WorldWideScience

Sample records for brain nicotine accumulation

  1. α7 Nicotinic acetylcholine receptor-specific antibody induces inflammation and amyloid β42 accumulation in the mouse brain to impair memory.

    Directory of Open Access Journals (Sweden)

    Olena Lykhmus

    Full Text Available Nicotinic acetylcholine receptors (nAChRs expressed in the brain are involved in regulating cognitive functions, as well as inflammatory reactions. Their density is decreased upon Alzheimer disease accompanied by accumulation of β-amyloid (Aβ42, memory deficit and neuroinflammation. Previously we found that α7 nAChR-specific antibody induced pro-inflammatory interleukin-6 production in U373 glioblastoma cells and that such antibodies were present in the blood of humans. We raised a hypothesis that α7 nAChR-specific antibody can cause neuroinflammation when penetrating the brain. To test this, C57Bl/6 mice were either immunized with extracellular domain of α7 nAChR subunit α7(1-208 or injected with bacterial lipopolysaccharide (LPS for 5 months. We studied their behavior and the presence of α3, α4, α7, β2 and β4 nAChR subunits, Aβ40 and Aβ42 and activated astrocytes in the brain by sandwich ELISA and confocal microscopy. It was found that either LPS injections or immunizations with α7(1-208 resulted in region-specific decrease of α7 and α4β2 and increase of α3β4 nAChRs, accumulation of Aβ42 and activated astrocytes in the brain of mice and worsening of their episodic memory. Intravenously transferred α7 nAChR-specific-antibodies penetrated the brain parenchyma of mice pre-injected with LPS. Our data demonstrate that (1 neuroinflammation is sufficient to provoke the decrease of α7 and α4β2 nAChRs, Aβ42 accumulation and memory impairment in mice and (2 α7(1-208 nAChR-specific antibodies can cause inflammation within the brain resulting in the symptoms typical for Alzheimer disease.

  2. Differential effects of passive immunization with nicotine-specific antibodies on the acute and chronic distribution of nicotine to brain in rats.

    Science.gov (United States)

    Pentel, P R; Dufek, M B; Roiko, S A; Lesage, M G; Keyler, D E

    2006-05-01

    Vaccination against nicotine blocks or attenuates nicotine-related behaviors relevant to addiction in rats. Passive immunization with nicotine-specific antibodies is an alternative to vaccination with the potential advantages of allowing control of antibody dose and affinity. In the current study, the effects of two antibodies on the distribution of nicotine to brain were evaluated during chronic nicotine administration in rats; the monoclonal antibody Nic311 (K(d) = 60 nM) and nicotine-specific antiserum (K(d) = 1.6 nM). Nicotine was administered via repeated i.v. bolus doses over 2 days and antibody was administered during the first day. Neither antibody appreciably reduced the chronic accumulation of nicotine in brain, despite high protein binding of nicotine in serum (98.9%) and a 73% reduction in the unbound serum nicotine concentration with the highest Nic311 dose. However, both antibodies substantially reduced the early distribution of nicotine to brain 5 min after a dose. The higher affinity antibody was no more effective than Nic311. The highest Nic311 dose produced serum antibody levels 10 times higher than those reported with vaccination. The efficacy of Nic311 was dose-related, with the highest dose producing a 76% decrease in the early distribution of nicotine to brain. These findings, along with previous data, suggest that the primary effect of passive immunization is to slow, rather than prevent, the distribution of nicotine to brain. In the setting of chronic nicotine dosing, antibodies with a moderate affinity for nicotine produced substantial effects on the early distribution of nicotine to brain and were as effective as higher affinity antibodies. PMID:16407464

  3. Regional brain activity correlates of nicotine dependence.

    Science.gov (United States)

    Rose, Jed E; Behm, Frederique M; Salley, Alfred N; Bates, James E; Coleman, R Edward; Hawk, Thomas C; Turkington, Timothy G

    2007-12-01

    Fifteen smokers participated in a study investigating brain correlates of nicotine dependence. Dependence was reduced by having subjects switch to denicotinized cigarettes for 2 weeks while wearing nicotine skin patches. Positron emission tomography (PET) scans assessed regional cerebral metabolic rate for glucose (rCMRglc) after overnight nicotine abstinence on three occasions: (1) at baseline; (2) after 2 weeks of exposure to denicotinized cigarettes+nicotine patches; and (3) 2 weeks after returning to smoking the usual brands of cigarettes. Craving for cigarettes and scores on the Fagerström Test of Nicotine Dependence (FTND) questionnaire decreased at the second session relative to the first and last sessions. Regional brain metabolic activity (normalized to whole brain values) at session 2 also showed a significant decrease in the right hemisphere anterior cingulate cortex. Exploratory post hoc analyses showed that the change in craving across sessions was negatively correlated with the change in rCMRglc in several structures within the brain reward system, including the ventral striatum, orbitofrontal cortex and pons. The between-session difference in thalamus activity (right hemisphere) was positively correlated with the difference in FTND scores. Correlational analyses also revealed that reported smoking for calming effects was associated with a decrease (at session 2) in thalamus activity (bilaterally) and with an increase in amygdala activity (left hemisphere). Reported smoking to enhance pleasurable relaxation was associated with an increase in metabolic activity of the dorsal striatum (caudate, putamen) at session 2. These findings suggest that reversible changes in regional brain metabolic activity occur in conjunction with alterations in nicotine dependence. The results also highlight the likely role of thalamic gating processes as well as striatal reward and corticolimbic regulatory pathways in the maintenance of cigarette addiction. PMID:17356570

  4. Nicotine-induced brain metabolism associated with anger provocation

    OpenAIRE

    Jamner Larry D; Whalen Carol K; Loughlin Sandra E; Leslie Frances M; Potkin Steven G; Gehricke Jean-G; Mbogori James; Fallon James H

    2009-01-01

    Abstract Cortico-limbic brain activity associated with anger may be susceptible to nicotine and, thus, may contribute to smoking initiation and nicotine addiction. The purpose of the study was to identify the brain regions that are most reactive to nicotine and show the greatest association with anger task performance. Twenty adult nonsmokers (9 women, 11 men) participated in two laboratory sessions to assess brain metabolism with fluoro deoxy-glucose Positron Emission Topography (FDG-PET) in...

  5. Nicotine-induced brain metabolism associated with anger provocation

    OpenAIRE

    Gehricke, Jean-G; Potkin, Steven G; Leslie, Frances M.; Loughlin, Sandra E.; Whalen, Carol K; Jamner, Larry D; Mbogori, James; Fallon, James H.

    2009-01-01

    Cortico-limbic brain activity associated with anger may be susceptible to nicotine and, thus, may contribute to smoking initiation and nicotine addiction. The purpose of the study was to identify the brain regions that are most reactive to nicotine and show the greatest association with anger task performance. Twenty adult nonsmokers (9 women, 11 men) participated in two laboratory sessions to assess brain metabolism with fluoro deoxy-glucose Positron Emission Topography (FDG-PET) in response...

  6. Monoclonal nicotine-specific antibodies reduce nicotine distribution to brain in rats: dose- and affinity-response relationships.

    Science.gov (United States)

    Keyler, D E; Roiko, S A; Benlhabib, E; LeSage, M G; St Peter, J V; Stewart, S; Fuller, S; Le, C T; Pentel, P R

    2005-07-01

    Vaccination against nicotine is being studied as a potential treatment for nicotine dependence. Some of the limitations of vaccination, such as variability in antibody titer and affinity, might be overcome by instead using passive immunization with nicotine-specific monoclonal antibodies. The effects of antibodies on nicotine distribution to brain were studied using nicotine-specific monoclonal antibodies (NICmAbs) with K(d) values ranging from 60 to 250 nM and a high-affinity polyclonal rabbit antiserum (K(d) = 1.6 nM). Pretreatment with NICmAbs substantially increased the binding of nicotine in serum after a single nicotine dose, reduced the unbound nicotine concentration in serum, and reduced the distribution of nicotine to brain. Efficacy was directly related to antibody affinity for nicotine. Efficacy of the highest affinity NICmAb, NICmAb311, was dose-related, with the highest dose reducing nicotine distribution to brain by 78%. NICmAb311 decreased nicotine clearance by 90% and prolonged the terminal half-life of nicotine by 120%. At equivalent doses, NICmAb311 was less effective than the higher affinity rabbit antiserum but comparable efficacy could be achieved by increasing the NICmAb311 dose. These data suggest that passive immunization with nicotine-specific monoclonal antibodies substantially alters nicotine pharmacokinetics in a manner similar to that previously reported for vaccination against nicotine. Antibody efficacy is a function of both dose and affinity for nicotine. PMID:15843487

  7. Passive immunization with a nicotine-specific monoclonal antibody decreases brain nicotine levels but does not precipitate withdrawal in nicotine-dependent rats.

    Science.gov (United States)

    Roiko, Samuel A; Harris, Andrew C; LeSage, Mark G; Keyler, Daniel E; Pentel, Paul R

    2009-08-01

    Vaccination against nicotine is under investigation as a treatment for tobacco dependence. Passive immunization with nicotine-specific antibodies represents a complementary strategy to vaccination. A potential adverse effect of passive immunization in nicotine-dependent individuals is that it may lead to a rapid reduction in brain nicotine levels and trigger withdrawal. The goal of this study was to determine if passive immunization with the nicotine-specific monoclonal antibody Nic311 precipitated withdrawal in nicotine-dependent rats as measured by increases in brain reward thresholds and somatic signs. Another cohort of rats was used to measure brain nicotine levels after Nic311 administration. Nic311 30, 80 or 240 mg/kg reduced brain nicotine concentrations by 45, 83 or 92% compared to controls. None of these Nic311 doses precipitated withdrawal measured at intervals up to 72 h following antibody administration. Administration of the nicotinic antagonist mecamylamine precipitated a robust nicotine withdrawal syndrome. Therefore, a substantial, but not complete, acute reduction in brain nicotine levels following passive immunization was not sufficient to precipitate nicotine withdrawal in nicotine-dependent rats. The Nic311 doses used have been shown to attenuate the behavioral effects of nicotine, suggesting that the use of passive immunization to treat nicotine addiction is not likely to precipitate withdrawal. PMID:19393688

  8. Passive immunization with a nicotine-specific monoclonal antibody decreases brain nicotine levels but does not precipitate withdrawal in nicotine-dependent rats

    OpenAIRE

    Roiko, Samuel A.; Harris, Andrew C.; LeSage, Mark G.; Keyler, Daniel E.; Pentel, Paul R.

    2009-01-01

    Vaccination against nicotine is under investigation as a treatment for tobacco dependence. Passive immunization with nicotine-specific antibodies represents a complementary strategy to vaccination. A potential adverse effect of passive immunization in nicotine-dependent individuals is that it may lead to a rapid reduction in brain nicotine levels and trigger withdrawal. The goal of this study was to determine if passive immunization with the nicotine-specific monoclonal antibody Nic311 precip...

  9. A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans

    Energy Technology Data Exchange (ETDEWEB)

    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.

  10. An autoradiographic analysis of cholinergic receptors in mouse brain after chronic nicotine treatment

    International Nuclear Information System (INIS)

    Quantitative autoradiographic procedures were used to examine the effects of chronic nicotine infusion on the number of central nervous system nicotinic cholinergic receptors. Female DBA mice were implanted with jugular cannulas and infused with saline or various doses of nicotine (0.25, 0.5, 1.0 or 2.0 mg/kg/hr) for 10 days. The animals were then sacrificed and the brains were removed and frozen in isopentane. Cryostat sections were collected and prepared for autoradiographic procedures as previously described. Nicotinic cholinergic receptors were labeled with L-[3H]nicotine or alpha-[125I]bungarotoxin; [3H]quinuclidinyl benzilate was used to measure muscarinic cholinergic receptor binding. Chronic nicotine infusion increased the number of sites labeled by [3H]nicotine in most brain areas. However, the extent of the increase in binding as well as the dose-response curves for the increase were widely different among brain regions. After the highest treatment dose, binding was increased in 67 of 86 regions measured. Septal and thalamic regions were most resistant to change. Nicotinic binding measured by alpha-[125I]bungarotoxin also increased after chronic treatment, but in a less robust fashion. At the highest treatment dose, only 26 of 80 regions were significantly changes. Muscarinic binding was not altered after chronic nicotine treatment. These data suggest that brain regions are not equivalent in the mechanisms that regulate alterations in nicotinic cholinergic receptor binding after chronic nicotine treatment

  11. Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

    International Nuclear Information System (INIS)

    Cigarette smoking and nicotine have complex effects on human physiology and behavior, including some effects similar to those elicited by inhibition of aromatase, the last enzyme in estrogen biosynthesis. We report the first in vivo primate study to determine whether there is a direct effect of nicotine administration on brain aromatase. Brain aromatase availability was examined with positron emission tomography and the selective aromatase inhibitor (11C)vorozole in six baboons before and after exposure to IV nicotine at .015 and .03 mg/kg. Nicotine administration produced significant, dose-dependent reductions in (11C)vorozole binding. The amygdala and preoptic area showed the largest reductions. Plasma levels of nicotine and its major metabolite cotinine were similar to those found in cigarette smokers. Nicotine interacts in vivo with primate brain aromatase in regions involved in mood, aggression, and sexual behavior.

  12. Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A.; Biegon, A.; Kim, S.-W.; Logan, J.; Hooker, J.M.; Muench, L.; Fowler, J.S.

    2010-01-12

    Cigarette smoking and nicotine have complex effects on human physiology and behavior, including some effects similar to those elicited by inhibition of aromatase, the last enzyme in estrogen biosynthesis. We report the first in vivo primate study to determine whether there is a direct effect of nicotine administration on brain aromatase. Brain aromatase availability was examined with positron emission tomography and the selective aromatase inhibitor [{sup 11}C]vorozole in six baboons before and after exposure to IV nicotine at .015 and .03 mg/kg. Nicotine administration produced significant, dose-dependent reductions in [{sup 11}C]vorozole binding. The amygdala and preoptic area showed the largest reductions. Plasma levels of nicotine and its major metabolite cotinine were similar to those found in cigarette smokers. Nicotine interacts in vivo with primate brain aromatase in regions involved in mood, aggression, and sexual behavior.

  13. In vivo PET imaging of brain nicotinic cholinergic receptors

    International Nuclear Information System (INIS)

    Neuronal acetylcholine receptors (nAChRs) are widely distributed throughout the central nervous system where they modulate a number of CNS functions including neurotransmitter release, cognitive function, anxiety, analgesia and control of cerebral blood flow. In the brain, a major subtype is composed of the α4β2 subunit combination. Density of this subtype has been shown to be decreased in patients with neuro-degenerative disease such as Alzheimer and Parkinson's disease (AD and PD), and mutated receptors has been described in some familial epilepsy. Thus, in vivo mapping of the nicotinic nAChRs by Positron Emission Tomography (PET) are of great interest to monitor the evolution of these pathologies and changes in the neuronal biochemistry induced by therapeutic agents. Recently, a new compound, 3-[2(S)-2-azetidinyl-methoxy]pyridine (A-85380) has been synthesised and labelled with fluorine-18, [18F]fluoro-A-85380 (Dolle et al., 1999). The [18F]fluoro-A-85380 has been shown to bind with high affinity t o nAChRs in vitro (Saba et al., 2004), and its toxicity was low and compatible with it s use at tracer dose in human PET studies (Valette, 2002). PET studies in baboons showed that, after in vivo administration of [ 18F]fluoro-A-85380 at a tracer dose, the distribution of the radioactivity in the brain reflect the distribution of the 18F]fluoro-A-8538 0 combined with its low toxicity make possible the imaging of the nicotinic receptor s in human by PET (Bottlaender 2003). Studies were performed in healthy non-smoker volunteers to evaluate the brain kinetics of [18F]fluoro-A-85380 and to assess the quantification of its nAChRs binding in the human brain with PET (Gallezot et a., 2005). The [18F]fluoro-A-85380 was also used in epileptic patients to whom a mutation in the α4 or β2 nAChRs subunit have been identified. We found that, in these patients, the pattern of the brain distribution of the radiotracer was found different when compared to the healthy subjects

  14. [3H]methylcarbamylcholine, a new radioligand for studying brain nicotinic receptors

    International Nuclear Information System (INIS)

    A new radioligand, [3H]methylcarbamylcholine, has been developed for the study of the nicotinic cholinergic and nicotine-like binding sites in rat brain membranes. A Scatchard analysis with the radioligand yielded a Ksub(d) of 1.1 x 10-9 M and a Bsub(max) of 4.0 x 10-14 moles/mg protein which compares with a lower affinity site for (-)-[3H]nicotine having a Ksub(d) of 3 x 10-9 M and a Bsub(max) of 2x 10-14 moles/mg. Comparable values for the Ksub(d) were obtained from a Hill plot and from calculations based on rate constants for association and dissociation. A comparison of the binding affinities of various nicotine analogues, nicotinic cholinergic agents, and other neurotropic agents revealed a close similarity between the two radioligands, with the exception that quaternization of nicotine or carbamate esters increased affinity by at least an order of magnitude with [3H]methylcarbamylcholine and resulted in a comparable decrease in affinity with [3H]nicotine as the ligand. The binding of [3H]methylcarbamylcholine, like [3H]nicotine, was not displaceable by muscarinic cholinergic antagonists. It was concluded that, although [3H]methylcarbamylcholine and [3H]nicotine bind to a common receptor in brain, the functional and chemical characteristics of the receptor(s) differ in some respects from peripheral nicotinic cholinergic receptors. (author)

  15. In vivo PET imaging of brain nicotinic cholinergic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Bottlaender, M.; Valette, H.; Saba, W.; Schollhorn-Peyronneau, M.A.; Dolle, F.; Syrota, A. [Service Hospitalier Frederic Joliot (CEA/DSV/DRM), 91 - Orsay (France)

    2006-07-01

    Neuronal acetylcholine receptors (nAChRs) are widely distributed throughout the central nervous system where they modulate a number of CNS functions including neurotransmitter release, cognitive function, anxiety, analgesia and control of cerebral blood flow. In the brain, a major subtype is composed of the {alpha}4{beta}2 subunit combination. Density of this subtype has been shown to be decreased in patients with neuro-degenerative disease such as Alzheimer and Parkinson's disease (AD and PD), and mutated receptors has been described in some familial epilepsy. Thus, in vivo mapping of the nicotinic nAChRs by Positron Emission Tomography (PET) are of great interest to monitor the evolution of these pathologies and changes in the neuronal biochemistry induced by therapeutic agents. Recently, a new compound, 3-[2(S)-2-azetidinyl-methoxy]pyridine (A-85380) has been synthesised and labelled with fluorine-18, [{sup 18}F]fluoro-A-85380 (Dolle et al., 1999). The [{sup 18}F]fluoro-A-85380 has been shown to bind with high affinity t o nAChRs in vitro (Saba et al., 2004), and its toxicity was low and compatible with it s use at tracer dose in human PET studies (Valette, 2002). PET studies in baboons showed that, after in vivo administration of [ {sup 18}F]fluoro-A-85380 at a tracer dose, the distribution of the radioactivity in the brain reflect the distribution of the < 4R2 nAChRs. Competition and pre-blocking studies, using nicotinic agonists, confirm that the radiotracer binds specifically to the heteromeric nAChRs in the brain (Valette et al., 1999). The in vivo, characteristics of the [{sup 18}F]fluoro-A-8538 0 combined with its low toxicity make possible the imaging of the nicotinic receptor s in human by PET (Bottlaender 2003). Studies were performed in healthy non-smoker volunteers to evaluate the brain kinetics of [{sup 18}F]fluoro-A-85380 and to assess the quantification of its nAChRs binding in the human brain with PET (Gallezot et a., 2005). The [{sup 18}F

