigate the effect of acute nicotine in an animal model of contextual safety discrimination. Following saline or nicotine (at 0.0275, 0.045, 0.09 and 0.18 mg/kg) administration, C57BL/6J mice were trained in a contextual discrimination paradigm, in which the subjects received presentations of conditioned stimuli (CS) that co-terminated with a foot-shock in one context (context A (CXA)) and only CS presentations without foot-shock in a different context (context B (CXB)). Therefore, CXA was designated as the 'dangerous context', whereas CXB was designated as the 'safe context'. Our results suggested that saline-treated animals showed a strong discrimination between dangerous and safe contexts, while acute nicotine dose-dependently impaired contextual safety discrimination (Experiment 1). Furthermore, our results demonstrate that nicotine-induced impairment of contextual safety discrimination learning was not a result of increased generalized freezing (Experiment 2) or contingent on the common CS presentations in both contexts (Experiment 3). Finally, our results show that increasing the temporal gap between CXA and CXB during training abolished the impairing effects of nicotine (Experiment 4). The findings of this study may help link nicotine exposure to the safety learning deficits seen in anxiety disorder and PTSD patients.

  20. Nicotinic acetylcholine receptors: from basic science to therapeutics.

    PubMed

    Hurst, Raymond; Rollema, Hans; Bertrand, Daniel

    2013-01-01

    Substantial progress in the identification of genes encoding for a large number of proteins responsible for various aspects of neurotransmitter release, postsynaptic detection and downstream signaling, has advanced our understanding of the mechanisms by which neurons communicate and interact. Nicotinic acetylcholine receptors represent a large and well-characterized family of ligand-gated ion channels that is expressed broadly throughout the central and peripheral nervous system, and in non-neuronal cells. With 16 mammalian genes identified that encode for nicotinic receptors and the ability of the subunits to form heteromeric or homomeric receptors, the repertoire of conceivable receptor subtype combinations is enormous and offers unique possibilities for the design and development of new therapeutics that target nicotinic acetylcholine receptors. The aim of this review is to provide the reader with recent insights in nicotinic acetylcholine receptors from genes, structure and function to diseases, and with the latest findings on the pharmacology of these receptors. Although so far only a few nicotinic drugs have been marketed or are in late stage development, much progress has been made in the design of novel chemical entities that are being explored for the treatment of various diseases, including addiction, depression, ADHD, cognitive deficits in schizophrenia and Alzheimer's disease, pain and inflammation. A pharmacological analysis of these compounds, including those that were discontinued, can improve our understanding of the pharmacodynamic and pharmacokinetic requirements for nicotinic 'drug-like' molecules and will reveal if hypotheses on therapies based on targeting specific nicotinic receptor subtypes have been adequately tested in the clinic.

  1. Nicotine induces Nme2-mediated apoptosis in mouse testes.

    PubMed

    Gu, Yunqi; Xu, Wangjie; Nie, Dongsheng; Zhang, Dong; Dai, Jingbo; Zhao, Xianglong; Zhang, Meixing; Wang, Zhaoxia; Chen, Zhong; Qiao, Zhongdong

    2016-04-15

    In mouse testes, germ cell apoptosis can be caused by cigarette smoke and lead to declining quality of semen, but the exact molecular mechanisms remain unclear. To evaluate the effects of nicotine exposure on apoptosis during spermatogenesis, we first constructed a nicotine-treated mouse model and detected germ cell apoptosis activity in the testes using the TUNEL method. Then we analyzed the variation of telomere length and telomerase activity by real-time PCR and TRAP-real-time PCR, respectively. Further, we investigated a highly expressed gene, Nme2, in mouse testes after nicotine treatment from our previous results, which has close correlation with the apoptosis activity predicted by bioinformatics. We performed NME2 overexpression in Hela cells to confirm whether telomere length and telomerase activity were regulated by the Nme2 gene. Finally, we examined methylation of CpG islands in the Nme2 promoter with the Bisulfite Sequencing (BSP) method. The results showed that apoptosis had increased significantly, and then telomerase activity became weak. Further, telomere length was shortened in the germ cells among the nicotine-treated group. In Hela cells, both overexpression of the Nme2 gene and nicotine exposure can suppress the activity of telomerase activity and shorten telomere length. BSP results revealed that the Nme2 promoter appeared with low methylation in mouse testes after nicotine treatment. We assume that nicotine-induced apoptosis may be caused by telomerase activity decline, which is inhibited by the up expression of Nme2 because of its hypomethylation in mouse germ cells.

  2. Nicotine Dependence and Alcohol Problems from Adolescence to Young Adulthood

    PubMed Central

    Dierker, Lisa; Selya, Arielle; Rose, Jennifer; Hedeker, Donald; Mermelstein, Robin

    2016-01-01

    Background Despite the highly replicated relationship between symptoms associated with both alcohol and nicotine, little is known about this association across time and exposure to both drinking and smoking. In the present study, we evaluate if problems associated with alcohol use are related to emerging nicotine dependence symptoms and whether this relationship varies from adolescence to young adulthood, after accounting for both alcohol and nicotine exposure. Methods The sample was drawn from the Social and Emotional Contexts of Adolescent Smoking Patterns Study which measured smoking, nicotine dependence, alcohol use and alcohol related problems over 6 assessment waves spanning 6 years. Analyses were based on repeated assessment of 864 participants reporting some smoking and drinking 30 days prior to individual assessment waves. Mixed-effects regression models were estimated to examine potential time, smoking and/or alcohol varying effects in the association between alcohol problems and nicotine dependence. Findings Inter-individual differences in mean levels of alcohol problems and within subject changes in alcohol problems from adolescence to young adulthood were each significantly associated with nicotine dependence symptoms over and above levels of smoking and drinking behaviour. This association was consistent across both time and increasing levels of smoking and drinking. Conclusions Alcohol related problems are a consistent risk factor for nicotine dependence over and above measures of drinking and smoking and this association can be demonstrated from the earliest experiences with smoking in adolescents, through the establishment of more regular smoking patterns across the transition to young adulthood. These findings add to accumulating evidence suggesting that smoking and drinking may be related through a mechanism that cannot be wholly accounted for by exposure to either substance. PMID:27610424

  3. A potentially novel nicotinic receptor in Aplysia neuroendocrine cells.

    PubMed

    White, Sean H; Carter, Christopher J; Magoski, Neil S

    2014-07-15

    Nicotinic receptors form a diverse group of ligand-gated ionotropic receptors with roles in both synaptic transmission and the control of excitability. In the bag cell neurons of Aplysia, acetylcholine activates an ionotropic receptor, which passes inward current to produce a long-lasting afterdischarge and hormone release, leading to reproduction. While testing the agonist profile of the cholinergic response, we observed a second current that appeared to be gated only by nicotine and not acetylcholine. The peak nicotine-evoked current was markedly smaller in magnitude than the acetylcholine-induced current, cooperative (Hill value of 2.7), had an EC50 near 500 μM, readily recovered from desensitization, showed Ca(2+) permeability, and was blocked by mecamylamine, dihydro-β-erythroidine, or strychnine, but not by α-conotoxin ImI, methyllycaconitine, or hexamethonium. Aplysia transcriptome analysis followed by PCR yielded 20 full-length potential nicotinic receptor subunits. Sixteen of these were predicted to be cation selective, and real-time PCR suggested that 15 of the 16 subunits were expressed to varying degrees in the bag cell neurons. The acetylcholine-induced current, but not the nicotine current, was reduced by double-strand RNA treatment targeted to both subunits ApAChR-C and -E. Conversely, the nicotine-evoked current, but not the acetylcholine current, was lessened by targeting both subunits ApAChR-H and -P. To the best of our knowledge, this is the first report suggesting that a nicotinic receptor is not gated by acetylcholine. Separate receptors may serve as a means to differentially trigger plasticity or safeguard propagation by assuring that only acetylcholine, the endogenous agonist, initiates large enough responses to trigger reproduction.