  16. Comparison of [3H]nicotine and [3H]acetylcholine binding in mouse brain: regional distribution

    International Nuclear Information System (INIS)

    In a continuing study of nicotine binding sites, the authors determined the relative amount of nicotine binding and acetylcholine binding in various brain regions of C57/BL and of DBA mice. Although midbrain showed the highest and cerebellum the lowest binding for both [3H]nicotine and [3H]acetylcholine, the ratio of nicotine to acetylcholine binding showed a three-fold regional variation. Acetylcholine inhibition of [3H]nicotine binding indicated that a portion of nicotine binding was not inhibited by acetylcholine. These results indicate important differences between the binding of (+/-)-[3H]nicotine and that of [3H]acetylcholine

  17. Brain activation by short-term nicotine exposure in anesthetized wild-type and beta2-nicotinic receptors knockout mice: a BOLD fMRI study

    Energy Technology Data Exchange (ETDEWEB)

    Suarez, S.V.; Changeux, J.P.; Granon, S. [Unite de Neurobiologie Integrative du Systeme Cholinergique, URA CNRS 2182, Institut Pasteur, Departement de Neuroscience, 25 rue du Dr Roux, 75015 Paris (France); Amadon, A.; Giacomini, E.; Le Bihan, D. [Service Hospitalier Frederic Joliot, 4 place du general Leclerc, 91400 Orsay (France); Wiklund, A. [Section of Anaesthesiology and Intensive Care Medicine, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (Sweden)

    2009-07-01

    Rationale: The behavioral effects of nicotine and the role of the beta2-containing nicotinic receptors in these behaviors are well documented. However, the behaviors altered by nicotine rely on the functioning on multiple brain circuits where the high-affinity {beta}2-containing nicotinic receptors ({beta}2*nAChRs) are located. Objectives We intend to see which brain circuits are activated when nicotine is given in animals naive for nicotine and whether the {beta}2*nAChRs are needed for its activation of the blood oxygen level dependent (BOLD) signal in all brain areas. Materials and methods: We used functional magnetic resonance imaging (fMRI) to measure the brain activation evoked by nicotine (1 mg/kg delivered at a slow rate for 45 min) in anesthetized C57BL/6J mice and {beta}2 knockout (KO) mice. Results: Acute nicotine injection results in a significant increased activation in anterior frontal, motor, and somatosensory cortices and in the ventral tegmental area and the substantia nigra. Anesthetized mice receiving no nicotine injection exhibited a major decreased activation in all cortical and subcortical structures, likely due to prolonged anesthesia. At a global level, {beta}2 KO mice were not rescued from the globally declining BOLD signal. However, nicotine still activated regions of a meso-cortico-limbic circuit likely via {alpha}7 nicotinic receptors. Conclusions: Acute nicotine exposure compensates for the drop in brain activation due to anesthesia through the meso-cortico-limbic network via the action of nicotine on {beta}2*nAChRs. The developed fMRI method is suitable for comparing responses in wild-type and mutant mice. (authors)

  18. Brain activation by short-term nicotine exposure in anesthetized wild-type and beta2-nicotinic receptors knockout mice: a BOLD fMRI study

    International Nuclear Information System (INIS)

    Rationale: The behavioral effects of nicotine and the role of the beta2-containing nicotinic receptors in these behaviors are well documented. However, the behaviors altered by nicotine rely on the functioning on multiple brain circuits where the high-affinity β2-containing nicotinic receptors (β2*nAChRs) are located. Objectives We intend to see which brain circuits are activated when nicotine is given in animals naive for nicotine and whether the β2*nAChRs are needed for its activation of the blood oxygen level dependent (BOLD) signal in all brain areas. Materials and methods: We used functional magnetic resonance imaging (fMRI) to measure the brain activation evoked by nicotine (1 mg/kg delivered at a slow rate for 45 min) in anesthetized C57BL/6J mice and β2 knockout (KO) mice. Results: Acute nicotine injection results in a significant increased activation in anterior frontal, motor, and somatosensory cortices and in the ventral tegmental area and the substantia nigra. Anesthetized mice receiving no nicotine injection exhibited a major decreased activation in all cortical and subcortical structures, likely due to prolonged anesthesia. At a global level, β2 KO mice were not rescued from the globally declining BOLD signal. However, nicotine still activated regions of a meso-cortico-limbic circuit likely via α7 nicotinic receptors. Conclusions: Acute nicotine exposure compensates for the drop in brain activation due to anesthesia through the meso-cortico-limbic network via the action of nicotine on β2*nAChRs. The developed fMRI method is suitable for comparing responses in wild-type and mutant mice. (authors)

  19. Evaluation of the antagonism of nicotine by mecamylamine and pempidine in the brain

    International Nuclear Information System (INIS)

    Antagonists have been crucial in the characterization of nicotine's pharmacology. Initial evidence for the existence of central nicotinic receptors was based on the fact that nicotine produced a number of behavioral effects that were antagonized by ganglionic blockers that crossed the blood-brain barrier, such as mecamylamine and pempidine. These compounds are thought to be noncompetitive antagonists due to the fact that they do not compete for agonist binding to brain homogenate in vitro. However, pharmacological evidence in support of noncompetitive antagonism is lacking. Dose-response curves for nicotine were determined in the presence of various doses of pempidine for depression of spontaneous activity and antinociception in mice. Pempidine was found to shift the dose response curves for these effects of nicotine in a manner consistent with noncompetitive antagonism. A number of mecamylamine analogs were investigated for antagonism of these central effects of nicotine as well. These studies revealed that the N-, 2-, and 3-methyls were crucial for optimal efficacy and potency and suggests that these compounds possess a specific mechanism of action, possibly involving a receptor. Furthermore, the structure-activity relationships for the mecamylamine analogs were found to be different than that previously reported for the agonists, suggesting that they do not act at the same site. The binding of [3 H]-L-nicotine and [3H]-pempidine was studied in vitro to mouse brain homogentate and in situ to rat brain slices. The in situ binding of [3H]-L-nicotine to rat brain slices was quantitated autoradiographically to discrete brain areas in the presence and absence of 1, 10 and 100 μM nicotine and pempidine. Pempidine did not effectively displace [3H]-L-nicotine binding

  20. Accumulation of human full-length tau induces degradation of nicotinic acetylcholine receptor α4 via activating calpain-2

    Science.gov (United States)

    Yin, Yaling; Wang, Yali; Gao, Di; Ye, Jinwang; Wang, Xin; Fang, Lin; Wu, Dongqin; Pi, Guilin; Lu, Chengbiao; Zhou, Xin-Wen; Yang, Ying; Wang, Jian-Zhi

    2016-01-01

    Cholinergic impairments and tau accumulation are hallmark pathologies in sporadic Alzheimer’s disease (AD), however, the intrinsic link between tau accumulation and cholinergic deficits is missing. Here, we found that overexpression of human wild-type full-length tau (termed hTau) induced a significant reduction of α4 subunit of nicotinic acetylcholine receptors (nAChRs) with an increased cleavage of the receptor producing a ~55kDa fragment in primary hippocampal neurons and in the rat brains, meanwhile, the α4 nAChR currents decreased. Further studies demonstrated that calpains, including calpain-1 and calpain-2, were remarkably activated with no change of caspase-3, while simultaneous suppression of calpain-2 by selective calpain-2 inhibitor but not calpain-1 attenuated the hTau-induced degradation of α4 nAChR. Finally, we demonstrated that hTau accumulation increased the basal intracellular calcium level in primary hippocampal neurons. We conclude that the hTau accumulation inhibits nAChRs α4 by activating calpain-2. To our best knowledge, this is the first evidence showing that the intracellular accumulation of tau causes cholinergic impairments. PMID:27277673

  1. Imaging Nicotine in Rat Brain Tissue by Use of Nanospray Desorption Electrospray Ionization Mass Spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Lanekoff, Ingela T.; Thomas, Mathew; Carson, James P.; Smith, Jordan N.; Timchalk, Charles; Laskin, Julia

    2013-01-15

    Imaging mass spectrometry offers simultaneous detection of drugs, drug metabolites and endogenous substances in a single experiment. This is important when evaluating effects of a drug on a complex organ system such as the brain, where there is a need to understand how regional drug distribution impacts function. Nicotine is an addictive drug and its action in the brain is of high interest. Here we use nanospray desorption electrospray ionization, nano-DESI, imaging to discover the localization of nicotine in rat brain tissue after in vivo administration of nicotine. Nano-DESI is a new ambient technique that enables spatially-resolved analysis of tissue samples without special sample pretreatment. We demonstrate high sensitivity of nano-DESI imaging that enables detection of only 0.7 fmole nicotine per pixel in the complex brain matrix. Furthermore, by adding deuterated nicotine to the solvent, we examined how matrix effects, ion suppression, and normalization affect the observed nicotine distribution. Finally, we provide preliminary results suggesting that nicotine localizes to the hippocampal substructure called dentate gyrus.

  2. TIME DEPENDENT ACCUMULATION OF NICOTINE DERIVATIVES IN THE CULTURE MEDIUM OF ARTHROBACTER NICOTINOVORANS pAO1

    Directory of Open Access Journals (Sweden)

    Răzvan Ștefan Boiangiu

    2014-12-01

    Full Text Available Previous studies have shown that the metabolic intermediate 6-hidroxy-D-nicotine (6HNic found in the Arthrobacter nicotinovorans pAO1+ nicotine catabolic pathway has the ability to bind nicotinic acetylcholine receptors and to sustain spatial memory in rats. These properties make 6HNic a valuable compound with some potential for medical applications, thereby a suitable, simple and efficient method for producing 6-hidroxy-D-nicotine is necessary. Here, we focus on identifying the best moment for harvesting A. nicotinovorans cells in order to directly convert nicotine to 6HNic with the best yield.  The growth of  A. nicotinovorans pAO1+ was monitored and the correlation between the growth phases and nicotine metabolism was established. After about 5 hours of lag,the strain entered the log phase and was fully grown after 10 hours. The nicotine concentration began to drop dramatically as the pAO1+ culture reached saturation and was depleted in 5 hours. As the nicotine concentration dropped, 6HNic began to accumulate, reaching the maximum levels after about 11 hours of growth. Two other products could be detected by HPLC, one which was identified as the nicotine-blue (NB pigment and a second a still unknown end-product. 

  3. Autoradiographic localization of putative nicotinic receptors in the rat brain using 125I-neuronal bungarotoxin

    International Nuclear Information System (INIS)

    Neuronal bungarotoxin (NBT), a snake venom neurotoxin, selectively blocks nicotinic receptors in many peripheral and central neuronal preparations. alpha-Bungarotoxin (alpha BT), on the other hand, a second toxin isolated from the venom of the same snake, is an ineffective nicotinic antagonist in most vertebrate neuronal preparations studied thus far. To examine central nicotinic receptors recognized by NBT, we have characterized the binding of 125I-labeled NBT (125I-NBT) to rat brain membranes and have mapped the distribution of 125I-NBT binding in brain sections using quantitative light microscopic autoradiography. The binding of 125I-NBT was found to be saturable, of high affinity, and heterogeneously distributed in the brain. Pharmacological studies suggested that more than one population of sites is labeled by 125I-NBT. For example, one component of 125I-NBT binding was also recognized by alpha BT, while a second component, not recognized by alpha BT, was recognized by the nicotinic agonist nicotine. The highest densities of these alpha BT-insensitive, nicotine-sensitive sites were found in the fasciculus retroflexus, the lateral geniculate nucleus, the medial terminal nucleus of the accessory optic tract, and the olivary pretectal nucleus. alpha BT-sensitive NBT binding sites were found in highest density in the lateral geniculate nucleus, the subthalamic nucleus, the dorsal tegmental nucleus, and the medial mammillary nucleus (lateral part). The number of brain regions with a high density of 125I-NBT binding sites, blocked either by alpha BT or by nicotine, is low when compared with results obtained using other approaches to studying the central distribution of nicotinic receptors, such as labeling with 3H-nicotine or labeling with cDNA probes to mRNAs coding for putative receptor subunits

  4. Accumulation and persistence of nicotine derived DNA and hemoglobin adducts in mice after multiple administration of 14C-nicotine at low dose level

    International Nuclear Information System (INIS)

    The hypothetic role of nicotine in causing smoking related diseases has not been well established. Based on our early finding of the genotoxicity of nicotine, a sub-chronic study on the accumulation and persistence of nicotine derived DNA and hemoglobin (Hb) adducts in mice following multiple low dose exposures was carried out by accelerator mass spectrometry (AMS). AMS is a sophisticated ultrasensitive nuclear method, which facilitates the detection of adduction of DNA and other bio-macromolecules with xenobiotics at human relevant environmental dose levels. Briefly, in this study [N-14CH3]-nicotine (s.a. 16.2 μCi/μmol) was administered to mice by gavage once daily at 3.0 μg/kg b.w., which is equivalent to an estimated nicotine dose inhaled by a 70 kg person smoking 5 cigarettes, for 14 consecutive days. Lung DNA, liver DNA and Hb were isolated from tissues and blood samples which were collected at 1, 3, 5, 7, 10, 14, 15, 17, 21 and 25 days time point, respectively. (orig.)

  5. Nicotinic binding in rat brain: autoradiographic comparison of [3H]acetylcholine, [3H]nicotine, and [125I]-alpha-bungarotoxin

    International Nuclear Information System (INIS)

    Three radioligands have been commonly used to label putative nicotinic cholinoceptors in the mammalian central nervous system: the agonists [3H]nicotine and [3H]acetylcholine ([3H]ACh--in the presence of atropine to block muscarinic receptors), and the snake venom extract, [125I]-alpha-bungarotoxin([125I]BTX), which acts as a nicotinic antagonist at the neuromuscular junction. Binding studies employing brain homogenates indicate that the regional distributions of both [3H]nicotine and [3H]ACh differ from that of [125I]BTX. The possible relationship between brain sites bound by [3H]nicotine and [3H]ACh has not been examined directly. The authors have used the technique of autoradiography to produce detailed maps of [3H]nicotine, [3H]ACh, and [125I]BTX labeling; near-adjacent tissue sections were compared at many levels of the rat brain. The maps of high affinity agonist labeling are strikingly concordant, with highest densities in the interpeduncular nucleus, most thalamic nuclei, superior colliculus, medial habenula, presubiculum, cerebral cortex (layers I and III/IV), and the substantia nigra pars compacta/ventral tegmental area. The pattern of [125I]BTX binding is strikingly different, the only notable overlap with agonist binding being the cerebral cortex (layer I) and superior colliculus. [125I]BTX binding is also dense in the inferior colliculus, cerebral cortex (layer VI), hypothalamus, and hippocampus, but is virtually absent in thalamus. Various lines of evidence suggest that the high affinity agonist-binding sites in brain correspond to nicotinic cholinergic receptors similar to those found at autonomic ganglia; BTX-binding sites may also serve as receptors for nicotine and are possibly related to neuromuscular nicotinic cholinoceptors

  6. The effects of tobacco smoke and nicotine on cognition and the brain.

    Science.gov (United States)

    Swan, Gary E; Lessov-Schlaggar, Christina N

    2007-09-01

    Tobacco smoke consists of thousands of compounds including nicotine. Many constituents have known toxicity to the brain, cardiovascular, and pulmonary systems. Nicotine, on the other hand, by virtue of its short-term actions on the cholinergic system, has positive effects on certain cognitive domains including working memory and executive function and may be, under certain conditions, neuroprotective. In this paper, we review recent literature, laboratory and epidemiologic, that describes the components of mainstream and sidestream tobacco smoke, including heavy metals and their toxicity, the effect of medicinal nicotine on the brain, and studies of the relationship between smoking and (1) preclinical brain changes including silent brain infarcts; white matter hyperintensities, and atrophy; (2) single measures of cognition; (3) cognitive decline over repeated measures; and (4) dementia. In most studies, exposure to smoke is associated with increased risk for negative preclinical and cognitive outcomes in younger people as well as in older adults. Potential mechanisms for smoke's harmful effects include oxidative stress, inflammation, and atherosclerotic processes. Recent evidence implicates medicinal nicotine as potentially harmful to both neurodevelopment in children and to catalyzing processes underlying neuropathology in Alzheimer's Disease. The reviewed evidence suggests caution with the use of medicinal nicotine in pregnant mothers and older adults at risk for certain neurological disease. Directions for future research in this area include the assessment of comorbidities (alcohol consumption, depression) that could confound the association between smoking and neurocognitive outcomes, the use of more specific measures of smoking behavior and cognition, the use of biomarkers to index exposure to smoke, and the assessment of cognition-related genotypes to better understand the role of interactions between smoking/nicotine and variation in genotype in determining

  7. Neurodegeneration with Brain Iron Accumulation: An Overview

    Directory of Open Access Journals (Sweden)

    Seyed Hassan TONEKABONI*

    2014-12-01

    Full Text Available How to Cite This Article: Tonekaboni SH, Mollamohammadi M. Neurodegeneration with Brain Iron Accumulation: An Overview. Iran J Child Neurol. 2014 Autumn;8(4: 1-8.AbstractObjectiveNeurodegeneration with brain iron accumulation (NBIA is a group of neurodegenerative disorder with deposition of iron in the brain (mainly Basal Ganglia leading to a progressive Parkinsonism, spasticity, dystonia, retinal degeneration, optic atrophy often accompanied by psychiatric manifestations and cognitive decline. 8 of the 10 genetically defined NBIA types are inherited as autosomal recessive and the remaining two by autosomal dominant and X-linked dominant manner. Brain MRI findings are almost specific and show abnormal brain iron deposition in basal ganglia some other related anatomicallocations. In some types of NBIA cerebellar atrophy is the major finding in MRI.ReferencesShevel M. Racial hygiene, activeeuthanasia, and Julius Hallervorden. Neurology 1992;42:2214-2219.HayflickSJ. Neurodegeneration with brain Iron accumulation: from genes to pathogenesis.Semin Pediatr Neurol 2006;13:182-185.Zhou B, Westawy SK, Levinson B, et al. A novel pantothenate kinase gene(PANK2 is defective in Hallervorden-Spatzsyndrome. Nat Genet 2001;28:345- 349.www.ncbi.nlm.nihgov/NBK111Y/university of Washington, seattle. Allison Gregory and Susan Hayflick.Paisan-Ruiz C, Li A, Schneider SA, et al. Widesread Levy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging 2012;33:814-823.Dick KJ, Eckhardt M, Paison-Ruiz C, et al. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia(SPG 35. Hum Mutat 31: E1251-E1260.Edvardson S, Hama H, Shaag A, et al. Mutation in the fatty acid 2-Hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am I Hum Genet 2008;83:647-648.Schneider SA, Aggarwal A, Bhatt m, et al. Severe tongue protrusion dystonia: clinical syndromes

  8. Potential contribution of aromatase inhibition to the effects of nicotine and related compounds on the brain

    Directory of Open Access Journals (Sweden)

    Anat Biegon

    2012-11-01

    Full Text Available Cigarette smoking continues to be a major public health problem, and while smoking rates in men have shown some decrease over the last few decades, smoking rates among girls and young women are increasing. Practically all of the important aspects of cigarette smoking are sexually dimorphic. Women become addicted more easily than men, while finding it harder to quit. Nicotine replacement appears to be less effective in women. This may be linked to the observation that women are more sensitive than men to non-nicotine cues or ingredients in cigarettes. The reasons for these sex differences are mostly unknown. Several lines of evidence suggest that many of the reported sex differences related to cigarette smoking may stem from the inhibitory effects of nicotine and other tobacco alkaloids on estrogen synthesis via the enzyme aromatase (cyp19a gene product. Aromatase is the last enzyme in estrogen biosynthesis, catalyzing the conversion of androgens to estrogens. This review provides a summary of experimental evidence supporting brain aromatase as a potential mediator and/or modulator of nicotine actions in the brain, contributing to sex differences in smoking behavior. Additional research on the interaction between tobacco smoke, nicotine and aromatase may help devise new, sex specific methods for prevention and treatment of smoking addiction.

  9. Characterization of a purified nicotinic receptor from rat brain by using idiotypic and anti-idiotypic antibodies

    International Nuclear Information System (INIS)

    The availability of an anti-nicotine monoclonal antibody has made it possible to further establish the nature of the nicotine recognition proteins purified from rat brain by affinity chromatography and to provide a highly sensitive assay for determining [3H]nicotine binding to the purified material. An enantiomeric analogue of nicotine. (-)-6-hydroxymethylnicotine, was used to prepare the affinity column. In addition, with the use of an anti-idiotypic monoclonal antibody, it was confirmed that the recognition site for nicotine resides on a protein complex composed of two components with molecular masses of 62 and 57 kDa. It was also demonstrated that the same two proteins could be purified by immunoaffinity chromatography with the use of an anti-idiotypic monoclonal antibody. With the use of the anti-nicotine antibody to measure [3H]nicotine binding, the purified material was shown to bind 250 pmol/mg of protein. By utilizing a procedure in which the purified receptor protein was conjugated to membranes by disulfide bonds, a binding activity of 80 pmol/mg was obtained. With the availability of sterospecific monoclonal antibodies to (-)-nicotine as well as monoclonal anti-idiotypic antibodies derived when the anti-nicotine antibodies were used as immunogens, additional procedures became available for the further characterization of the purified nicotine receptor and examining its (-)-[3H]nicotine-binding characteristics

  10. Long-term exposure to nicotine markedly reduces kynurenic acid in rat brain - In vitro and ex vivo evidence

    International Nuclear Information System (INIS)

    Kynurenic acid (KYNA) is a recognized broad-spectrum antagonist of excitatory amino acid receptors with a particularly high affinity for the glycine co-agonist site of the N-methyl-D-aspartate (NMDA) receptor complex. KYNA is also a putative endogenous neuroprotectant. Recent studies show that KYNA strongly blocks α7 subtype of nicotinic acetylcholine receptors (nAChRs). The present studies were aimed at assessing effects of acute and chronic nicotine exposure on KYNA production in rat brain slices in vitro and ex vivo. In brain slices, nicotine significantly increased KYNA formation at 10 mM but not at 1 or 5 mM. Different nAChR antagonists (dihydro-β-erythroidine, methyllycaconitine and mecamylamine) failed to block the influence exerted by nicotine on KYNA synthesis in cortical slices in vitro. Effects of acute (1 mg/kg, i.p.), subchronic (10-day) and chronic (30-day) administration of nicotine in drinking water (100 μg/ml) on KYNA brain content were evaluated ex vivo. Acute treatment with nicotine (1 mg/kg i.p.) did not affect KYNA level in rat brain. The subchronic exposure to nicotine in drinking water significantly increased KYNA by 43%, while chronic exposure to nicotine resulted in a reduction in KYNA by 47%. Co-administration of mecamylamine with nicotine in drinking water for 30 days reversed the effect exerted by nicotine on KYNA concentration in the cerebral cortex. The present results provide evidence for the hypothesis of reciprocal interaction between the nicotinic cholinergic system and the kynurenine pathway in the brain.

  11. Aluminum accumulation in human brain tissues

    Energy Technology Data Exchange (ETDEWEB)

    Ishihara, R.; Takeuchi, T.; Ohta, T. [Dept. of Psychiatry, Nagoya University School of Medicine, Nagoya, Aichi (Japan); Ektessabi, A.M. [Graduate School of Engineering, Kyoto University, Kyoto (Japan); Hanaichi, T.; Ishihara, Y. [Hanaichi Ultrastructure Research Institute Co. Okazaki, Okazaki, Aichi (Japan); Fujita, Y. [Equipment Center for Research and Education, Nagoya, Aichi (Japan)

    1999-07-01

    Normal cell functions of the brain are often impaired by an excess accumulation of metal ions. There have been increasing efforts in recent years to measure and quantify excessive accumulations of biological constituent elements (such as Fe, Zn, Cu, and Ca), as well as the presence and distribution of contaminating elements (such as Al) in the brain tissues. Since Al might be associated with cases of neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amiotrophic lateral screlosis (ALS), it is very important to measure and quantify Al levels using precise analytical techniques. The aim of this investigation is to measure the Al contents present in the temporal cortices for three cases. The specimens concerned were taken from unfixed autopsy brains, which have been preserved in a deep freezer at -80degC. A tandem type accelerator of 2 MeV energy was used to measure the concentrations of Al in these specimen tissues. In order to increase the sensitivity of the signals in the low energy region of the spectra, the absorber was removed. The results show that peak intensity depends on the site measured. In certain cases, however, an extremely high concentration of Al was observed in PIXE spectra, with an intensity higher than those of the other major elements present in the brain. Samples from the same subjects were also analyzed using EPMA-EDX. X-ray maps produced by EPMA-EDX showed the presence of extremely high concentrations of Al. The results yielded by PIXE analysis was in good qualitative agreement with those from EPMA-EDX. (author)

  12. Isolation and characterization of a factor from rat liver which inhibits 3H-nicotine binding to brain nicotine receptors

    International Nuclear Information System (INIS)

    In studies of 3H-nicotine binding sites in rat brain membranes, it was observed that crude rat liver homogenates are capable of inhibiting this binding. The purpose of this work was to isolate from the liver homogenate the factor (or factors) responsible for this nicotinelike activity and to identify it. Isolation procedures, including heat denaturation, ultrafiltration, and reverse phase high pressure liquid chromatography, resulted in an incompletely purified substance whose chemical properties were compatible with those of dimethylaminoethyl (DMAE) carbamate, as reflected in infrared, ultraviolet, NMR, and mass spectra; in HPLC elution characteristics into mobile phases; and in IC50's with respect to 3H-nicotine binding to neural membranes, although additional purification and characterization will be necessary to confirm or reject this identification. This compound has not previously been described in mammalian tissue, although its two component functional moieties, dimethylaminoethanol and carbamic acid, are present in the liver. The binding properties of DMAE carbamate are compared with those of structurally and pharmacological related compounds to assess its potential as an endogenous cholinergic ligand

  13. Characterization of nicotine binding in mouse brain and comparison with the binding of alpha-bungarotoxin and quinuclidinyl benzilate

    International Nuclear Information System (INIS)

    The binding of [3H]nicotine to mouse brain has been measured and subsequently compared with the binding of [125I]alpha-bungarotoxin (alpha-BTX) and L-[3H]quinuclidinyl benzilate (QNB). The binding of nicotine was saturable, reversible, and stereospecific. The average KD and Bmax were 59 nM and 88 fmoles/mg of protein, respectively. Although the rates of association and dissociation of nicotine were temperature-dependent, the incubation temperature had no effect on either KD or Bmax. When measured at 20 degrees or 37 degrees, nicotine appeared to bind to a single class of binding sites, but a second, very low-affinity, binding site was observed at 4 degrees. Nicotine binding was unaffected by the addition of NaCl, KCl, CaCl2, or MgSO4 to the incubation medium. Nicotinic cholinergic agonists were potent inhibitors of nicotine binding; however, nicotinic antagonists were poor inhibitors. The regional distribution of binding was not uniform: midbrain and striatum contained the highest number of receptors, whereas cerebellum had the fewest. Differences in site densities, regional distribution, inhibitor potencies, and thermal denaturation indicated that nicotine binding was not the same as either QNB or alpha-BTX binding, and therefore that receptors for nicotine may represent a unique population of cholinergic receptors

  14. Selective effects of carbamate pesticides on rat neuronal nicotinic acetylcholine receptors and rat brain acetylcholinesterase

    International Nuclear Information System (INIS)

    Effects of commonly used carbamate pesticides on rat neuronal nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes have been investigated using the two-electrode voltage clamp technique. The potencies of these effects have been compared to the potencies of the carbamates to inhibit rat brain acetylcholinesterase. The potency order of six carbamates to inhibit α4β4 nicotinic receptors is fenoxycarb > EPTC > carbaryl, bendiocarb > propoxur > aldicarb with IC50 values ranging from 3 μM for fenoxycarb to 165 μM for propoxur and >1 mM for aldicarb. Conversely, the potency order of these carbamates to inhibit rat brain acetylcholinesterase is bendiocarb > propoxur, aldicarb > carbaryl >> EPTC, fenoxycarb with IC50 values ranging from 1 μM for bendiocarb to 17 μM for carbaryl and >>1 mM for EPTC and fenoxycarb. The α4β2, α3β4, and α3β2 nicotinic acetylcholine receptors are inhibited by fenoxycarb, EPTC, and carbaryl with potency orders similar to that for α4β4 receptors. Comparing the potencies of inhibition of the distinct subtypes of nicotinic acetylcholine receptors shows that the α3β2 receptor is less sensitive to inhibition by fenoxycarb and EPTC. The potency of inhibition depends on the carbamate as well as on a combination of α and β subunit properties. It is concluded that carbamate pesticides affect different subtypes of neuronal nicotinic receptors independently of acetylcholinesterase inhibition. This implicates that neuronal nicotinic receptors are additional targets for some carbamate pesticides and that these receptors may contribute to carbamate pesticide toxicology, especially after long-term exposure

  15. Quantitative Molecular Imaging of Neuronal Nicotinic Acetylcholine Receptors in the Human Brain with A-85380 Radiotracers

    OpenAIRE

    Lotfipour, Shahrdad; Mandelkern, Mark; Brody, Arthur L.

    2011-01-01

    Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in a spectrum of cognitive functions as well as psychiatric and neurodegenerative disorders, including tobacco addiction and Alzheimer's Disease. The examination of neuronal nAChRs in living humans is a relatively new field. Researchers have developed brain-imaging radiotracers for nAChRs, with radiolabeled A-85380 compounds having the most widespread use. We provide a brief background on nAChRs, followed by a discussion...

  16. Sex differences in resting state brain function of cigarette smokers and links to nicotine dependence.

    Science.gov (United States)

    Beltz, Adriene M; Berenbaum, Sheri A; Wilson, Stephen J

    2015-08-01

    Sex--a marker of biological and social individual differences--matters for drug use, particularly for cigarette smoking, which is the leading cause of preventable death in the United States. More men than women smoke, but women are less likely than men to quit. Resting state brain function, or intrinsic brain activity that occurs in the absence of a goal-directed task, is important for understanding cigarette smoking, as it has been shown to differentiate between smokers and nonsmokers. But, it is unclear whether and how sex influences the link between resting state brain function and smoking behavior. In this study, the authors demonstrate that sex is indeed associated with resting state connectivity in cigarette smokers, and that sex moderates the link between resting state connectivity and self-reported nicotine dependence. Using functional MRI and behavioral data from 50 adult daily smokers (23 women), the authors found that women had greater connectivity than men within the default mode network, and that increased connectivity within the reward network was related to increased nicotine tolerance in women but to decreased nicotine tolerance in men. Findings highlight the importance of sex-related individual differences reflected in resting state connectivity for understanding the etiology and treatment of substance use problems. PMID:26237322

  17. Characterization of (3H)-nicotine binding in rodent brain and comparison with the binding of other labelled nicotinic ligands

    International Nuclear Information System (INIS)

    In an investigation of the receptor through which nicotine exerts its central actions, radioactively labelled nicotine was used in biochemical in vitro binding studies. Tritium-labelled nicotine (tritium-NIC) binding to mouse hippocampus was studied and the effect of temperature on the binding was analyzed by saturation-binding experiments. The specific tritium-NIC binding was found to be approximately four times higher at 4 C than at 25 C

  18. Lower glial metabolite levels in brains of young children with prenatal nicotine exposure.

    Science.gov (United States)

    Chang, Linda; Cloak, Christine C; Jiang, Caroline S; Hoo, Aaron; Hernandez, Antonette B; Ernst, Thomas M

    2012-03-01

    Many pregnant women smoke cigarettes during pregnancy, but the effect of nicotine on the developing human brain is not well understood, especially in young children. This study aims to determine the effects of prenatal nicotine exposure (PNE) on brain metabolite levels in young (3-4 years old) children, using proton magnetic resonance spectroscopy ((1)H MRS). Twenty-six children with PNE and 24 nicotine-unexposed children (controls) were evaluated with a structured examination, a battery of neuropsychological tests, and MRI/(1)H MRS (without sedation). Concentrations of N-acetyl compounds (NA), total creatine (tCR), choline-containing compounds (CHO), myo-inositol (MI), and glutamate+glutamine (GLX) were measured in four brain regions. Children with PNE had similar performance to controls on neuropsychological testing. However, compared to controls, the PNE group had lower MI (repeated measures ANOVA-p = 0.03) and tCr levels (repeated measures ANOVA-p = 0.003), especially in the basal ganglia of the girls (-19.3%, p = 0.01). In contrast, GLX was elevated in the anterior cingulate cortex of the PNE children (+9.4%, p = 0.03), and those with the highest GLX levels had the poorest performance on vocabulary (r = -0.67; p metabolite concentrations. These findings suggest that PNE may lead to subclinical abnormalities in glial development, especially in the basal ganglia, and regionally specific changes in other neurometabolites. These alterations were not influenced by the amount of nicotine exposure prenatally. However, the effects of PNE on energy metabolism may be sex specific, with greater alterations in girls. PMID:21912896

  19. Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration.

    Science.gov (United States)

    Zanos, Panos; Georgiou, Polymnia; Metaxas, Athanasios; Kitchen, Ian; Winsky-Sommerer, Raphaelle; Bailey, Alexis

    2015-07-23

    Nicotine addiction is considered to be the main preventable cause of death worldwide. While growing evidence indicates that the neurohypophysial peptide oxytocin can modulate the addictive properties of several abused drugs, the regulation of the oxytocinergic system following nicotine administration has so far received little attention. Here, we examined the effects of long-term nicotine or saline administration on the central oxytocinergic system using [(125)I]OVTA autoradiographic binding in mouse brain. Male, 7-week old C57BL6J mice were treated with either nicotine (7.8 mg/kg daily; rate of 0.5 μl per hour) or saline for a period of 14-days via osmotic minipumps. Chronic nicotine administration induced a marked region-specific upregulation of the oxytocin receptor binding in the amygdala, a brain region involved in stress and emotional regulation. These results provide direct evidence for nicotine-induced neuroadaptations in the oxytocinergic system, which may be involved in the modulation of nicotine-seeking as well as emotional consequence of chronic drug use. PMID:26037668

  20. Immediate early gene expression reveals interactions between social and nicotine rewards on brain activity in adolescent male rats.

    Science.gov (United States)

    Bastle, Ryan M; Peartree, Natalie A; Goenaga, Julianna; Hatch, Kayla N; Henricks, Angela; Scott, Samantha; Hood, Lauren E; Neisewander, Janet L

    2016-10-15

    Smoking initiation predominantly occurs during adolescence, often in the presence of peers. Therefore, understanding the neural mechanisms underlying the rewarding effects of nicotine and social stimuli is vital. Using the conditioned place preference (CPP) procedure, we measured immediate early gene (IEG) expression in animals following exposure either to a reward-conditioned environment or to the unconditioned stimuli (US). Adolescent, male rats were assigned to the following CPP US conditions: (1) Saline+Isolated, (2) Nicotine+Isolated, (3) Saline+Social, or (4) Nicotine+Social. For Experiment 1, brain tissue was collected 90min following the CPP expression test and processed for Fos immunohistochemistry. We found that rats conditioned with nicotine with or without a social partner exhibited CPP; however, we found no group differences in Fos expression in any brain region analyzed, with the exception of the nucleus accumbens core that exhibited a social-induced attenuation in Fos expression. For Experiment 2, brain tissue was collected 90min following US exposure during the last conditioning session. We found social reward-induced increases in IEG expression in striatal and amydalar subregions. In contrast, nicotine reduced IEG expression in prefrontal and striatal subregions. Reward interactions were also found in the dorsolateral striatum, basolateral amygdala, and ventral tegmental area where nicotine alone attenuated IEG expression and social reward reversed this effect. These results suggest that in general social rewards enhance, whereas nicotine attenuates, activation of mesocorticolimbic regions; however, the rewards given together interact to enhance activation in some regions. The findings contribute to knowledge of how a social environment influences nicotine effects. PMID:27435419

  1. Chronic oral nicotine increases brain [3H]epibatidine binding and responsiveness to antidepressant drugs, but not nicotine, in the mouse forced swim test

    DEFF Research Database (Denmark)

    Andreasen T., Jesper; Nielsen, Elsebet O; Redrobe, John P

    2009-01-01

    Smoking rates among depressed individuals is higher than among healthy subjects, and nicotine alleviates depressive symptoms. Nicotine increases serotonergic and noradrenergic neuronal activity and facilitates serotonin and noradrenaline release. In mice, acute nicotine administration enhances the...

  2. 26Al uptake and accumulation in the rat brain

    Science.gov (United States)

    Yumoto, S.; Nagai, H.; Imamura, M.; Matsuzaki, H.; Hayashi, K.; Masuda, A.; Kumazawa, H.; Ohashi, H.; Kobayashi, K.

    1997-03-01

    To investigate the cause of Alzheimer's disease (senile dementia), 26Al incorporation in the rat brain was studied by accelerator mass spectrometry (AMS). When 26Al was injected into healthy rats, a considerable amount of 26Al entered the brain (cerebrum) through the blood-brain barrier 5 days after a single injection, and the brain 26Al level remained almost constant from 5 to 270 days. On the other hand, the level of 26Al in the blood decreased remarkably 75 days after injection. Approximately 89% of the 26Al taken in by the brain cell nuclei bound to chromatin. This study supports the theory that Alzheimer's disease is caused by irreversible accumulation of aluminium (Al) in the brain, and brain cell nuclei.