  4. Transport mechanisms of nicotine across the human intestinal epithelial cell line Caco-2.

    PubMed

    Fukada, Atsuko; Saito, Hideyuki; Inui, Ken-Ichi

    2002-08-01

    Ulcerative colitis is a disease more commonly seen in nonsmokers. Because nicotine was postulated to be a beneficial component of tobacco smoke for ulcerative colitis, various formulations of nicotine have been developed to improve the local bioavailability within the gastrointestinal tissue. In the present study, to characterize the disposition of nicotine in the intestines, we investigated intestinal nicotine transport using Caco-2 cells. Nicotine was predominantly transported across Caco-2 cell monolayers in a unidirectional mode, corresponding to intestinal secretion, by pH-dependent specific transport systems. The specific uptake systems appear to be distinct from organic cation transporters and the transport system for tertiary amines, in terms of its substrate specificity and the pattern of the interaction. These transport systems could play a role in the intestinal accumulation of nicotine from plasma and could also be responsible for the topical delivery of nicotine for ulcerative colitis therapy. These findings could provide useful information for the design of effective nicotine delivery.

  5. Kids Landing in ERs After Drinking Parents' E-Cig Nicotine Liquid

    MedlinePlus

    ... Landing in ERs After Drinking Parents' E-Cig Nicotine Liquid In one case, a 6-year-old ... News) -- A case study highlights the danger liquid nicotine for electronic cigarettes poses to children. Doctors in ...

  6. [Determination of nicotine in breast milk by coupling gas chromatography and mass spectrometry].

    PubMed

    Ataie, M; Hoffelt, J; Barrois-Larouze, V; Bourdon, R

    1984-01-01

    The authors describe the nicotine quantification in milk by GC - MS. In order to obtain a good chromatographic separation, the nicotine is previously separated by steam distillation. Quinoleine is used as internal standard. CV is lower than 5 per cent.

  7. The effects of nicotine administration on the pathophysiology of rat aortic wall.

    PubMed

    Kugo, H; Zaima, N; Tanaka, H; Urano, T; Unno, N; Moriyama, T

    2017-01-01

    Abdominal aortic aneurysm (AAA) is the progressive dilation of the abdominal aorta. Nicotine is reported to be associated with the development and rupture of AAA, but the pathological effects of nicotine on normal rat aorta have not been determined. We investigated pathological changes in the aortic wall of rats caused by the administration of nicotine. Nicotine administration weakened the vascular wall, increased gelatinolytic activity and promoted the destruction of elastin and collagen in the rat abdominal aorta. There were no differences in the areas positive for matrix metalloproteinase (MMP)-2 and MMP-9 between the control and nicotine treated groups. The areas positive for MMP-12 in the nicotine group were significantly greater than for the control group. Gelatinolytic activity in the aortic wall was increased significantly in the nicotine group. Our findings suggest that MMP-12 is sensitive to nicotine exposure in rats.

  8. Effect of nicotine on melanogenesis and antioxidant status in HEMn-LP melanocytes.

    PubMed

    Delijewski, Marcin; Beberok, Artur; Otręba, Michał; Wrześniok, Dorota; Rok, Jakub; Buszman, Ewa

    2014-10-01

    Nicotine is a natural ingredient of tobacco plants and is responsible for the addictive properties of tobacco. Nowadays nicotine is also commonly used as a form of smoking cessation therapy. It is suggested that nicotine may be accumulated in human tissues containing melanin. This may in turn affect biochemical processes in human cells producing melanin. The aim of this study was to examine the effect of nicotine on melanogenesis and antioxidant status in cultured normal human melanocytes HEMn-LP. Nicotine induced concentration-dependent loss in melanocytes viability. The value of EC50 was determined to be 7.43 mM. Nicotine inhibited a melanization process in human light pigmented melanocytes and caused alterations of antioxidant defense system. Significant changes in cellular antioxidant enzymes: superoxide dismutase and catalase activities and in hydrogen peroxide content were stated. The obtained results may explain a potential influence of nicotine on biochemical processes in melanocytes in vivo during long term exposition to nicotine.