  3. Cholinergic systems in brain development and disruption by neurotoxicants: nicotine, environmental tobacco smoke, organophosphates

    International Nuclear Information System (INIS)

    Acetylcholine and other neurotransmitters play unique trophic roles in brain development. Accordingly, drugs and environmental toxicants that promote or interfere with neurotransmitter function evoke neurodevelopmental abnormalities by disrupting the timing or intensity of neurotrophic actions. The current review discusses three exposure scenarios involving acetylcholine systems: nicotine from maternal smoking during pregnancy, exposure to environmental tobacco smoke (ETS), and exposure to the organophosphate insecticide, chlorpyrifos (CPF). All three have long-term, adverse effects on specific processes involved in brain cell replication and differentiation, synaptic development and function, and ultimately behavioral performance. Many of these effects can be traced to the sequence of cellular events surrounding the trophic role of acetylcholine acting on its specific cellular receptors and associated signaling cascades. However, for chlorpyrifos, additional noncholinergic mechanisms appear to be critical in establishing the period of developmental vulnerability, the sites and type of neural damage, and the eventual outcome. New findings indicate that developmental neurotoxicity extends to late phases of brain maturation including adolescence. Novel in vitro and in vivo exposure models are being developed to uncover heretofore unsuspected mechanisms and targets for developmental neurotoxicants

  4. Accumulation of silver nanoparticles by cultured primary brain astrocytes

    Science.gov (United States)

    Luther, Eva M.; Koehler, Yvonne; Diendorf, Joerg; Epple, Matthias; Dringen, Ralf

    2011-09-01

    Silver nanoparticles (AgNP) are components of various food industry products and are frequently used for medical equipment and materials. Although such particles enter the vertebrate brain, little is known on their biocompatibility for brain cells. To study the consequences of an AgNP exposure of brain cells we have treated astrocyte-rich primary cultures with polyvinylpyrrolidone (PVP)-coated AgNP. The incubation of cultured astrocytes with micromolar concentrations of AgNP for up to 24 h resulted in a time- and concentration-dependent accumulation of silver, but did not compromise the cell viability nor lower the cellular glutathione content. In contrast, the incubation of astrocytes for 4 h with identical amounts of silver as AgNO3 already severely compromised the cell viability and completely deprived the cells of glutathione. The accumulation of AgNP by astrocytes was proportional to the concentration of AgNP applied and significantly lowered by about 30% in the presence of the endocytosis inhibitors chloroquine or amiloride. Incubation at 4 °C reduced the accumulation of AgNP by 80% compared to the values obtained for cells that had been exposed to AgNP at 37 °C. These data demonstrate that viable cultured brain astrocytes efficiently accumulate PVP-coated AgNP in a temperature-dependent process that most likely involves endocytotic pathways.

  5. Accumulation of silver nanoparticles by cultured primary brain astrocytes

    International Nuclear Information System (INIS)

    Silver nanoparticles (AgNP) are components of various food industry products and are frequently used for medical equipment and materials. Although such particles enter the vertebrate brain, little is known on their biocompatibility for brain cells. To study the consequences of an AgNP exposure of brain cells we have treated astrocyte-rich primary cultures with polyvinylpyrrolidone (PVP)-coated AgNP. The incubation of cultured astrocytes with micromolar concentrations of AgNP for up to 24 h resulted in a time- and concentration-dependent accumulation of silver, but did not compromise the cell viability nor lower the cellular glutathione content. In contrast, the incubation of astrocytes for 4 h with identical amounts of silver as AgNO3 already severely compromised the cell viability and completely deprived the cells of glutathione. The accumulation of AgNP by astrocytes was proportional to the concentration of AgNP applied and significantly lowered by about 30% in the presence of the endocytosis inhibitors chloroquine or amiloride. Incubation at 4 0C reduced the accumulation of AgNP by 80% compared to the values obtained for cells that had been exposed to AgNP at 37 0C. These data demonstrate that viable cultured brain astrocytes efficiently accumulate PVP-coated AgNP in a temperature-dependent process that most likely involves endocytotic pathways.

  6. Accumulation of silver nanoparticles by cultured primary brain astrocytes

    Energy Technology Data Exchange (ETDEWEB)

    Luther, Eva M; Koehler, Yvonne; Dringen, Ralf [Center for Biomolecular Interactions Bremen, University of Bremen, PO Box 330440, D-28334 Bremen (Germany); Diendorf, Joerg; Epple, Matthias, E-mail: ralf.dringen@uni-bremen.de [Inorganic Chemistry and Center for Nanointegration Duisburg-Essen, University of Duisburg-Essen, Universitaetsstrasse 5-7, D-45117 Essen (Germany)

    2011-09-16

    Silver nanoparticles (AgNP) are components of various food industry products and are frequently used for medical equipment and materials. Although such particles enter the vertebrate brain, little is known on their biocompatibility for brain cells. To study the consequences of an AgNP exposure of brain cells we have treated astrocyte-rich primary cultures with polyvinylpyrrolidone (PVP)-coated AgNP. The incubation of cultured astrocytes with micromolar concentrations of AgNP for up to 24 h resulted in a time- and concentration-dependent accumulation of silver, but did not compromise the cell viability nor lower the cellular glutathione content. In contrast, the incubation of astrocytes for 4 h with identical amounts of silver as AgNO{sub 3} already severely compromised the cell viability and completely deprived the cells of glutathione. The accumulation of AgNP by astrocytes was proportional to the concentration of AgNP applied and significantly lowered by about 30% in the presence of the endocytosis inhibitors chloroquine or amiloride. Incubation at 4 {sup 0}C reduced the accumulation of AgNP by 80% compared to the values obtained for cells that had been exposed to AgNP at 37 {sup 0}C. These data demonstrate that viable cultured brain astrocytes efficiently accumulate PVP-coated AgNP in a temperature-dependent process that most likely involves endocytotic pathways.

  7. Determinants of iron accumulation in the normal aging brain.

    Science.gov (United States)

    Pirpamer, Lukas; Hofer, Edith; Gesierich, Benno; De Guio, François; Freudenberger, Paul; Seiler, Stephan; Duering, Marco; Jouvent, Eric; Duchesnay, Edouard; Dichgans, Martin; Ropele, Stefan; Schmidt, Reinhold

    2016-07-01

    In a recent postmortem study, R2* relaxometry in gray matter (GM) of the brain has been validated as a noninvasive measure for iron content in brain tissue. Iron accumulation in the normal aging brain is a common finding and relates to brain maturation and degeneration. The goal of this study was to assess the determinants of iron accumulation during brain aging. The study cohort consisted of 314 healthy community-dwelling participants of the Austrian Stroke Prevention Study. Their age ranged from 38-82 years. Quantitative magnetic resonance imaging was performed on 3T and included R2* mapping, based on a 3D multi-echo gradient echo sequence. The median of R2* values was measured in all GM regions, which were segmented automatically using FreeSurfer. We investigated 25 possible determinants for cerebral iron deposition. These included demographics, brain volume, lifestyle factors, cerebrovascular risk factors, serum levels of iron, and single nucleotide polymorphisms related to iron regulating genes (rs1800562, rs3811647, rs1799945, and rs1049296). The body mass index (BMI) was significantly related to R2* in 15/32 analyzed brain regions with the strongest correlations found in the amygdala (p = 0.0091), medial temporal lobe (p = 0.0002), and hippocampus (p ≤ 0.0001). Further associations to R2* values were found in deep GM for age and smoking. No significant associations were found for gender, GM volume, serum levels of iron, or iron-associated genetic polymorphisms. In conclusion, besides age, the BMI and smoking are the only significant determinants of brain iron accumulation in normally aging subjects. Smoking relates to iron deposition in the basal ganglia, whereas higher BMI is associated with iron content in the neocortex following an Alzheimer-like distribution. PMID:27255824

  8. Nicotine mediates expression of genes related to antioxidant capacity and oxidative stress response in HIV-1 transgenic rat brain.

    Science.gov (United States)

    Song, Guohua; Nesil, Tanseli; Cao, Junran; Yang, Zhongli; Chang, Sulie L; Li, Ming D

    2016-02-01

    Oxidative stress plays an important role in the progression of HIV-1 infection. Nicotine can either protect neurons from neurodegeneration or induce oxidative stress, depending on its dose and degree of oxidative stress impairment. However, the relationship between nicotine and oxidative stress in the HIV-1-infected individuals remains largely unknown. The purpose of this study was to determine the effect of nicotine on expression of genes related to the glutathione (GSH)-centered antioxidant system and oxidative stress in the nucleus accumbens (NAc) and ventral tegmental area (VTA) of HIV-1 transgenic (HIV-1Tg) and F344 control rats. Adult HIV-1Tg and F344 rats received nicotine (0.4 mg/kg, base, s.c.) or saline injections once per day for 27 days. At the end of treatment, various brain regions including the NAc and VTA were collected from each rat. Following total RNA extraction and complementary DNA (cDNA) synthesis of each sample, quantitative reverse transcription PCR (RT-PCR) analysis was performed for 43 oxidative-stress-related genes. Compared with F344 control rats, HIV-1Tg rats showed a significant downregulation of genes involved in ATPase and cyctochrome oxidase at the messenger RNA (mRNA) level in both regions. Further, we found a significant downregulation of Gstm5 in the NAc and upregulation of Cox1, Cox3, and Gsta6 in the VTA of HIV-1Tg rats. HIV-1Tg rats showed brain-region-specific responses to chronic nicotine treatment. This response resulted in a change in the expression of genes involved in antioxidant mechanisms including the downregulation of genes such as Atp5h, Calml1, Gpx7, Gstm5, Gsr, and Gsta6 and upregulation of Sod1 in the NAc, as well as downregulation of genes like Cox5a, Gpx4, Gpx6, Gpx7, Gstm5, and Sod1 in the VTA of HIV-1Tg rats. Together, we conclude that chronic nicotine treatment has a dual effect on the antioxidant defense system and oxidative-stress-induced apoptosis signaling in HIV-1Tg rats. These findings suggest that

  9. Prenatal nicotine exposure enhances Cx43 and Panx1 unopposed channel activity in brain cells of adult offspring mice fed a high-fat/cholesterol diet

    Directory of Open Access Journals (Sweden)

    Juan Andrés Orellana

    2014-12-01

    Full Text Available Nicotine, the most important neuroteratogen of tobacco smoke, can reproduce brain and cognitive disturbances per se when administered prenatally. However, it is still unknown if paracrine signaling among brain cells participates in prenatal nicotine-induced brain impairment of adult offspring. Paracrine signaling is partly mediated by unopposed channels formed by connexins (hemichannels and pannexins serving as aqueous pores permeable to ions and small signaling molecules, allowing exchange between the intra- and extracellular milieus. Our aim was to address whether prenatal nicotine exposure changes the activity of those channels in adult mice offspring under control conditions or subjected to a second challenge during young ages: high-fat/cholesterol (HFC diet. To induce prenatal exposure to nicotine, osmotic minipumps were implanted in CF1 pregnant mice at gestational day 5 to deliver nicotine bitartrate or saline (control solutions. After weaning, offspring of nicotine-treated or untreated pregnant mice were fed ad libitum with chow or HFC diets for 8 weeks. The functional state of Cx43 and Panx1 unopposed channels was evaluated by dye uptake experiments in hippocampal slices from 11-week-old mice. We found that prenatal nicotine increased the opening of Cx43 hemichannels in astrocytes, and Panx1 channels in microglia and neurons only if offspring mice were fed with HFC diet. Blockade of iNOS, COX2 and EP1, P2X7 and NMDA receptors, showed differential inhibition of prenatal nicotine-induced channel opening in glial cells and neurons. Importantly, inhibition of the above mentioned enzymes and receptors, or blockade of Cx43 and Panx1 unopposed channels greatly reduced ATP and glutamate release from hippocampal slices of prenatally nicotine-exposed offspring. We propose that unregulated gliotransmitter release through Cx43 and Panx1 unopposed channels may participate in brain alterations observed in offspring of mothers exposed to tobacco smoke

  10. Self-mutilation in neurodegeneration with brain iron accumulation

    Directory of Open Access Journals (Sweden)

    Sadanandavalli Retnaswami Chandra

    2015-01-01

    Full Text Available Neurodegeneration with brain iron accumulation (NBIA is the term applied to a heterogeneous group of disorders resulting in iron deposition in the basal ganglia. Well-known phenotypic features are progressive regression with extra pyramidal involvement and a variable course. A 10-year-old child born to consanguineous parents presented with progressive generalized opisthotonic dystonia, retrocollis, oromandibular dyskinesias, apraxia for swallowing, optic atrophy and severe self-mutilation of lips. MR imaging showed brain iron accumulation. Other causes of self-mutilation were excluded. Early infantile onset, ophisthotonic dystonia with oromandibular dyskinesias and characteristic MR images are suggestive of NBIA. There is only one case reported in the literature of self-mutilation in this condition.

  11. Tissue Distribution of [3H]—Nicotine in Rats

    Institute of Scientific and Technical Information of China (English)

    ParimalChowdhury; RyuichiroDOI; 等

    1993-01-01

    This study was conducted in adult male Sprageue-Dawley rats to determine the distribution of [3H]-nicotine in blood and tissues following a bolus injection and a constant infusion of pure nicotine.The animalw were anesthetized and injectd with either 0.5ml of nicotine solution or given a constant infusion of the same nicotine solution with indentical amounts of radioactive nicotine.After sacrifice.blood,brain,trachea,salivery gland, esophagus,lung,heart,liver,fundus,antrum,spleen,pancreas,duodenum,jejunum,ileum, cecum,colon,kidneys,adrenal gland,and testes were collected and measured for radioactivity by scintillation counting.The distribution of nicotine was found highest in kidneys by both routes of administration.Higher accumulations were also found in salivary and adrenal glands,fundus,antrum,duodenum,jejunum,ileum and colon.Retention of nicotine via constant infusion was significantly higher in esophagus,fundus antrum,spleen,cecum, pancreas,testes,heart and muscle when compared with bolus injection,Six-fold increase in retention of blood levels of nicotine were ofund with constant infusion.(P<0.05).The results indicate that longer retention of nicotine occurs in blood and other specific tissues such as esophagus,fundus,antrum,spleen,cecum,pancreas,testes,heart and muscle via constant exposure.These data may implicate the predisposition of these tissues to patologic manifestations.

  12. Aberrant accumulation of phospholipase C-delta in Alzheimer brains.

    OpenAIRE

    Shimohama, S.; Homma, Y.; Suenaga, T.; Fujimoto, S; Taniguchi, T; Araki, W.; Yamaoka, Y; Takenawa, T.; Kimura, J

    1991-01-01

    Since phosphoinositide-specific phospholipase C (PLC) is one of the key molecules in signal transduction, the authors assessed its involvement in Alzheimer's disease (AD). Immunostaining of a specific antibody against the PLC isozyme, PLC-delta, demonstrated that this enzyme was abnormally accumulated in neurofibrillary tangles (NFT), the neurites surrounding senile plaque (SP) cores, and neuropil threads in AD brains. Western blot analysis confirmed that PLC-delta was concentrated in the pai...

  13. Characterization of nicotine binding to the rat brain P2 preparation: the identification of multiple binding sites which include specific up-regulatory site(s)

    International Nuclear Information System (INIS)

    These studies show that nicotine binds to the rat brain P2 preparation by saturable and reversible processes. Multiple binding sites were revealed by the configuration of saturation, kinetic and Scatchard plots. A least squares best fit of Scatchard data using nonlinear curve fitting programs confirmed the presence of a very high affinity site, an up-regulatory site, a high affinity site and one or two low affinity sites. Stereospecificity was demonstrated for the up-regulatory site where (+)-nicotine was more effective and for the high affinity site where (-)-nicotine had a higher affinity. Drugs which selectively up-regulate nicotine binding site(s) have been identified. Further, separate very high and high affinity sites were identified for (-)- and (+)-[3H]nicotine, based on evidence that the site density for the (-)-isomer is 10 times greater than that for the (+)-isomer at these sites. Enhanced nicotine binding has been shown to be a statistically significant phenomenon which appears to be a consequence of drugs binding to specific site(s) which up-regulate binding at other site(s). Although Scatchard and Hill plots indicate positive cooperatively, up-regulation more adequately describes the function of these site(s). A separate up-regulatory site is suggested by the following: (1) Drugs vary markedly in their ability to up-regulate binding. (2) Both the affinity and the degree of up-regulation can be altered by structural changes in ligands. (3) Drugs with specificity for up-regulation have been identified. (4) Some drugs enhance binding in a dose-related manner. (5) Competition studies employing cold (-)- and (+)-nicotine against (-)- and (+)-[3H]nicotine show that the isomers bind to separate sites which up-regulate binding at the (-)- and (+)-nicotine high affinity sites and in this regard (+)-nicotine is more specific and efficacious than (-)-nicotine

  14. Brain α7 nicotinic acetylcholine receptors in MPTP-lesioned monkeys and parkinsonian patients.

    Science.gov (United States)

    Morissette, Marc; Morin, Nicolas; Grégoire, Laurent; Rajput, Alex; Rajput, Ali H; Di Paolo, Thérèse

    2016-06-01

    L-DOPA-induced dyskinesias (LID) appear in the majority of Parkinson's disease (PD) patients. Nicotinic acetylcholine (nACh) receptor-mediated signaling has been implicated in PD and LID and modulation of brain α7 nACh receptors might be a potential therapeutic target for PD. This study used [(125)I]α-Bungarotoxin autoradiography to investigate α7 nACh receptors in LID in post-mortem brains from PD patients (n=14) and control subjects (n=11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n=5), L-DOPA (n=4) or L-DOPA+2-methyl-6-(phenylethynyl)pyridine (MPEP) (n=5), and control monkeys (n=4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist; it reduced the development of LID in these monkeys. [(125)I]α-Bungarotoxin specific binding to striatal and pallidal α7 nACh receptors were only increased in L-DOPA-treated dyskinetic MPTP monkeys as compared to controls, saline and L-DOPA+MPEP MPTP monkeys; dyskinesia scores correlated positively with this binding. The total group of Parkinsonian patients had higher [(125)I]α-Bungarotoxin specific binding compared to controls in the caudate nucleus but not in the putamen. PD patients without motor complications had higher [(125)I]α-Bungarotoxin specific binding compared to controls only in the caudate nucleus. PD patients with LID only had higher [(125)I]α-Bungarotoxin specific binding compared to controls in the caudate nucleus and compared to those without motor complications and controls in the putamen. PD patients with wearing-off only, had [(125)I]α-Bungarotoxin specific binding at control values in the caudate nucleus and lower in the putamen. Reduced motor complications were associated with normal striatal α7 nACh receptors, suggesting the potential of this receptor to manage motor complications in PD. PMID:27038656

  15. Genetic deletion of the adenosine A(2A) receptor prevents nicotine-induced upregulation of α7, but not α4β2* nicotinic acetylcholine receptor binding in the brain.