  9. COMPARISON OF WEEKLY EXPOSURES TO ANATOXIN-A AND NICOTINE ON THE MOTOR ACTIVITY OF RATS.

    EPA Science Inventory

    Anatoxin-a is a nicotinic cholinergic agonist that is produced by several genera of cyanobacteria, and has been implicated in several poisoning episodes of wildlife, livestock, domestic animals and people. Previous research on nicotine has obtained tolerance and sensitization ...

  10. Alpha4* nicotinic receptors in preBotzinger complex mediate cholinergic/nicotinic modulation of respiratory rhythm.

    PubMed

    Shao, Xuesi M; Tan, Wenbin; Xiu, Joanne; Puskar, Nyssa; Fonck, Carlos; Lester, Henry A; Feldman, Jack L

    2008-01-09

    Acetylcholine and nicotine can modulate respiratory patterns by acting on nicotinic acetylcholine receptors (nAChRs) in the preBötzinger complex (preBötC). To further explore the molecular composition of these nAChRs, we studied a knock-in mouse strain with a leucine-to-alanine mutation in the M2 pore-lining region (L9'A) of the nAChR alpha4 subunit; this mutation renders alpha4-containing receptors hypersensitive to agonists. We recorded respiratory-related rhythmic motor activity from hypoglossal nerve (XIIn) and patch-clamped preBötC inspiratory neurons in an in vitro medullary slice preparation from neonatal mice. Nicotine affected respiratory rhythm at concentrations approximately 100-fold lower in the homozygous L9'A knock-in mice compared with wild-type mice. Bath application of 5 nm nicotine increased the excitability of preBötC inspiratory neurons, increased respiratory frequency, and induced tonic/seizure-like activities in XIIn in L9'A mice, effects similar to those induced by 1 microM nicotine in wild-type mice. In L9'A mice, microinjection of low nanomolar concentrations of nicotine into the preBötC increased respiratory frequency, whereas injection into the ipsilateral hypoglossal (XII) nucleus induced tonic/seizure-like activity. The alpha4*-selective nAChR antagonist dihydro-beta-erythroidine produced opposite effects and blocked the nicotinic responses. These data, showing that nAChRs in the preBötC and XII nucleus in L9'A mice are hypersensitive to nicotine and endogenous ACh, suggest that functional alpha4* nAChRs are present in the preBötC. They mediate cholinergic/nicotinic modulation of the excitability of preBötC inspiratory neurons and of respiratory rhythm. Furthermore, functional alpha4* nAChRs are present in XII nucleus and mediate cholinergic/nicotinic modulation of tonic activity in XIIn.

  11. Nicotine-induced up-regulation and desensitization of alpha4beta2 neuronal nicotinic receptors depend on subunit ratio.

    PubMed

    López-Hernández, Gretchen Y; Sánchez-Padilla, Javier; Ortiz-Acevedo, Alejandro; Lizardi-Ortiz, José; Salas-Vincenty, Janice; Rojas, Legier V; Lasalde-Dominicci, José A