    Science.gov (United States)

    Metaxas, Athanasios; Al-Hasani, Ream; Farshim, Pamela; Tubby, Kristina; Berwick, Amy; Ledent, Catherine; Hourani, Susanna; Kitchen, Ian; Bailey, Alexis

    2013-08-01

    Considerable evidence indicates that adenosine A(2A) receptors (A(2A)Rs) modulate cholinergic neurotransmission, nicotinic acetylcholine receptor (nAChR) function, and nicotine-induced behavioural effects. To explore the interaction between A(2A) and nAChRs, we examined if the complete genetic deletion of adenosine A(2A)Rs in mice induces compensatory alterations in the binding of different nAChR subtypes, and whether the long-term effects of nicotine on nAChR regulation are altered in the absence of the A(2A)R gene. Quantitative autoradiography was used to measure cytisine-sensitive [¹²⁵I]epibatidine and [¹²⁵I]α-bungarotoxin binding to α4β2* and α7 nAChRs, respectively, in brain sections of drug-naïve (n = 6) or nicotine treated (n = 5-7), wild-type and adenosine A(2A)R knockout mice. Saline or nicotine (7.8 mg/kg/day; free-base weight) were administered to male CD1 mice via subcutaneous osmotic minipumps for a period of 14 days. Blood plasma levels of nicotine and cotinine were measured at the end of treatment. There were no compensatory developmental alterations in nAChR subtype distribution or density in drug-naïve A(2A)R knockout mice. In nicotine treated wild-type mice, both α4β2* and α7 nAChR binding sites were increased compared with saline treated controls. The genetic ablation of adenosine A(2A)Rs prevented nicotine-induced upregulation of α7 nAChRs, without affecting α4β2* receptor upregulation. This selective effect was observed at plasma levels of nicotine that were within the range reported for smokers (10-50 ng ml⁻¹). Our data highlight the involvement of adenosine A(2A)Rs in the mechanisms of nicotine-induced α7 nAChR upregulation, and identify A(2A)Rs as novel pharmacological targets for modulating the long-term effects of nicotine on α7 receptors. PMID:23583933

  16. Protective effect of novel substituted nicotine hydrazide analogues against hypoxic brain injury in neonatal rats via inhibition of caspase.

    Science.gov (United States)

    Deng, Chang-Bo; Li, Juan; Li, Lu-Yi; Sun, Feng-Jie

    2016-07-01

    In hypoxic-ischemic injury of the brain of neonates, the level of caspase-3 was found to be aberrantly activated. Its overexpression leads to the alteration of cytoskeleton protein fodrin and loss of DNA repair enzyme which ultimately results in neurological impairment and disability. Concerning this, the present study was intended to develop novel nicotine hydrazide analogues as caspase inhibitors via efficient synthetic route. These compounds were subsequently tested for inhibitory activity against caspase-3 and -7 where they exhibit highly potent activity against caspase-3 revealing compound 5k as most potent inhibitor (IC50=19.4±2.5μM). In Western blot analysis, 5k considerably inhibits the overexpression of caspase-3. The aryl nicotinate of compound 5k, as indicated by molecular docking was found to engage His121 and critical enzyme thiols, i.e., Cys163 of caspase-3 for its potent activity. Moreover, histopathological examination of brain tissues and hippocampus neurons showed that compound 5k considerably improves the brain injury and exert neuroprotective effects in hypoxic-ischemic (HI). In brain homogenate, 5k significantly improves the activity of MDA, SOD, GSH-Px, CAT and T-AOC to exert its beneficial effect against oxidative stress induced by HI injury. PMID:27216999

  17. Neurodegeneration with Brain Iron Accumulation: Diagnosis and Management

    Directory of Open Access Journals (Sweden)

    Penelope Hogarth

    2015-01-01

    Full Text Available Neurodegeneration with brain iron accumulation (NBIA encompasses a group of inherited disorders that share the clinical features of an extrapyramidal movement disorder accompanied by varying degrees of intellectual disability and abnormal iron deposition in the basal ganglia. The genetic basis of ten forms of NBIA is now known. The clinical features of NBIA range from rapid global neurodevelopmental regression in infancy to mild parkinsonism with minimal cognitive impairment in adulthood, with wide variation seen between and within the specific NBIA sub-type. This review describes the clinical presentations, imaging findings, pathologic features, and treatment considerations for this heterogeneous group of disorders.

  18. Brain iron accumulation in unexplained fetal and infant death victims with smoker mothers-The possible involvement of maternal methemoglobinemia

    Directory of Open Access Journals (Sweden)

    Corna Melissa F

    2011-07-01

    Full Text Available Abstract Background Iron is involved in important vital functions as an essential component of the oxygen-transporting heme mechanism. In this study we aimed to evaluate whether oxidative metabolites from maternal cigarette smoke could affect iron homeostasis in the brain of victims of sudden unexplained fetal and infant death, maybe through the induction of maternal hemoglobin damage, such as in case of methemoglobinemia. Methods Histochemical investigations by Prussian blue reaction were made on brain nonheme ferric iron deposits, gaining detailed data on their localization in the brainstem and cerebellum of victims of sudden death and controls. The Gless and Marsland's modification of Bielschowsky's was used to identify neuronal cell bodies and neurofilaments. Results Our approach highlighted accumulations of blue granulations, indicative of iron positive reactions, in the brainstem and cerebellum of 33% of victims of sudden death and in none of the control group. The modified Bielschowsky's method confirmed that the cells with iron accumulations were neuronal cells. Conclusions We propose that the free iron deposition in the brain of sudden fetal and infant death victims could be a catabolic product of maternal methemoglobinemia, a biomarker of oxidative stress likely due to nicotine absorption.

  19. Distribution of the a2, a3, and a5 nicotinic acetylcholine receptor subunits in the chick brain

    Directory of Open Access Journals (Sweden)

    Torrão A.S.

    1997-01-01

    Full Text Available Nicotinic acetylcholine receptors (nAChRs are ionotropic receptors comprised of a and ß subunits. These receptors are widely distributed in the central nervous system, and previous studies have revealed specific patterns of localization for some nAChR subunits in the vertebrate brain. In the present study we used immunohistochemical methods and monoclonal antibodies to localize the a2, a3, and a5 nAChR subunits in the chick mesencephalon and diencephalon. We observed a differential distribution of these three subunits in the chick brain, and showed that the somata and neuropil of many central structures contain the a5 nAChR subunit. The a2 and a3 subunits, on the other hand, exhibited a more restricted distribution than a5 and other subunits previously studied, namely a7, a8 and ß2. The patterns of distribution of the different nAChR subunits suggest that neurons in many brain structures may contain several subtypes of nAChRs and that in a few regions one particular subtype may determine the cholinergic nicotinic responses

  20. Molecular interactions between the specialist herbivore Manduca sexta (Lepidoptera, Sphingidae) and its natural host Nicotiana attenuata. IV. Insect-Induced ethylene reduces jasmonate-induced nicotine accumulation by regulating putrescine N-methyltransferase transcripts.

    Science.gov (United States)

    Winz, R A; Baldwin, I T

    2001-04-01

    Attack by the specialist herbivore, Manduca sexta, on its native host Nicotiana attenuata Torr. ex Wats. produces a dramatic ethylene release, a jasmonate burst, and a suppression of the nicotine accumulation that results from careful simulations of the herbivore's damage. Methyl-jasmonate (MeJA) treatment induces nicotine biosynthesis. However, this induction can be suppressed by ethylene as pretreatment of plants with 1-methylcyclopropene (1-MCP), a competitive inhibitor of ethylene receptors, restores the full MeJA-induced nicotine response in herbivore attacked plants (J. Kahl, D.H. Siemens, R.J. Aerts, R. Gäbler, F. Kühnemann, C.A. Preston, I.T. Baldwin [2000] Planta 210: 336-342). To understand whether this herbivore-induced signal cross-talk occurs at the level of transcript accumulation, we cloned the putrescine methyltransferase genes (NaPMT1 and NaPMT2) of N. attenuata, which are thought to represent the rate limiting step in nicotine biosynthesis, and measured transcript accumulations by northern analysis after various jasmonate, 1-MCP, ethephon, and herbivory treatments. Transcripts of both root putrescine N-methyltransferase (PMT) genes and nicotine accumulation increased dramatically within 10 h of shoot MeJA treatment and immediately after root treatments. Root ethephon treatments suppressed this response, which could be reversed by 1-MCP pretreatment. Moreover, 1-MCP pretreatment dramatically amplified the transcript accumulation resulting from both wounding and M. sexta herbivory. We conclude that attack from this nicotine-tolerant specialist insect causes N. attenuata to produce ethylene, which directly suppresses the nitrogen-intensive biosynthesis of nicotine. PMID:11299398

  1. Nicotine Gum

    Science.gov (United States)

    Nicotine chewing gum is used to help people stop smoking cigarettes. Nicotine chewing gum should be used together with a smoking cessation ... Nicotine gum is used by mouth as a chewing gum and should not be swallowed. Follow the directions ...

  2. A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand

    Directory of Open Access Journals (Sweden)

    Rodrigo Teodoro

    2015-10-01

    Full Text Available Changes in the expression of α7 nicotinic acetylcholine receptors (α7 nAChRs in the human brain are widely assumed to be associated with neurological and neurooncological processes. Investigation of these receptors in vivo depends on the availability of imaging agents such as radioactively labelled ligands applicable in positron emission tomography (PET. We report on a series of new ligands for α7 nAChRs designed by the combination of dibenzothiophene dioxide as a novel hydrogen bond acceptor functionality with diazabicyclononane as an established cationic center. To assess the structure-activity relationship (SAR of this new basic structure, we further modified the cationic center systematically by introduction of three different piperazine-based scaffolds. Based on in vitro binding affinity and selectivity, assessed by radioligand displacement studies at different rat and human nAChR subtypes and at the structurally related human 5-HT3 receptor, we selected the compound 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl-2-fluorodibenzo-[b,d]thiophene 5,5-dioxide (10a for radiolabeling and further evaluation in vivo. Radiosynthesis of [18F]10a was optimized and transferred to an automated module. Dynamic PET imaging studies with [18F]10a in piglets and a monkey demonstrated high uptake of radioactivity in the brain, followed by washout and target-region specific accumulation under baseline conditions. Kinetic analysis of [18F]10a in pig was performed using a two-tissue compartment model with arterial-derived input function. Our initial evaluation revealed that the dibenzothiophene-based PET radioligand [18F]10a ([18F]DBT-10 has high potential to provide clinically relevant information about the expression and availability of α7 nAChR in the brain.

  3. Neuronal nicotinic receptor subtypes in normal ageing, Alzheimer's disease and schizophrenia : Influences of neuropathological mechanisms as studied in human autopsy brain and transgenic mice

    OpenAIRE

    Marutle, Amelia

    2002-01-01

    Neuronal nicotinic acetylcholine receptors (nAChRs) are transmitter-gated ion channel receptors which are widely distributed in the brain. They mediate the effects of several neurotransmitters including ACh, DA, 5-HT and NA and are important for many normal physiological functions in the brain and are also implicated in a number of CNS disorders, such as AD, PD, schizophrenia, Tourette's syndrome and familial epilepsy. The overall aim of this thesis was to characterise chang...

  4. [Effect of phenibut and its composition with nicotinic acid on hemostasis in rats with brain ischemia].

    Science.gov (United States)

    Tiurenkov, I N; Volotova, E V; Kurkin, D V; Litvinov, A A; Tarasov, A S

    2012-01-01

    It is shown that, in rats with global cerebral ischemia modeled by a complete irreversible occlusion of the common carotid artery and forced hypotension, the hemostasis is characterized by a shift toward hypercoagulation. A single preventive introduction of phenibut and, to a greater degree, a composition of phenibut with nicotinic acid, in rats with acute cerebral ischemia reduced the extent of disturbances in the hemostasis system of experimental animals. PMID:22702103

  5. Chemical fate of the nicotinic acetylcholinergic radiotracer [123I]5-IA-85380 in baboon brain and plasma

    International Nuclear Information System (INIS)

    The fate of the nicotinic acetylcholinergic receptor radiotracer [123I]5-IA-85380 ([123I]5-IA) was studied in baboon by analyzing the chemical composition of brain tissue and plasma after intravenous administration of the tracer. Acetonitrile denaturation and high-performance liquid chromatography (HPLC) analysis showed predominantly unchanged (91-98%) parent tracer in all brain tissues examined, compared to significant metabolism (23% parent) in the plasma at 90 min postinjection, and control tissue recovery of 95-98%. [123I]5-IA was distributed to the thalamus with a standardized uptake value of 9.2 (0.04% dose/g) or a concentration 5.8 times higher than that of the cerebellum. The HPLC behavior of a synthesized sample of one hypothesized metabolite, 5-iodo-3-pyridinol (5-IP), was consistent with plasma radiometabolite fraction. Since only parent radiotracer compound was found in brain tissue, these results add confidence that information derived from single photon emission computed tomography images of 123I activity in the brain after [123I]5-IA administration can be interpreted as distribution of an intact radiotracer

  6. Nanoparticle accumulation and transcytosis in brain endothelial cell layers

    Science.gov (United States)

    Ye, Dong; Raghnaill, Michelle Nic; Bramini, Mattia; Mahon, Eugene; Åberg, Christoffer; Salvati, Anna; Dawson, Kenneth A.

    2013-10-01

    The blood-brain barrier (BBB) is a selective barrier, which controls and limits access to the central nervous system (CNS). The selectivity of the BBB relies on specialized characteristics of the endothelial cells that line the microvasculature, including the expression of intercellular tight junctions, which limit paracellular permeability. Several reports suggest that nanoparticles have a unique capacity to cross the BBB. However, direct evidence of nanoparticle transcytosis is difficult to obtain, and we found that typical transport studies present several limitations when applied to nanoparticles. In order to investigate the capacity of nanoparticles to access and transport across the BBB, several different nanomaterials, including silica, titania and albumin- or transferrin-conjugated gold nanoparticles of different sizes, were exposed to a human in vitro BBB model of endothelial hCMEC/D3 cells. Extensive transmission electron microscopy imaging was applied in order to describe nanoparticle endocytosis and typical intracellular localisation, as well as to look for evidence of eventual transcytosis. Our results show that all of the nanoparticles were internalised, to different extents, by the BBB model and accumulated along the endo-lysosomal pathway. Rare events suggestive of nanoparticle transcytosis were also observed for several of the tested materials.The blood-brain barrier (BBB) is a selective barrier, which controls and limits access to the central nervous system (CNS). The selectivity of the BBB relies on specialized characteristics of the endothelial cells that line the microvasculature, including the expression of intercellular tight junctions, which limit paracellular permeability. Several reports suggest that nanoparticles have a unique capacity to cross the BBB. However, direct evidence of nanoparticle transcytosis is difficult to obtain, and we found that typical transport studies present several limitations when applied to nanoparticles. In

  7. Assessment of α7 nicotinic acetylcholine receptor availability in juvenile pig brain with [18F]NS10743

    International Nuclear Information System (INIS)

    To conduct a quantitative PET assessment of the specific binding sites in the brain of juvenile pigs for [18F]NS10743, a novel diazabicyclononane derivative targeting α7 nicotinic acetylcholine receptors (α7 nAChRs). Dynamic PET recordings were made in isoflurane-anaesthetized juvenile pigs during 120 min after administration of [18F]NS10743 under baseline conditions (n = 3) and after blocking of the α7 nAChR with NS6740 (3 mg.kg-1 bolus + 1 mg.kg-1.h-1 continuous infusion; n = 3). Arterial plasma samples were collected for determining the input function of the unmetabolized tracer. Kinetic analysis of regional brain time-radioactivity curves was performed, and parametric maps were calculated relative to arterial input. Plasma [18F]NS10743 passed readily into the brain, with peak uptake occurring in α7 nAChR-expressing brain regions such as the colliculi, thalamus, temporal lobe and hippocampus. The highest SUVmax was approximately 2.3, whereas the lowest uptake was in the olfactory bulb (SUVmax 1.53 ± 0.32). Administration of NS6740 significantly decreased [18F]NS10743 binding late in the emission recording throughout the brain, except in the olfactory bulb, which was therefore chosen as reference region for calculation of BPND. The baseline BPND ranged from 0.39 ± 0.08 in the cerebellum to 0.76 ± 0.07 in the temporal lobe. Pretreatment and constant infusion with NS6740 significantly reduced the BPND in regions with high [18F]NS10743 binding (temporal lobe -29%, p = 0.01; midbrain: -35%, p = 0.02), without significantly altering the BPND in low binding regions (cerebellum: -16%, p = 0.2). This study confirms the potential of [18F]NS10743 as a target-specific radiotracer for the molecular imaging of central α7 nAChRs by PET. (orig.)

  8. Prion protein accumulation in lipid rafts of mouse aging brain.

    Directory of Open Access Journals (Sweden)

    Federica Agostini

    Full Text Available The cellular form of the prion protein (PrP(C is a normal constituent of neuronal cell membranes. The protein misfolding causes rare neurodegenerative disorders known as transmissible spongiform encephalopathies or prion diseases. These maladies can be sporadic, genetic or infectious. Sporadic prion diseases are the most common form mainly affecting aging people. In this work, we investigate the biochemical environment in which sporadic prion diseases may develop, focusing our attention on the cell membrane of neurons in the aging brain. It is well established that with aging the ratio between the most abundant lipid components of rafts undergoes a major change: while cholesterol decreases, sphingomyelin content rises. Our results indicate that the aging process modifies the compartmentalization of PrP(C. In old mice, this change favors PrP(C accumulation in detergent-resistant membranes, particularly in hippocampi. To confirm the relationship between lipid content changes and PrP(C translocation into detergent-resistant membranes (DRMs, we looked at PrP(C compartmentalization in hippocampi from acid sphingomyelinase (ASM knockout (KO mice and synaptosomes enriched in sphingomyelin. In the presence of high sphingomyelin content, we observed a significant increase of PrP(C in DRMS. This process is not due to higher levels of total protein and it could, in turn, favor the onset of sporadic prion diseases during aging as it increases the PrP intermolecular contacts into lipid rafts. We observed that lowering sphingomyelin in scrapie-infected cells by using fumonisin B1 led to a 50% decrease in protease-resistant PrP formation. This may suggest an involvement of PrP lipid environment in prion formation and consequently it may play a role in the onset or development of sporadic forms of prion diseases.

  9. PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators

    International Nuclear Information System (INIS)

    To gain insight on the expression of pregnane X receptor (PXR), we analyzed PXR.1 and PXR alternatively spliced transcripts in a panel of 36 human tissues. PXR.1 was expressed in many more tissues than previously determined, including human bone marrow and select regions of the human brain. In each of these tissues, we observed alternative splicing of various exons of PXR that generated multiple distinct PXR isoforms. The most abundant PXR alternative mRNA transcripts lacked 111 nucleotides, deleting 37 amino acids from the PXR LBD (PXR.2), or lacked 123 nt, deleting 41 amino acids from the PXR LBD (PXR.3). CYP3A4, a gene transcriptionally regulated by PXR, showed incomplete overlap with PXR in its tissue distribution. Quantitation of PXR mRNAs in human liver demonstrated that PXR.2 and PXR.3 represented 6.7% and 0.32% of total PXR mRNA transcripts. Brain expression of PXR prompted analysis of whether some brain acting chemicals were PXR ligands. The neurosteroids allopregnanolone and pregnanolone activated PXR and induced transcription of a CYP3A4-luciferase reporter. Nicotine, the psychoactive and addictive chemical in cigarettes, and a known inducer of brain CYP2B6, was an efficacious activator of PXR and inducer of CYP3A4 transcription. Because nicotine activation of PXR will enhance metabolism of nicotine to the non-psychoactive cotinine, these results provide one molecular mechanism for the development of tolerance to nicotine. Moreover, the identification of PXR in many human tissues, such as brain, and activation by tissue specific ligands (such as neurosteroids) suggests additional biological roles for this receptor in these tissues

  10. Nicotine effects on brain function during a visual oddball task: a comparison between conventional and EEG-informed fMRI analysis.