    2004-09-03

    Desensitization induced by chronic nicotine exposure has been hypothesized to trigger the up-regulation of the alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR) in the central nervous system. We studied the effect of acute and chronic nicotine exposure on the desensitization and up-regulation of different alpha4beta2 subunit ratios (1alpha:4beta, 2alpha:3beta, and 4alpha:1beta) expressed in Xenopus oocytes. The presence of alpha4 subunit in the oocyte plasmatic membrane increased linearly with the amount of alpha4 mRNA injected. nAChR function and expression were assessed during acute and after chronic nicotine exposure using a two-electrode voltage clamp and whole-mount immunofluorescence assay along with confocal imaging for the detection of the alpha4 subunit. The 2alpha4:3beta2 subunit ratio displayed the highest ACh sensitivity. Nicotine dose-response curves for the 1alpha4:4beta2 and 2alpha4:3beta2 subunit ratios displayed a biphasic behavior at concentrations ranging from 0.1 to 300 microm. A biphasic curve for 4alpha4:1beta2 was obtained at nicotine concentrations higher than 300 microm. The 1alpha4:4beta2 subunit ratio exhibited the lowest ACh- and nicotine-induced macroscopic current, whereas 4alpha4:1beta2 presented the largest currents at all agonist concentrations tested. Desensitization by acute nicotine exposure was more evident as the ratio of beta2:alpha4 subunits increased. All three alpha4beta2 subunit ratios displayed a reduced state of activation after chronic nicotine exposure. Chronic nicotine-induced up-regulation was obvious only for the 2alpha4: 3beta2 subunit ratio. Our data suggest that the subunit ratio of alpha4beta2 determines the functional state of activation, desensitization, and up-regulation of this neuronal nAChR. We propose that independent structural sites regulate alpha4beta2 receptor activation and desensitization.

  12. Preparation of MgH{sub 2} composite with a composition of 40%MgH{sub 2} + 30%LiBH{sub 4} + 30%(2LiBH{sub 4} + MgF{sub 2})

    SciTech Connect

    Hong, Seong-Hyeon; Song, Myoung Youp

    2012-09-15

    Graphical abstract: Hydrogen content vs. desorption time curves for consecutive 1st desorptions of 40 wt%MgH{sub 2} + 30 wt%LiBH{sub 4} + 30 wt%(2LiBH{sub 4} + MgF{sub 2}) at 533–873 K. Highlights: ► Addition of MgF{sub 2} and LiBH{sub 4} with a higher hydrogen storage capacity to MgH{sub 2}. ► Preparation of 40%MgH{sub 2} + 30%LiBH{sub 4} + 30% (2LiBH{sub 4} + MgF{sub 2}) composite. ► Examination of desorption properties of the composite. ► Total desorbed hydrogen quantity for consecutive 1st desorptions of 7.07 wt%. ► Reactions of LiBH{sub 4} → LiH + B + (3/2)H{sub 2}, and 2LiBH{sub 4} + MgF{sub 2} → 2LiF + MgB{sub 2} + 4H{sub 2}. -- Abstract: A mixture of containing two chemical equivalents of lithium borohyride and one equivalent of magnesium fluoride is known to yield hydrogen in an amount of about 7.6 wt% of the mixture when heated to about 150 °C at atmospheric pressure by the following reaction; 2LiBH{sub 4} + MgF{sub 2} = 2LiF + MgB{sub 2} + 4H{sub 2}. In order to increase hydrogen storage capacity of Mg-based materials, a mixture with a composition of 2LiBH{sub 4} + MgF{sub 2} and LiBH{sub 4}with a higher hydrogen storage capacity of 18.4 wt% were added to MgH{sub 2}. MgH{sub 2} composite with a composition of 40 wt%MgH{sub 2} + 30 wt%LiBH{sub 4} + 30 wt%(2LiBH{sub 4} + MgF{sub 2}) was prepared by reactive mechanical grinding. The hydrogen storage properties of the sample were then examined. Hydrogen content vs. desorption time curves for consecutive 1st desorptions of 40 wt%MgH{sub 2} + 30 wt%LiBH{sub 4} + 30 wt%(2LiBH{sub 4} + MgF{sub 2}) at 533–873 K showed that the total desorbed hydrogen quantity for consecutive 1st desorptions is 7.07 wt%.

  13. SAR of α7 nicotinic receptor agonists derived from tilorone: exploration of a novel nicotinic pharmacophore.

    PubMed

    Schrimpf, Michael R; Sippy, Kevin B; Briggs, Clark A; Anderson, David J; Li, Tao; Ji, Jianguo; Frost, Jennifer M; Surowy, Carol S; Bunnelle, William H; Gopalakrishnan, Murali; Meyer, Michael D

    2012-02-15

    The well-known interferon-inducer tilorone was found to possess potent affinity for the agonist site of the α7 neuronal nicotinic receptor (K(i)=56 nM). SAR investigations determined that both basic sidechains are essential for potent activity, however active monosubstituted derivatives can also be prepared if the flexible sidechains are replaced with conformationally rigidified cyclic amines. Analogs in which the fluorenone core is replaced with either dibenzothiophene-5,5-dioxide or xanthenone also retain potent activity.

  14. Atorvastatin improves Y-maze learning behaviour in nicotine treated male albino rats.

    PubMed

    Das S, Syam; Nair, Saritha S; Kavitha, S; Febi, John; Indira, M

    2015-11-01

    Nicotine is a parasympathomimetic alkaloid present in tobacco which can induce hyperlipidemia and has a direct effect on neural functions. Statins, competitive inhibitors of 3-hydroxymethyl-3-glutaryl-coenzyme-A reductase, are cholesterol lowering drugs. It has some neuroprotective effects. Hence we analysed the combined effect of nicotine and statin on the learning behaviour of male albino rats. We employed Y-Maze conditional discrimination task. Rats were divided into 4 groups with six rats in each group. (1) Control, (2) Atorvastatin (10mg/kgb.wt), (3) Nicotine (0.6mg/kgb.wt) and (4) Atorvastatin (10mg/kgb.wt)+Nicotine (0.6mg/kgb.wt). After 30days of treatment rats from each group were selected for behavioural study and they were observed for 30days. At the end of the experimental period rats were sacrificed, and brain and liver were dissected out for further biochemical analysis. Nicotine treated group showed least performance in learning in comparison with control, atorvastatin and atorvastatin+nicotine treated groups. Co-administration of atorvastatin and nicotine improved learning behaviour compared to nicotine treated group. Reactive oxygen species level was significantly increased in nicotine group compared to control. The level of neurotransmitter serotonin which has a significant role in learning was found to be decreased in nicotine treated group compared to the control group. Activity of Na(+) K(+) ATPase, Ca(2+) ATPase and glutathione content was significantly reduced in nicotine treated group compared to control. The activity of acetylcholine esterase was significantly increased in the nicotine treated group. Expression studies showed significant decrease in N-methyl D-aspartate receptors and increase in mono amine oxidase-A and mono amine oxidase-B in nicotine treated group and was reversed in atorvastatin + nicotine treated group. It can be concluded that co-administration of nicotine with statin ameliorates the neural functional alterations caused

  15. Thyroid receptor β involvement in the effects of acute nicotine on hippocampus-dependent memory.

    PubMed

    Leach, Prescott T; Kenney, Justin W; Connor, David A; Gould, Thomas J

    2015-06-01

    Cigarette smoking is common despite adverse health effects. Nicotine's effects on learning may contribute to addiction by enhancing drug-context associations. Effects of nicotine on learning could be direct or could occur by altering systems that modulate cognition. Because thyroid signaling can alter cognition and nicotine/smoking may change thyroid function, nicotine could affect learning through changes in thyroid signaling. These studies investigate the functional contributions of thyroid receptor (TR) subtypes β and α1 to nicotine-enhanced learning and characterize the effects of acute nicotine and learning on thyroid hormone levels. We conducted a high throughput screen of transcription factor activity to identify novel targets that may contribute to the effects of nicotine on learning. Based on these results, which showed that combined nicotine and learning uniquely acted to increase TR activation, we identified TRs as potential targets of nicotine. Further analyses were conducted to determine the individual and combined effects of nicotine and learning on thyroid hormone levels, but no changes were seen. Next, to determine the role of TRβ and TRα1 in the effects of nicotine on learning, mice lacking the TRβ or TRα1 gene and wildtype littermates were administered acute nicotine prior to fear conditioning. Nicotine enhanced contextual fear conditioning in TRα1 knockout mice and wildtypes from both lines but TRβ knockout mice did not show nicotine-enhanced learning. This finding supports involvement of TRβ signaling in the effect of acute nicotine on hippocampus-dependent memory. Acute nicotine enhances learning and these effects may involve processes regulated by the transcription factor TRβ.