    Science.gov (United States)

    Warbrick, Tracy; Mobascher, Arian; Brinkmeyer, Jürgen; Musso, Francesco; Stoecker, Tony; Shah, N Jon; Fink, Gereon R; Winterer, Georg

    2012-08-01

    In a previous oddball task study, it was shown that the inclusion of electrophysiology (EEG), that is, single-trial P3 ERP parameters, in the analysis of fMRI responses can detect activation that is not apparent with conventional fMRI data modeling strategies [Warbrick, T., Mobascher, A., Brinkmeyer, J., Musso, F., Richter, N., Stoecker, T., et al. Single-trial P3 amplitude and latency informed event-related fMRI models yield different BOLD response patterns to a target detection task. Neuroimage, 47, 1532-1544, 2009]. Given that P3 is modulated by nicotine, including P3 parameters in the fMRI analysis might provide additional information about nicotine effects on brain function. A 1-mg nasal nicotine spray (0.5 mg each nostril) or placebo (pepper) spray was administered in a double-blind, placebo-controlled, within-subject, randomized, cross-over design. Simultaneous EEG-fMRI and behavioral data were recorded from 19 current smokers in response to an oddball-type visual choice RT task. Conventional general linear model analysis and single-trial P3 amplitude informed general linear model analysis of the fMRI data were performed. Comparing the nicotine with the placebo condition, reduced RTs in the nicotine condition were related to decreased BOLD responses in the conventional analysis encompassing the superior parietal lobule, the precuneus, and the lateral occipital cortex. On the other hand, reduced RTs were related to increased BOLD responses in the precentral and postcentral gyri, and ACC in the EEG-informed fMRI analysis. Our results show how integrated analyses of simultaneous EEG-fMRI data can be used to detect nicotine effects that would not have been revealed through conventional analysis of either measure in isolation. This emphasizes the significance of applying multimodal imaging methods to pharmacoimaging. PMID:22452559

  11. Developmental cholinotoxicants: nicotine and chlorpyrifos.

    OpenAIRE

    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...

  12. Meningitic Escherichia coli K1 penetration and neutrophil transmigration across the blood-brain barrier are modulated by alpha7 nicotinic receptor.

    Directory of Open Access Journals (Sweden)

    Feng Chi

    Full Text Available Alpha7 nicotinic acetylcholine receptor (nAChR, an essential regulator of inflammation, is abundantly expressed in hippocampal neurons, which are vulnerable to bacterial meningitis. However, it is unknown whether α7 nAChR contributes to the regulation of these events. In this report, an aggravating role of α7 nAChR in host defense against meningitic E. coli infection was demonstrated by using α7-deficient (α7(-/- mouse brain microvascular endothelial cells (BMEC and animal model systems. As shown in our in vitro and in vivo studies, E. coli K1 invasion and polymorphonuclear neutrophil (PMN transmigration across the blood-brain barrier (BBB were significantly reduced in α7(-/- BMEC and α7(-/- mice. Stimulation by nicotine was abolished in the α7(-/- cells and animals. The same blocking effect was achieved by methyllycaconitine (α7 antagonist. The tight junction molecules occludin and ZO-1 were significantly reduced in the brain cortex of wildtype mice infected with E. coli and treated with nicotine, compared to α7(-/- cells and animals. Decreased neuronal injury in the hippocampal dentate gyrus was observed in α7(-/- mice with meningitis. Proinflammatory cytokines (IL-1β, IL-6, TNFα, MCP-1, MIP-1alpha, and RANTES and adhesion molecules (CD44 and ICAM-1 were significantly reduced in the cerebrospinal fluids of the α7(-/- mice with E. coli meningitis. Furthermore, α7 nAChR is the major calcium channel for nicotine- and E. coli K1-increased intracellular calcium concentrations of mouse BMEC. Taken together, our data suggest that α7 nAChR plays a detrimental role in the host defense against meningitic infection by modulation of pathogen invasion, PMN recruitment, calcium signaling and neuronal inflammation.

  13. Synthesis and evaluation of [{sup 125}I]I-TSA as a brain nicotinic acetylcholine receptor {alpha}{sub 7} subtype imaging agent

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, Mikako [Laboratory of Genome Bio-Photonics, Photon Medical Research Center, Hamamatsu Medical University, Hamamatsu 431-3192 (Japan); Tatsumi, Ryo [Pharmaceuticals Research Unit, Research and Development Division, Mitsubishi Pharma Corporation, Yokohama 227-0033 (Japan); Fujio, Masakazu [Pharmaceuticals Research Unit, Research and Development Division, Mitsubishi Pharma Corporation, Yokohama 227-0033 (Japan); Katayama, Jiro [Pharmaceuticals Research Unit, Research and Development Division, Mitsubishi Pharma Corporation, Yokohama 227-0033 (Japan); Magata, Yasuhiro [Laboratory of Genome Bio-Photonics, Photon Medical Research Center, Hamamatsu Medical University, Hamamatsu 431-3192 (Japan)]. E-mail: magata@hama-med.ac.jp

    2006-04-15

    Introduction: Some in vitro investigations have suggested that the nicotinic acetylcholine receptor (nAChR) {alpha}{sub 7} subtype is implicated in Alzheimer's disease, schizophrenia and others. Recently, we developed (R)-3'-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5'-[1',3'] oxazolidin]-2'-one (Br-TSA), which has a high affinity and selectivity for {alpha}{sub 7} nAChRs. Therefore we synthesized (R)-3'-(5-[{sup 125}I]iodothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5'- [1',3']oxazolidin]-2'-one ([{sup 125}I]I-TSA) and evaluated its potential for the in vivo detection of {alpha}{sub 7} nAChR in brain. Methods: In vitro binding affinity of I-TSA was measured in rat brain homogenates. Radioiodination was accomplished by a Br-I exchange reaction. Biodistribution studies were undertaken in mice by tail vein injection of [{sup 125}I]I-TSA. In vivo receptor blocking studies were carried out by treating mice with methyllycaconitine (MLA; 5 nmol/5 {mu}l, i.c.v.) or nonradioactive I-TSA (50 {mu}mol/kg, i.v.). Results: I-TSA exhibited a high affinity and selectivity for the {alpha}{sub 7} nAChR (K {sub i} for {alpha}{sub 7} nAChR=0.54 nM). Initial uptake in the brain was high (4.42 %dose/g at 5 min), and the clearance of radioactivity was relatively slow in the hippocampus ({alpha}{sub 7} nAChR-rich region) and was rather rapid in the cerebellum ({alpha}{sub 7} nAChR poor region). The hippocampus to cerebellum uptake ratio was 0.9 at 5 min postinjection, but it was increased to 1.8 at 60 min postinjection. Although the effect was not statistically significant, administration of I-TSA and MLA decreased the accumulation of radioactivity in hippocampus. Conclusion: Despite its high affinity and selectivity, [{sup 125}I]I-TSA does not appear to be a suitable tracer for in vivo {alpha}{sub 7} nAChR receptor imaging studies due to its high nonspecific binding. Further structural optimization is needed.

  14. Assessment of {alpha}7 nicotinic acetylcholine receptor availability in juvenile pig brain with [{sup 18}F]NS10743

    Energy Technology Data Exchange (ETDEWEB)

    Deuther-Conrad, Winnie; Fischer, Steffen; Hiller, Achim; Funke, Uta; Brust, Peter [Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmacy, Leipzig (Germany); Becker, Georg; Sabri, Osama [Univ. of Leipzig, Dept. of Nuclear Medicine, Leipzig (Germany); Cumming, Paul; Xiong, Guoming [Univ. of Munich, Dept. of Nuclear Medicine, Munich (Germany); Peters, Dan [NeuroSearch A/S, Ballerup (Denmark)

    2011-08-15

    To conduct a quantitative PET assessment of the specific binding sites in the brain of juvenile pigs for [{sup 18}F]NS10743, a novel diazabicyclononane derivative targeting {alpha}7 nicotinic acetylcholine receptors ({alpha}7 nAChRs). Dynamic PET recordings were made in isoflurane-anaesthetized juvenile pigs during 120 min after administration of [{sup 18}F]NS10743 under baseline conditions (n = 3) and after blocking of the {alpha}7 nAChR with NS6740 (3 mg.kg{sup -1} bolus + 1 mg.kg{sup -1}.h{sup -1} continuous infusion; n = 3). Arterial plasma samples were collected for determining the input function of the unmetabolized tracer. Kinetic analysis of regional brain time-radioactivity curves was performed, and parametric maps were calculated relative to arterial input. Plasma [{sup 18}F]NS10743 passed readily into the brain, with peak uptake occurring in {alpha}7 nAChR-expressing brain regions such as the colliculi, thalamus, temporal lobe and hippocampus. The highest SUV{sub max} was approximately 2.3, whereas the lowest uptake was in the olfactory bulb (SUV{sub max} 1.53 {+-} 0.32). Administration of NS6740 significantly decreased [{sup 18}F]NS10743 binding late in the emission recording throughout the brain, except in the olfactory bulb, which was therefore chosen as reference region for calculation of BP{sub ND}. The baseline BP{sub ND} ranged from 0.39 {+-} 0.08 in the cerebellum to 0.76 {+-} 0.07 in the temporal lobe. Pretreatment and constant infusion with NS6740 significantly reduced the BP{sub ND} in regions with high [{sup 18}F]NS10743 binding (temporal lobe -29%, p = 0.01; midbrain: -35%, p = 0.02), without significantly altering the BP{sub ND} in low binding regions (cerebellum: -16%, p = 0.2). This study confirms the potential of [{sup 18}F]NS10743 as a target-specific radiotracer for the molecular imaging of central {alpha}7 nAChRs by PET. (orig.)

  15. Aging and iron accumulation in the monkey brain

    International Nuclear Information System (INIS)

    Iron is deposited in the mammalian brain with a characteristic distribution, its amount increasing with aging. The relative abundance of iron in the globus pallidus, substantia nigra and putamen is thought to be responsible for the hypointensity of these nuclei on T2-weighted MR images, due to magnetic susceptibility effects. However, no quantitative correlation between iron content and hypointensity has been made to confirm this hypothesis. Two young (1-year-old) and two older (18-year-old) rhesus monkeys were studied with MR imaging at different field strengths (0.5, 1.5, 2.0 T). MR signal intensities from different anatomic structures were measured on T2-weighted coronal images (2,6000/80 [repetition time msec/echo time msec]). At completion of the MR studies, the monkeys were killed, coronal brain sections were stained for iron (Perls method), and optical densities of anatomic structures were measured. A quantitative correlation between the iron content and the signal intensity decrease was found on T2-weighted images in both deep and superficial cerebral structures. The detectability of magnetic susceptibility effects in a single structure is determined by the amount of iron present, with the threshold being inversely correlated to the strength of the magnetic field

  16. Age dependent accumulation of N-acyl-ethanolamine phospholipids in ischemic rat brain

    DEFF Research Database (Denmark)

    Moesgaard, B.; Petersen, G.; Hansen, Harald S.;

    2000-01-01

    N-acyl-ethanolamine phospholipids (NAPE) can be formed as a stress response during neuronal injury, and they are precursors for N-acyl- ethanolamines (NAE), some of which are endocannabinoids. The levels of NAPE accumulated during post-decapitative ischemia (6 h at 37°C) were studied in rat brains...... of various age (1, 6, 12, 19, 30, and ~70 days) by the use of P NMR spectroscopy of lipid extracts. This ability to accumulate NAPE was compared with the activity of N-acyltransferase and of NAPE-hydrolyzing phospholipase D (NAPE-PLD) in brain microsomes. These two enzymes are involved in the formation...

  17. Temporal assessment of nanoparticle accumulation after experimental brain injury: Effect of particle size

    Science.gov (United States)

    Bharadwaj, Vimala N.; Lifshitz, Jonathan; Adelson, P. David; Kodibagkar, Vikram D.; Stabenfeldt, Sarah E.

    2016-01-01

    Nanoparticle (NP) based therapeutic and theranostic agents have been developed for various diseases, yet application to neural disease/injury is restricted by the blood-brain-barrier (BBB). Traumatic brain injury (TBI) results in a host of pathological alterations, including transient breakdown of the BBB, thus opening a window for NP delivery to the injured brain tissue. This study focused on investigating the spatiotemporal accumulation of different sized NPs after TBI. Specifically, animal cohorts sustaining a controlled cortical impact injury received an intravenous injection of PEGylated NP cocktail (20, 40, 100, and 500 nm, each with a unique fluorophore) immediately (0 h), 2 h, 5 h, 12 h, or 23 h after injury. NPs were allowed to circulate for 1 h before perfusion and brain harvest. Confocal microscopy demonstrated peak NP accumulation within the injury penumbra 1 h post-injury. An inverse relationship was found between NP size and their continued accumulation within the penumbra. NP accumulation preferentially occurred in the primary motor and somatosensory areas of the injury penumbra as compared to the parietal association and visual area. Thus, we characterized the accumulation of particles up to 500 nm at different times acutely after injury, indicating the potential of NP-based TBI theranostics in the acute period after injury. PMID:27444615

  18. Effects of single-dose and fractionated cranial irradiation on rat brain accumulation of methotrexate

    International Nuclear Information System (INIS)

    The effects of single-dose and fractionated whole-brain irradiation on brain methotrexate (MTX) has been studied in a rat model. The amount of MTX present in the brain 24 hr after a single i.p. dose (100 mg/kg) was the same whether animals were sham irradiated or given a single dose of 2000 rads 6 or 48 hr prior to the drug (6.9, 8.3, and 6.8 pmol MTX/g, wet weight, respectively). Animals sham irradiated or given 2000 rads in 10 fractions over 11 days and treated with an average dose of 1.2 mg MTX/kg i.p. twice a week for 24 weeks did not differ significantly in their brain MTX concentration (7.9 and 8.3 pmol MTX/g, wet weight, respectively). Chronically MTX-treated animals became folate deficient whether they were irradiated or not (450 and 670 pmol folate/g, wet weight, brain in MTX-treated and control animals). Thus, MTX accumulates in the brain with acute or chronic administration, and this accumulation is not altered by this amount of brain irradiation

  19. In vitro and ex vivo autoradiographic studies of nicotinic acetylcholine receptors using [18F]fluoronorchloroepibatidine in rodent and human brain

    International Nuclear Information System (INIS)

    A fluorine-18-labeled analog of the potent nicotinic agonist epibatidine is a candidate radioligand for positron emission tomographic (PET) studies of nicotinic acetylcholine receptors (nAcChR). Following intravenous administration of [18F]exo-2-(2'-fluoro-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane (NFEP), high uptake in thalamus was visualized in sections of mouse and rat brain by autoradiography using a phosphor imaging device. Binding of [18F]NFEP to rat thalamic homogenate was consistent with a single class of binding site with a Kd value of 71 pM. In vitro autoradiography of thaw-mounted sections of human thalamus revealed a heterogeneous pattern of binding; Bmax values for ventrolateral nucleus, insular cortex and dorsomedial nucleus, and internal capsule were 20, 8, and 3 pmol/cc of tissue, respectively. However, similar Kd values close to 50 pM were calculated for all regions. These studies support the suitability of [18F]NFEP as a radioligand for PET studies of nAcChR in the living human brain

  20. Enhanced immunogenicity of a bivalent nicotine vaccine.

    Science.gov (United States)

    Keyler, D E; Roiko, S A; Earley, C A; Murtaugh, M P; Pentel, P R

    2008-11-01

    The efficacy of nicotine vaccines for smoking cessation is dependent upon their ability to elicit sufficiently high serum antibody concentrations. This study compared two nicotine immunogens representing different hapten presentations, 3'-aminomethyl nicotine conjugated to recombinant Pseudomonas exoprotein A (3'-AmNic-rEPA) and 6-carboxymethlureido nicotine conjugated to keyhole limpet hemocyanin (6-CMUNic-KLH), and assessed whether their concurrent administration would produce additive serum antibody concentrations in rats. Effects of vaccination on nicotine pharmacokinetics were also studied. Vaccination of rats with these immunogens produced non cross-reacting nicotine-specific antibodies (NicAb). Serum NicAb concentrations elicited by each individual immunogen were not affected by whether the immunogens were administered alone as monovalent vaccines or together as a bivalent vaccine. The total NicAb concentration in the bivalent vaccine group was additive compared to that of the monovalent vaccines alone. Higher serum NicAb concentrations, irrespective of which immunogen elicited the antibodies, were associated with greater binding of nicotine in serum, a lower unbound nicotine concentration in serum, and lower brain nicotine concentration. These results demonstrate that it is possible to design immunogens which provide distinct nicotine epitopes for immune presentation, and which produce additive serum antibody levels. The concurrent administration of these immunogens as a bivalent vaccine may provide a general strategy for enhancing the antibody response to small molecules such as nicotine. PMID:18656557

  1. AMYLOID BETA ACCUMULATION IN HIV-1-INFECTED BRAIN: THE ROLE OF THE BLOOD BRAIN BARRIER

    OpenAIRE

    András, Ibolya E.; Toborek, Michal

    2012-01-01

    In recent years we face an increase in the aging of the HIV-1-infected population, which is not only due to effective antiretroviral therapy but also to new infections among older people. Even with the use of the antiretroviral therapy, HIV-associated neurocognitive disorders represent an increasing problem as the HIV-1-infected population ages. Increased amyloid beta (Aβ) deposition is characteristic of HIV-1-infected brains, and it has been hypothesized that brain vascular dysfunction contr...

  2. 18F-fluorodeoxyglucose accumulation in the heart, brain and skeletal muscle of rats; the influence of time after injection, depressed lipid metabolism and glucose-insulin

    International Nuclear Information System (INIS)

    To study the effect of lipid depressing drugs on 18FDG myocardial concentration. The changes of 18FDG uptake in myocardium, brain and skeletal muscle of rats were compared as influenced by acipimox, tyloxapol and glucose with insulin. 5.55 MBq of 18FDG were administered to Wistar rats. Control rats were killed 15, 30, 45 and 60 minutes following intravenous injection and the radioactivity concentration (cpm/g of tissue) in relation to injected cpm was determined in a well crystal adjusted to 511 KeV in order to check the time of maximal 18FDG tissue uptake. The radioactivity in myocardium, skeletal muscle and brain in intact animals was compared with that of rats treated with tyloxapol (tritton WR 1339, 125 mg intravenously immediately before 18FDG injection), acipimox (nicotinic acid derivative, 25 mg by stomach cannula 15 minutes before 18FDG), or glucose with insulin (intravenous injection of 0.04 g and 0.04 UI immediately before 18FDG). The animals were killed 45 minutes following 18FDG injection. Tyloxapol and acipimox significantly elevated myocardial 18FDG concentration (tyloxapol +37% and acipimox +48%), but the increase in 18FDG concentration after glucose and insulin was slight and insignificant. The changes in skeletal muscle after lipid depressing agents were quite contrasting; the decrease in 18FDG concentration was -74% after tyloxapol and -44% following acipimox administration. The accumulation of 18FDG in brain was not influenced markedly by the drugs used or by glucose with insulin. The highest 18FDG uptake in myocardium could be achieved by depressing the lipid metabolism and not by administration of glucose with insulin only. A marked increase in glucose accumulation in myocardium is not possible without previous shift from the utilisation of fatty acids. This finding is fully in agreement with present knowledge about energetic metabolism of myocardium. (author)

  3. Accumulation of N-acyl-ethanolamine phospholipids in rat brains during post-decapitative ischemia

    DEFF Research Database (Denmark)

    Moesgaard, B.; Hansen, Harald S.; Jaroszewski, J.W.