  16. Voluntary co-consumption of alcohol and nicotine: Effects of abstinence, intermittency, and withdrawal in mice.

    PubMed

    O'Rourke, Kyu Y; Touchette, Jillienne C; Hartell, Elizabeth C; Bade, Elizabeth J; Lee, Anna M

    2016-10-01

    Alcohol and nicotine are often used together, and there is a high rate of co-occurrence between alcohol and nicotine addiction. Most animal models studying alcohol and nicotine interactions have utilized passive drug administration, which may not be relevant to human co-addiction. In addition, the interactions between alcohol and nicotine in female animals have been understudied, as most studies have used male animals. To address these issues, we developed models of alcohol and nicotine co-consumption in male and female mice that utilized voluntary, oral consumption of unsweetened alcohol, nicotine and water. We first examined drug consumption and preference in single-drug, sequential alcohol and nicotine consumption tests in male and female C57BL/6 and DBA/2J mice. We then tested chronic continuous and intermittent access alcohol and nicotine co-consumption procedures. We found that male and female C57BL/6 mice readily co-consumed unsweetened alcohol and nicotine. In our continuous co-consumption procedures, we found that varying the available nicotine concentration during an alcohol abstinence period affected compensatory nicotine consumption during alcohol abstinence, and affected rebound alcohol consumption when alcohol was re-introduced. Consumption of alcohol and nicotine in an intermittent co-consumption procedure produced higher alcohol consumption levels, but not nicotine consumption levels, compared with the continuous co-consumption procedures. Finally, we found that intermittent alcohol and nicotine co-consumption resulted in physical dependence. Our data show that these voluntary co-consumption procedures can be easily performed in mice and can be used to study behavioral interactions between alcohol and nicotine consumption, which may better model human alcohol and nicotine co-addiction.

  17. Precipitated Withdrawal From Nicotine Reduces Reinforcing Effects of a Visual Stimulus for Rats

    PubMed Central

    Sweitzer, Maggie; Coddington, Sarah; Sheppard, Jaimee; Verdecchia, Nicole; Caggiula, Anthony R.; Sved, Alan F.; Donny, Eric C.

    2012-01-01

    Introduction: Research has identified at least two positive reinforcement-related effects of nicotine: (a) primary reinforcement and (b) enhancement of reinforcement from concurrently available stimuli. Prior examples of the reinforcement-enhancing effects with rats showed that repeated, intermittent nicotine exposure increased responding for non-nicotine reinforcers, and this effect remained robust over several weeks. However, the effects of continuous nicotine exposure on responding for a non-nicotine reinforcer are unknown, as are the effects of abruptly withdrawing continuous nicotine on behavior maintained by the same reinforcer. Methods: Lever pressing for a visual reinforcer under a fixed ratio schedule was assessed while rats were maintained on a chronic, continuous infusion of nicotine (3.16 mg/kg/day; osmotic minipump). The effects of precipitated withdrawal on responding, following 16 days of continuous nicotine exposure, were assessed by pre-session subcutaneous injections of mecamylamine (1.0 mg/kg). Results: Continuous nicotine initially increased active responding for the visual reinforcer; however, continued exposure resulted in an attenuation of this effect. Precipitated withdrawal from nicotine resulted in a significant decline in active responding. Conclusions: The initial increase in responding for the visual reinforcer with chronic nicotine exposure is consistent with prior research showing that intermittent exposure to nicotine acts as a reinforcement enhancer. However, the attenuation of this enhancement following prolonged nicotine exposure is in contrast with the persistent effects previously reported. Finally, the decrease in visual reinforcers below control levels (nicotine-naive animals) following nicotine withdrawal highlights a potential for affective withdrawal, which may serve as a motive for continued nicotine use. PMID:22218403