    1999-01-01

    Phosphorus-31 nuclear magnetic resonance (P NMR) spectroscopy has been used to study accumulation of N-acyl-ethanolamine phospholipids in rat brains during post-decapitative ischemia. Lipids were extracted from rat brain homogenates and the extracts were thoroughly washed with aq. potassium...... NMR spectra at 0.18 and 0.22 ppm (relative to the chemical shift of 1,2-diacyl-sn-glycero-3-phosphocholine (PCD(DIACYL)) at -0.84 ppm). These signals were identified as originating from 1,2-diacyl- sn-glycero-3-phospho-(N-acyl)-ethanolamine (NAPED(DIACYL)) and 1-(1'- alkenyl)-2-acyl-sn-glycero-3......-phospho(N-acyl)-ethanolamine (NAPE(PLAS)), respectively, by spiking with authentic materials. Additionally, the identification was verified by thin-layer chromatography, which also showed the accumulation of N-acyl-ethanolamine phospholipids. The use of K-EDTA instead of the commonly used Cs-EDTA in the...

  4. Accumulation of neurotoxic organochlorines and trace elements in brain of female European eel (Anguilla anguilla).

    Science.gov (United States)

    Bonnineau, C; Scaion, D; Lemaire, B; Belpaire, C; Thomé, J-P; Thonon, M; Leermaker, M; Gao, Y; Debier, C; Silvestre, F; Kestemont, P; Rees, J-F

    2016-07-01

    Xenobiotics such as organochlorine compounds (OCs) and metals have been suggested to play a significant role in the collapse of European eel stocks in the last decades. Several of these pollutants could affect functioning of the nervous system. Still, no information is so far available on levels of potentially neurotoxic pollutants in eel brain. In present study, carried out on female eels caught in Belgian rivers and canals, we analyzed brain levels of potentially-neurotoxic trace elements (Ag, Al, As, Cd, Co, Cr, Cu, Fe, Hg, MeHg, Mn, Ni, Pb, Sn, Sb, Zn) and OCs (Polychlorinated biphenyls, PCBs; Hexachlorocyclohexanes, HCHs; Dichlorodiphenyltrichloroethane and its metabolites, DDTs). Data were compared to levels in liver and muscle tissues. Eel brain contained very high amounts of OCs, superior to those found in the two other tissues. Interestingly, the relative abundance of PCB congeners markedly differed between tissues. In brain, a predominance of low chlorinated PCBs was noted, whereas highly chlorinated congeners prevailed in muscle and liver. HCHs were particularly abundant in brain, which contains the highest amounts of β-HCH and ϒ-HCH. p,p'-DDTs concentration was similar between brain and muscle (i.e., about twice that of liver). A higher proportion of p,p'-DDT was noticed in brain. Except for Cr and inorganic Hg, all potentially neurotoxic metals accumulated in brain to levels equal to or lower than hepatic levels. Altogether, results indicate that eel brain is an important target for organic and, to a lesser extent, for inorganic neurotoxic pollutants. PMID:27376663

  5. (S)- and (R)-[11C]nicotine and the metabolite (R/S)-[11C]cotinine. Preparation, metabolite studies and in vivo distribution in the human brain using PET

    International Nuclear Information System (INIS)

    In order to investigate [11C]nicotine binding and metabolism in the living human brain by PET, routine protocols were developed for the preparation and purification of (S)-and (R)-[11C]nicotine and the metabolite (R/S)-[11C]cotinine. (S)- and (R)-[11C]nicotine were prepared by N-methylation with [11C]methyl iodide of the appropriate secondary amine, which was liberated in situ by 2,2,6,6,-tetramethylpiperidine (TMP) from its corresponding biscamsylate-salt. (R/S)-[11C]Cotinine was prepared by N-methylation of the amide precursor using tetrabutylammonium hydroxide as a phase transfer catalyst. Straight-phase semipreparative HPLC was in all purifications found to be superior to reversed-phase since the contamination by the norcompounds was eliminated. Reaction in acetonitrile for both (S)- and (R)-[11C]nicotine and (R/S)-[11C]cotinine with subsequent straight-phase HPLC purification resulted in 35-45% radiochemical yield with a total synthesis time of 30-35 min, a specific radioactivity of 1000-1500 Ci/mmol (37-55 GBq/μmol, EOS) and a radiochemical purity >99%. The uptake and distribution of these tracers in the human brain was studied in healthy volunteers by PET. The metabolite (R/S)-[11C]cotinine did not cross the blood-brain barrier to any significant degree. (author)

  6. Renal transport and metabolism of nicotinic acid

    International Nuclear Information System (INIS)

    Renal metabolism and brush-border transport of nicotinic acid were studied in renal cortical slices and brush-border membrane vesicles exposed to a physiological concentration of vitamin (2.2-3.5 microM). Vesicle transport of [3H]nicotinic acid was found to be Na+ dependent and concentrative. The presence of a Na+ gradient resulted in a fivefold increase in the rate of nicotinic acid uptake over that observed with mannitol and caused a transient nicotinic acid accumulation two- to fourfold above the equilibrium value. The effects of membrane potential, pH, and elimination of Na+-H+ exchange were also studied. Cortical slices and isolated tubules exposed to 2.2 microM [14C]nicotinic acid took up vitamin and rapidly metabolized most of it to intermediates in the Preiss-Handler pathway for NAD biosynthesis; little free nicotinic acid was detectable intracellularly. The replacement of Na+ with Li+ in the bathing medium reduced total accumulation of 14C label primarily as a result of reduced nicotinic acid uptake. Cortical tissue concentrated free nicotinic acid only when the involved metabolic pathways were saturated by levels of nicotinic acid far in excess of what occurs in vivo

  7. Gene co-expression networks shed light into diseases of brain iron accumulation

    Science.gov (United States)

    Bettencourt, Conceição; Forabosco, Paola; Wiethoff, Sarah; Heidari, Moones; Johnstone, Daniel M.; Botía, Juan A.; Collingwood, Joanna F.; Hardy, John; Milward, Elizabeth A.; Ryten, Mina; Houlden, Henry

    2016-01-01

    Aberrant brain iron deposition is observed in both common and rare neurodegenerative disorders, including those categorized as Neurodegeneration with Brain Iron Accumulation (NBIA), which are characterized by focal iron accumulation in the basal ganglia. Two NBIA genes are directly involved in iron metabolism, but whether other NBIA-related genes also regulate iron homeostasis in the human brain, and whether aberrant iron deposition contributes to neurodegenerative processes remains largely unknown. This study aims to expand our understanding of these iron overload diseases and identify relationships between known NBIA genes and their main interacting partners by using a systems biology approach. We used whole-transcriptome gene expression data from human brain samples originating from 101 neuropathologically normal individuals (10 brain regions) to generate weighted gene co-expression networks and cluster the 10 known NBIA genes in an unsupervised manner. We investigated NBIA-enriched networks for relevant cell types and pathways, and whether they are disrupted by iron loading in NBIA diseased tissue and in an in vivo mouse model. We identified two basal ganglia gene co-expression modules significantly enriched for NBIA genes, which resemble neuronal and oligodendrocytic signatures. These NBIA gene networks are enriched for iron-related genes, and implicate synapse and lipid metabolism related pathways. Our data also indicates that these networks are disrupted by excessive brain iron loading. We identified multiple cell types in the origin of NBIA disorders. We also found unforeseen links between NBIA networks and iron-related processes, and demonstrate convergent pathways connecting NBIAs and phenotypically overlapping diseases. Our results are of further relevance for these diseases by providing candidates for new causative genes and possible points for therapeutic intervention. PMID:26707700

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

    Science.gov (United States)

    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. Deficiency of Calcium-Independent Phospholipase A2 Beta Induces Brain Iron Accumulation through Upregulation of Divalent Metal Transporter 1

    OpenAIRE

    Goichi Beck; Koei Shinzawa; Hideki Hayakawa; Kousuke Baba; Toru Yasuda; Hisae Sumi-Akamaru; Yoshihide Tsujimoto; Hideki Mochizuki

    2015-01-01

    Mutations in PLA2G6 have been proposed to be the cause of neurodegeneration with brain iron accumulation type 2. The present study aimed to clarify the mechanism underlying brain iron accumulation during the deficiency of calcium-independent phospholipase A2 beta (iPLA2β), which is encoded by the PLA2G6 gene. Perl's staining with diaminobenzidine enhancement was used to visualize brain iron accumulation. Western blotting was used to investigate the expression of molecules involved in iron hom...

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

    OpenAIRE

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

    2011-01-01

    Nicotine is the primary psychoactive substance in tobacco and it exerts its effects by interaction with various subtypes of nicotinic acetylcholine receptors (nAChRs) in the brain. One of the major subtypes expressed in brain, the alpha4beta2-nAChR, endogenously modulates neuronal excitability and thereby, modifies certain normal, as well as nicotine-induced, behaviors. Although alpha4-containing nAChRs are widely expressed across the brain, a major focus has been on their roles within midbra...

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

    Science.gov (United States)

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

    2015-02-01

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

  12. Nicotine Nasal Spray

    Science.gov (United States)

    Nicotine nasal spray is used to help people stop smoking. Nicotine nasal spray should be used together with a smoking cessation ... counseling, or specific behavior change techniques. Nicotine nasal spray is in a class of medications called smoking ...

  13. Metabolomics analysis reveals elevation of 3-indoxyl sulfate in plasma and brain during chemically-induced acute kidney injury in mice: Investigation of nicotinic acid receptor agonists

    International Nuclear Information System (INIS)

    An investigative renal toxicity study using metabolomics was conducted with a potent nicotinic acid receptor (NAR) agonist, SCH 900424. Liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were used to identify small molecule biomarkers of acute kidney injury (AKI) that could aid in a better mechanistic understanding of SCH 900424-induced AKI in mice. The metabolomics study revealed 3-indoxyl sulfate (3IS) as a more sensitive marker of SCH 900424-induced renal toxicity than creatinine or urea. An LC-MS assay for quantitative determination of 3IS in mouse matrices was also developed. Following treatment with SCH 900424, 3IS levels were markedly increased in murine plasma and brain, thereby potentially contributing to renal- and central nervous system (CNS)-related rapid onset of toxicities. Furthermore, significant decrease in urinary excretion of 3IS in those animals due to compromised renal function may be associated with the elevation of 3IS in plasma and brain. These data suggest that 3IS has a potential to be a marker of renal and CNS toxicities during chemically-induced AKI in mice. In addition, based on the metabolomic analysis other statistically significant plasma markers including p-cresol-sulfate and tryptophan catabolites (kynurenate, kynurenine, 3-indole-lactate) might be of toxicological importance but have not been studied in detail. This comprehensive approach that includes untargeted metabolomic and targeted bioanalytical sample analyses could be used to investigate toxicity of other compounds that pose preclinical or clinical development challenges in a pharmaceutical discovery and development. - Research highlights: → Nicotinic acid receptor agonist, SCH 900424, caused acute kidney injury in mice. → MS-based metabolomics was conducted to identify potential small molecule markers of renal toxicity. → 3-indoxyl-sulfate was found to be as a more sensitive marker of renal toxicity than

  14. The Volitional Nature of Nicotine Exposure Alters Anandamide and Oleoylethanolamide Levels in the Ventral Tegmental Area

    OpenAIRE

    Buczynski, Matthew W.; Polis, Ilham Y; Parsons, Loren H.

    2012-01-01

    Cannabinoid-1 receptors (CB1) have an important role in nicotine reward and their function is disrupted by chronic nicotine exposure, suggesting nicotine-induced alterations in endocannabinoid (eCB) signaling. However, the effects of nicotine on brain eCB levels have not been rigorously evaluated. Volitional intake of nicotine produces physiological and behavioral effects distinct from forced drug administration, although the mechanisms underlying these effects are not known. This study compa...

  15. Spectral Confocal Imaging of Fluorescently tagged Nicotinic Receptors in Knock-in Mice with Chronic Nicotine Administration

    OpenAIRE

    Renda, Anthony; Nashmi, Raad

    2012-01-01

    Ligand-gated ion channels in the central nervous system (CNS) are implicated in numerous conditions with serious medical and social consequences. For instance, addiction to nicotine via tobacco smoking is a leading cause of premature death worldwide (World Health Organization) and is likely caused by an alteration of ion channel distribution in the brain1. Chronic nicotine exposure in both rodents and humans results in increased numbers of nicotinic acetylcholine receptors (nAChRs) in brain t...

  16. Intrathecal morphine therapy in the management of status dystonicus in neurodegeneration brain iron accumulation type 1.

    Science.gov (United States)

    Lopez, William Omar Contreras; Kluge Schroeder, Humberto; Santana Neville, Iuri; Jacobsen Teixeira, Manoel; Costa Barbosa, Danilo; Assumpçao de Mônaco, Bernardo; Talamoni Fonoff, Erich

    2015-01-01

    Neurodegeneration with brain iron accumulation type 1 (NBIA-1) is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. NBIA-1 encompasses typical iron brain accumulation, mostly in the globus pallidus with secondary dementia, spasticity, rigidity, dystonia, and choreoathetosis. Treatment remains mostly symptomatic and is challenging. We present the case of a 14-year-old boy diagnosed with NBIA-1, presenting intractable progressive generalized dystonia leading to unresponsive status dystonicus (SD). The patient received a SynchroMed II (model 8637) programmable system pump (Medtronic®, Inc.) implant with an Ascenda intrathecal catheter for intrathecal morphine therapy (IMT). The initial dose of morphine was 1.0 mg/day. Overall, we observed no complications with IMT treatment and important improvement of the patient's motor function with stabilization of his incapacitating dystonia and his quality of life. On the Global Dystonia Severity Rating Scale, he presented 52% improvement, 30% improvement on the Unified Dystonia Rating Scale, and 38% improvement on the Fahn-Marsden Rating Scale after 10 months, when the dose was 1.7 mg/day. IMT should be considered as a potential palliative treatment in the management of intractable dystonia and SD secondary to NBIA-1. PMID:25896138

  17. Reduced number of (3H)nicotine and (3H)acelylcholine binding sites in the frontal cortex of Alzheimer brains

    International Nuclear Information System (INIS)

    Nicotinic cholinergic receptors were measured in human frontal cortex using (3H)nicotine and (3H)acetylcholine (in the presence of atropine) as receptor ligands. A parallel marked reduction in number of (3H)nicotine (52%, P3H)acetylcholine (-55%, P3H)quinuclidinyl benzilate and found to be significantly increased (+23%, P<0.01) in AD/SDAT compared to controls. (author)

  18. Xanthurenic acid distribution, transport, accumulation and release in the rat brain.

    Science.gov (United States)

    Gobaille, Serge; Kemmel, Véronique; Brumaru, Daniel; Dugave, Christophe; Aunis, Dominique; Maitre, Michel

    2008-05-01

    Tryptophan metabolism through the kynurenine pathway leads to several neuroactive compounds, including kynurenic and picolinic acids. Xanthurenic acid (Xa) has been generally considered as a substance with no physiological role but possessing toxic and apoptotic properties. In the present work, we present several findings which support a physiological role for endogenous Xa in synaptic signalling in brain. This substance is present in micromolar amounts in most regions of the rat brain with a heterogeneous distribution. An active vesicular synaptic process inhibited by bafilomycin and nigericin accumulates xanthurenate into pre-synaptic terminals. A neuronal transport, partially dependant on adenosine 5'-triphosphate (ATP), sodium and chloride ions exists in NCB-20 neurons which could participate in the clearance of extracellular xanthurenate. Both transports (neuronal and vesicular) are greatly enhanced by the presence of micromolar amounts of zinc ions. Finally, electrical in vivo stimulation of A10-induced Xa release in the extracellular spaces of the rat prefrontal cortex. This phenomenon is reproduced by veratrine, K+ ions and blocked by EGTA and tetrodotoxin. These results strongly argue for a role for Xa in neurotransmission/neuromodulation in the rat brain, thus providing the existence of specific Xa receptors. PMID:18182052

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

    Science.gov (United States)

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

    2012-01-01

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

  20. α4β2 nicotinic acetylcholine receptors on dopaminergic neurons mediate nicotine reward and anxiety relief.

    Science.gov (United States)

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

    2011-07-27

    Nicotine is the primary psychoactive substance in tobacco, and it exerts its effects by interaction with various subtypes of nicotinic acetylcholine receptors (nAChRs) in the brain. One of the major subtypes expressed in brain, the α4β2-nAChR, endogenously modulates neuronal excitability and thereby, modifies certain normal as well as nicotine-induced behaviors. Although α4-containing nAChRs are widely expressed across the brain, a major focus has been on their roles within midbrain dopaminergic regions involved in drug addiction, mental illness, and movement control in humans. We developed a unique model system to examine the role of α4-nAChRs within dopaminergic neurons by a targeted genetic deletion of the α4 subunit from dopaminergic neurons in mice. The loss α4 mRNA and α4β2-nAChRs from dopaminergic neurons was confirmed, as well as selective loss of α4β2-nAChR function from dopaminergic but not GABAergic neurons. Two behaviors central to nicotine dependence, reward and anxiety relief, were examined. α4-nAChRs specifically on dopaminergic neurons were demonstrated to be necessary for nicotine reward as measured by nicotine place preference, but not for another drug of addiction, cocaine. α4-nAChRs are necessary for the anxiolytic effects of nicotine in the elevated plus maze, and elimination of α4β2-nAChRs specifically from dopaminergic neurons decreased sensitivity to the anxiolytic effects of nicotine. Deletion of α4-nAChRs specifically from dopaminergic neurons also increased sensitivity to nicotine-induced locomotor depression; however, nicotine-induced hypothermia was unaffected. This is the first work to develop a dopaminergic specific deletion of a nAChR subunit and examine resulting changes in nicotine-related behaviors. PMID:21795541

  1. Nicotinic modulation of synaptic transmission and plasticity in cortico-limbic circuits

    OpenAIRE

    2009-01-01

    Nicotine is the principle addictive agent delivered via cigarette smoking. The addictive activity of nicotine is due to potent interactions with nicotinic acetylcholine receptors (nAChRs) on neurons in the reinforcement and reward circuits of the brain. Beyond its addictive actions, nicotine is thought to have positive effects on performance in working memory and short-term attention-related tasks. The brain areas involved in such behaviors are part of an extensive cortico-limbic network that...

  2. The Yin and Yang of nicotine: harmful during development, beneficial in adult patient populations

    OpenAIRE

    SabineSpijker

    2012-01-01

    Nicotine has remarkably diverse effects on the brain. Being the main active compound in tobacco, nicotine can aversively affect brain development. However, it has the ability to act positively by restoring attentional capabilities in smokers. Here, we focus on nicotine exposure during the prenatal and adolescent developmental periods and specifically, we will review the long-lasting effects of nicotine on attention, both in humans and animal models. We discuss the reciprocal relation of the b...