  18. AAV-directed persistent expression of a gene encoding anti-nicotine antibody for smoking cessation.

    PubMed

    Hicks, Martin J; Rosenberg, Jonathan B; De, Bishnu P; Pagovich, Odelya E; Young, Colin N; Qiu, Jian-ping; Kaminsky, Stephen M; Hackett, Neil R; Worgall, Stefan; Janda, Kim D; Davisson, Robin L; Crystal, Ronald G

    2012-06-27

    Current strategies to help tobacco smokers quit have limited success as a result of the addictive properties of the nicotine in cigarette smoke. We hypothesized that a single administration of an adeno-associated virus (AAV) gene transfer vector expressing high levels of an anti-nicotine antibody would persistently prevent nicotine from reaching its receptors in the brain. To test this hypothesis, we constructed an AAVrh.10 vector that expressed a full-length, high-affinity, anti-nicotine antibody derived from the Fab fragment of the anti-nicotine monoclonal antibody NIC9D9 (AAVantiNic). In mice treated with this vector, blood concentrations of the anti-nicotine antibody were dose-dependent, and the antibody showed high specificity and affinity for nicotine. The antibody shielded the brain from systemically administered nicotine, reducing brain nicotine concentrations to 15% of those in naïve mice. The amount of nicotine sequestered in the serum of vector-treated mice was more than seven times greater than that in untreated mice, with 83% of serum nicotine bound to immunoglobulin G. Treatment with the AAVantiNic vector blocked nicotine-mediated alterations in arterial blood pressure, heart rate, and locomotor activity. In summary, a single administration of a gene transfer vector expressing a high-affinity anti-nicotine monoclonal antibody elicited persistent (18 weeks), high titers of an anti-nicotine antibody that obviated the physiologic effects of nicotine. If this degree of efficacy translates to humans, AAVantiNic could be an effective preventative therapy for nicotine addiction.

  19. Cotinine antagonizes the behavioral effects of nicotine exposure in the planarian Girardia tigrina.

    PubMed

    Bach, Daniel J; Tenaglia, Matthew; Baker, Debra L; Deats, Sean; Montgomery, Erica; Pagán, Oné R

    2016-10-06

    Nicotine is one of the most addictive drugs abused by humans. Our laboratory and others have demonstrated that nicotine decreases motility and induces seizure-like behavior in planarians (pSLM, which are vigorous writhing and bending of the body) in a concentration-dependent manner. Nicotine also induces withdrawal-like behaviors in these worms. Cotinine is the major nicotine metabolite in humans, although it is not the final product of nicotine metabolism. Cotinine is mostly inactive in vertebrate nervous systems and is currently being explored as a molecule which possess most of nicotine's beneficial effects and few of its undesirable ones. It is not known whether cotinine is a product of nicotine metabolism in planarians. We found that cotinine by itself does not seem to elicit any behavioral effects in planarians up to a concentration of 1mM. We also show that cotinine antagonizes the aforementioned nicotine-induced motility decrease and also decreases the expression of nicotine-induced pSLMs in a concentration-dependent manner. Also cotinine prevents the manifestation of some of the withdrawal-like behaviors induced by nicotine in our experimental organism. Thus, we obtained evidence supporting that cotinine antagonizes nicotine in this planarian species. Possible explanations include competitive binding of both compounds at overlapping binding sites, at different nicotinic receptor subtypes, or maybe allosteric interactions.

  20. Measures of Affect and Nicotine Dependence Predict Differential Response to Smoking Cessation Treatments.

    ERIC Educational Resources Information Center

    Zelman, Diane C.; And Others

    1992-01-01

    Randomly assigned smokers (n=126) to six-session smoking cessation treatments consisting of skills training or support counseling strategies and nicotine gum or rapid smoking nicotine exposure strategies. Counseling and nicotine strategies were completely crossed; all four combinations resulted in equivalent one-year abstinence rates. Treatments…