  3. Phasic D1 and tonic D2 dopamine receptor signaling double dissociate the motivational effects of acute nicotine and chronic nicotine withdrawal

    OpenAIRE

    Grieder, Taryn E; George, Olivier; Tan, Huibing; George, Susan R.; Le Foll, Bernard; Laviolette, Steven R; van der Kooy, Derek

    2012-01-01

    Nicotine, the main psychoactive ingredient of tobacco smoke, induces negative motivational symptoms during withdrawal that contribute to relapse in dependent individuals. The neurobiological mechanisms underlying how the brain signals nicotine withdrawal remain poorly understood. Using electrophysiological, genetic, pharmacological, and behavioral methods, we demonstrate that tonic but not phasic activity is reduced during nicotine withdrawal in ventral tegmental area dopamine (DA) neurons, a...

  4. Review: Insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation: unifying theories.

    Science.gov (United States)

    Arber, C E; Li, A; Houlden, H; Wray, S

    2016-04-01

    Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by dystonia, parkinsonism and spasticity. Iron accumulates in the basal ganglia and may be accompanied by Lewy bodies, axonal swellings and hyperphosphorylated tau depending on NBIA subtype. Mutations in 10 genes have been associated with NBIA that include Ceruloplasmin (Cp) and ferritin light chain (FTL), both directly involved in iron homeostasis, as well as Pantothenate Kinase 2 (PANK2), Phospholipase A2 group 6 (PLA2G6), Fatty acid hydroxylase 2 (FA2H), Coenzyme A synthase (COASY), C19orf12, WDR45 and DCAF17 (C2orf37). These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy. A greater understanding of the cellular pathways that link these genes and the disease mechanisms leading to iron dyshomeostasis is needed. Additionally, the major overlap seen between NBIA and more common neurodegenerative diseases may highlight conserved disease processes. In this review, we will discuss clinical and pathological findings for each NBIA-related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis, and speculate the potential overlap between NBIA subtypes. PMID:25870938

  5. The presence of serum alters the properties of iron oxide nanoparticles and lowers their accumulation by cultured brain astrocytes

    International Nuclear Information System (INIS)

    Iron oxide nanoparticles (IONPs) are considered for various diagnostic and therapeutic applications. Such particles are able to cross the blood–brain barrier and are taken up into brain cells. To test whether serum components affect the properties of IONPs and/or their uptake into brain cells, we have incubated dimercaptosuccinate-coated magnetic IONPs without and with fetal calf serum (FCS) and have exposed cultured brain astrocytes with IONPs in the absence or presence of FCS. Incubation with FCS caused a concentration-dependent increase in the average hydrodynamic diameter of the particles and of their zeta-potential. In the presence of 10 % FCS, the diameter of the IONPs increased from 57 ± 2 to 107 ± 6 nm and the zeta-potential of the particles from −22 ± 5 to −9 ± 1 mV. FCS affected also strongly the uptake of IONPs by cultured astrocytes. The efficient time- and temperature-dependent cellular accumulation of IONPs was lowered with increasing concentration of FCS by up to 90 %. In addition, in the absence of serum, endocytosis inhibitors did not alter the IONP accumulation by astrocytes, while chlorpromazine or wortmannin lowered significantly the accumulation of IONPs in the presence of FCS, suggesting that clathrin-mediated endocytosis and macropinocytosis are involved in astrocytic IONP uptake from serum-containing medium. These data demonstrate that the presence of FCS strongly affects the properties of IONPs as well as their accumulation by cultured brain cells.

  6. The presence of serum alters the properties of iron oxide nanoparticles and lowers their accumulation by cultured brain astrocytes

    Energy Technology Data Exchange (ETDEWEB)

    Geppert, Mark; Petters, Charlotte [University of Bremen, Centre for Biomolecular Interactions Bremen (Germany); Thiel, Karsten [Fraunhofer Institute for Manufacturing Technology and Advanced Materials (Germany); Dringen, Ralf, E-mail: ralf.dringen@uni-bremen.de [University of Bremen, Centre for Biomolecular Interactions Bremen (Germany)

    2013-01-15

    Iron oxide nanoparticles (IONPs) are considered for various diagnostic and therapeutic applications. Such particles are able to cross the blood-brain barrier and are taken up into brain cells. To test whether serum components affect the properties of IONPs and/or their uptake into brain cells, we have incubated dimercaptosuccinate-coated magnetic IONPs without and with fetal calf serum (FCS) and have exposed cultured brain astrocytes with IONPs in the absence or presence of FCS. Incubation with FCS caused a concentration-dependent increase in the average hydrodynamic diameter of the particles and of their zeta-potential. In the presence of 10 % FCS, the diameter of the IONPs increased from 57 {+-} 2 to 107 {+-} 6 nm and the zeta-potential of the particles from -22 {+-} 5 to -9 {+-} 1 mV. FCS affected also strongly the uptake of IONPs by cultured astrocytes. The efficient time- and temperature-dependent cellular accumulation of IONPs was lowered with increasing concentration of FCS by up to 90 %. In addition, in the absence of serum, endocytosis inhibitors did not alter the IONP accumulation by astrocytes, while chlorpromazine or wortmannin lowered significantly the accumulation of IONPs in the presence of FCS, suggesting that clathrin-mediated endocytosis and macropinocytosis are involved in astrocytic IONP uptake from serum-containing medium. These data demonstrate that the presence of FCS strongly affects the properties of IONPs as well as their accumulation by cultured brain cells.

  7. Exome Sequence Reveals Mutations in CoA Synthase as a Cause of Neurodegeneration with Brain Iron Accumulation

    OpenAIRE

    Dusi, Sabrina; Valletta, Lorella; Haack, Tobias B.; Tsuchiya, Yugo; Venco, Paola; Pasqualato, Sebastiano; Goffrini, Paola; Tigano, Marco; Demchenko, Nikita; Wieland, Thomas; Schwarzmayr, Thomas; Strom, Tim M; Invernizzi, Federica; Garavaglia, Barbara; Gregory, Allison

    2014-01-01

    Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in one NBIA-affected subject. A second unrelated individual carrying mutations in COASY was identified by Sanger sequence analys...

  8. Hyperphosphorylation and accumulation of neurofilament proteins in Alzheimer brain and the possible mechanism

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    SMI34 were increased, and the elevated p-NF-H/M tended to be condensed in the proximal end of the cell processes after treated with 15 nmol/L OA. Further accumulation of p-NF-H/M to the cell plasma and parikarya was seen after increasing the concentration of OA to 30 nmol/L. On the other hand, the majority of np-NF-H/M bound to SMI32 and SMI33 were seen in the cell body although it was also detected in cell processes before OA treatment. The immunoreaction of np-NF-H/M was significantly decreased in the cell body and it became to be condensed in the proximal end of the cell processes after treatment of the cell by 15 nmol/L of OA. Further decreasing of the staining was observed when the concentration of OA was raised to 30 nmol/L. The data demonstrated that an Alzheimer-like inhibition of PP-2A and PP-1 induced hyperphosphorylation and accumulation of NF proteins as seen in AD brain, indicating that abnormality of NF might be involved in AD neurofibrillary degeneration. As SY5Y contains negligible amount of tau protein which was reported to cross-react with p-NF subunits, it might be served as a proper cell model for NF study.

  9. It's not “either/or”: activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood

    OpenAIRE

    Picciotto, Marina R.; Addy, Nii A.; Mineur, Yann S.; Brunzell, Darlene H.

    2007-01-01

    Nicotine can both activate and desensitize/inactivate nicotinic acetylcholine receptors (nAChRs). An ongoing controversy in the field is to what extent the behavioral effects of nicotine result from activation of nAChRs, and to what extent receptor desensitization is involved in these behavioral processes. Recent electrophysiological studies have shown that both nAChR activation and desensitization contribute to the effects of nicotine in the brain, and these experiments have provided cellula...

  10. Design and synthesis of new agents for neuronal nicotinic acetylcholine receptor (nAChRs) imaging

    International Nuclear Information System (INIS)

    Introduction: The most abundant subtype of cerebral nicotinic acetylcholine receptors (nAChR), α4β2, plays a critical role in various brain functions and pathological states. Due to rapid technological progress in chemistry, bioinformatics, structural biology and computer technology, computer aided drug design (CADD) plays a more and more important role in today's drug discovery. Methods: Two novel 3-pyridyl ether nicotinic ligands-3-((pyridine-2-yl)methoxy)-5-iodopyridine, and 3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)-methyl)pyridine were designed and synthesized and radiolabeled with I-125 based on our 3D-QSAR models reported previously. Their ability to label high-affinity brain nicotinic acetylcholine receptors (nAChRs) was evaluated. Results: [125I]3-((pyridin-2-yl)methoxy)-5-iodopyridine shows rapid accumulation and elimination with peak (1.86%ID/g) at 5 min post injection, but has high blood uptake. [125I]3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)methyl)pyridine entered the brain with maximal uptake value 3.01%ID/g at 15 min after injection, and showed approximately 27% inhibition of radioactivity uptake in thalamus in mice pretreated with nicotine. Conclusions: The results of this preliminary study show that [125I]3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)methyl)pyridine shows relatively high uptake to the brain, however, since the in vivo selectivity for α4β2 nAChRs was not enough, [125I]3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)methyl)pyridine does not have the required properties for imaging nAChRs using SPECT. Structure optimization is needed for specific visualization of brain α4β2 nAChRs in vivo.

  11. Combined active and passive immunization enhances the efficacy of immunotherapy against nicotine in rats.

    Science.gov (United States)

    Roiko, Samuel A; Harris, Andrew C; Keyler, Daniel E; Lesage, Mark G; Zhang, Yan; Pentel, Paul R

    2008-06-01

    Vaccination against nicotine reduces the behavioral effects of nicotine in rats, and it is under clinical evaluation as a treatment for tobacco addiction. Efficacy is limited by the need for high serum nicotine-specific antibody (NicAb) levels, and currently available nicotine vaccines do not uniformly generate the required NicAb levels. Passive immunization with a nicotine-specific monoclonal antibody (Nic311) has also shown efficacy in rats. The principal aim of this study was to determine whether the combined use of vaccination and passive immunization would produce greater effects than vaccination alone on nicotine pharmacokinetics and locomotor sensitization (LMS) to nicotine. Rats were treated with vaccination alone, Nic311 alone, both, or neither, and then they were administered 10 daily injections of 0.3 mg/kg nicotine s.c. Treatment with Nic311 or vaccination alone increased the binding of nicotine in serum, reduced the unbound serum nicotine concentration and nicotine distribution to brain, and attenuated the development of LMS. Combined use of vaccination and passive immunization produced higher total serum NicAb levels, greater changes in nicotine pharmacokinetics, and a greater attenuation of LMS than either treatment alone. The total serum NicAb concentration was significantly correlated with brain nicotine levels and locomotor activity. These data indicate that providing higher serum NicAb concentrations improves the efficacy of immunotherapy against nicotine and that supplementing vaccination with passive immunization is a potential strategy to accomplish this. PMID:18305013

  12. Automated radioimmunoassay of nicotine

    International Nuclear Information System (INIS)

    The authors have developed an automated nonequilibrium procedure for the radioimmunoassay of nicotine. The use of a unique iodinated nicotine derivative in this procedure gave a sensitivity of 10 μg/l for nicotine with a between-run precision of 7.4% and within-run precision of 6.0%. Nicotine levels of 60 to 67 μg/l were found in subjects 15 min after smoking one standard cigarette. The technique herein reported is a very rapid, and sensitive radioimmunoassay for nicotine and facilitates the determination of nicotine in smoking subjects during the actual process of smoking. (Auth.)

  13. Demystifying "free will": the role of contextual information and evidence accumulation for predictive brain activity.

    Science.gov (United States)

    Bode, Stefan; Murawski, Carsten; Soon, Chun Siong; Bode, Philipp; Stahl, Jutta; Smith, Philip L

    2014-11-01

    Novel multivariate pattern classification analyses have enabled the prediction of decision outcomes from brain activity prior to decision-makers' reported awareness. These findings are often discussed in relation to the philosophical concept of "free will". We argue that these studies demonstrate the role of unconscious processes in simple free choices, but they do not inform the philosophical debate. Moreover, these findings are difficult to relate to cognitive decision-making models, due to misleading assumptions about random choices. We review evidence suggesting that sequential-sampling models, which assume accumulation of evidence towards a decision threshold, can also be applied to free decisions. If external evidence is eliminated by the task instructions, decision-makers might use alternative, subtle contextual information as evidence, such as their choice history, that is not consciously monitored and usually concealed by the experimental design. We conclude that the investigation of neural activity patterns associated with free decisions should aim to investigate how decisions are jointly a function of internal and external contexts, rather than to resolve the philosophical "free will" debate. PMID:25452111

  14. Nicotine Microaerosol Inhaler

    Directory of Open Access Journals (Sweden)

    Paul G Andrus

    1999-01-01

    Full Text Available OBJECTIVE: To measure the droplet size distribution of a nicotine pressurized metered-dose inhaler using a nicotine in ethanol solution formulation with hydrofluoroalkane as propellant.

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

    Science.gov (United States)

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

    2016-03-24

    Despite efforts to produce suitable smoking cessation aids, addiction to nicotine continues to carry a substantive risk of recidivism. An attractive alternative to current therapies is the pharmacokinetic strategy of antinicotine vaccination. A major hurdle in the development of the strategy has been to elicit a sufficiently high antibody concentration to curb nicotine distribution to the brain. Herein, we detail investigations into a new hapten design, which was able to elicit an antibody response of significantly higher specificity for nicotine. We also explore the use of a mutant flagellin carrier protein with adjuvanting properties. These studies underlie the feasibility of improvement in antinicotine vaccine formulations to move toward clinical efficacy. PMID:26918428

  16. Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation

    Science.gov (United States)

    Hayflick, Susan J.; Kruer, Michael C.; Gregory, Allison; Haack, Tobias B.; Kurian, Manju A.; Houlden, Henry H.; Anderson, James; Boddaert, Nathalie; Sanford, Lynn; Harik, Sami I.; Dandu, Vasuki H.; Nardocci, Nardo; Zorzi, Giovanna; Dunaway, Todd; Tarnopolsky, Mark; Skinner, Steven; Holden, Kenton R.; Frucht, Steven; Hanspal, Era; Schrander-Stumpel, Connie; Mignot, Cyril; Héron, Delphine; Saunders, Dawn E.; Kaminska, Margaret; Lin, Jean-Pierre; Lascelles, Karine; Cuno, Stephan M.; Meyer, Esther; Garavaglia, Barbara; Bhatia, Kailash; de Silva, Rajith; Crisp, Sarah; Lunt, Peter; Carey, Martyn; Hardy, John; Meitinger, Thomas; Prokisch, Holger; Hogarth, Penelope

    2013-01-01

    Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a ‘halo’ of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features. PMID:23687123

  17. Possible link between Hg and Cd accumulation in the brain of long-finned pilot whales (Globicephala melas).

    Science.gov (United States)

    Gajdosechova, Zuzana; Brownlow, Andrew; Cottin, Nicolas T; Fernandes, Mariana; Read, Fiona L; Urgast, Dagmar S; Raab, Andrea; Feldmann, Jörg; Krupp, Eva M

    2016-03-01

    The bioaccumulation of metals was investigated by analysis of liver, kidney, muscle and brain tissue of a pod of 21 long-finned pilot whales (Globicephala melas) of all ages stranded in Scotland, UK. The results are the first to report cadmium (Cd) passage through the blood-brain barrier of pilot whales and provide a comprehensive study of the long-term (up to 35 years) mammalian exposure to the environmental pollutants. Additionally, linear accumulation of mercury (Hg) was observed in all studied tissues, whereas for Cd this was only observed in the liver. Total Hg concentration above the upper neurochemical threshold was found in the sub-adult and adult brains and methylmercury (MeHg) of 2.2mg/kg was found in the brain of one individual. Inter-elemental analysis showed significant positive correlations of Hg with selenium (Se) and Cd with Se in all studied tissues. Furthermore, differences in the elemental concentrations in the liver and brain tissues were found between juvenile, sub-adult and adult groups. The highest concentrations of manganese, iron, zinc, Se, Hg and MeHg were noted in the livers, whereas Cd predominantly accumulated in the kidneys. High concentrations of Hg and Cd in the tissues of pilot whales presented in this study reflect ever increasing toxic stress on marine mammals. PMID:26748005

  18. Mitochondrial dysfunction and defects in lipid homeostasis as therapeutic targets in neurodegeneration with brain iron accumulation

    Science.gov (United States)

    Kinghorn, Kerri J.; Castillo-Quan, Jorge Iván

    2016-01-01

    ABSTRACT The PLA2G6 gene encodes a group VIA calcium independent phospholipase A2 (iPLA2β), which hydrolyses glycerophospholipids to release fatty acids and lysophospholipids. Mutations in PLA2G6 are associated with a number of neurodegenerative disorders including neurodegeneration with brain iron accumulation (NBIA), infantile neuroaxonal dystrophy (INAD), and dystonia parkinsonism, collectively known as PLA2G6-associated neurodegeneration (PLAN). Recently Kinghorn et al. demonstrated in Drosophila and PLA2G6 mutant fibroblasts that loss of normal PLA2G6 activity is associated with mitochondrial dysfunction and mitochondrial lipid peroxidation. Furthermore, they were able to show the beneficial effects of deuterated polyunsaturated fatty acids (D-PUFAs), which reduce lipid peroxidation. D-PUFAs were able to rescue the locomotor deficits of flies lacking the fly ortholog of PLA2G6 (iPLA2-VIA), as well as the mitochondrial abnormalities in PLA2G6 mutant fibroblasts. This work demonstrated that the iPLA2-VIA knockout fly is a useful organism to dissect the mechanisms of pathogenesis of PLAN, and that further investigation is required to determine the therapeutic potential of D-PUFAs in patients with PLA2G6 mutations. The fruit fly has also been used to study some of the other genetic causes of NBIA, and here we also describe what is known about the mechanisms of pathogenesis of these NBIA variants. Mitochondrial dysfunction, defects in lipid metabolism, as well as defective Coenzyme A (CoA) biosynthesis, have all been implicated in some genetic forms of NBIA, including PANK2, CoASY, C12orf19 and FA2H.

  19. Behavioral stress reduces RIP140 expression in astrocyte and increases brain lipid accumulation

    OpenAIRE

    Feng, Xudong; Lin, Yu-Lung; Wei, Li-Na

    2015-01-01

    Receptor-interacting protein 140 (RIP140) is highly expressed in the brain, and acts in neurons and microglia to affect emotional responses. The present study reveals an additional function of RIP140 in the brain, which is to regulate brain lipid homeostasis via its action in astrocytes. We found forced swim stress (FSS) significantly reduces the expression level of RIP140 and elevates cholesterol content in the brain. Mechanistically, FSS elevates endoplasmic reticulum stress, which suppress...

  20. Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure.

    Science.gov (United States)

    Ye, Qi; Kim, Jonghan

    2016-06-01

    Increased accumulation of manganese (Mn) in the brain is significantly associated with neurobehavioral deficits and impaired brain function. Airborne Mn has a high systemic bioavailability and can be directly taken up into the brain, making it highly neurotoxic. While Mn transport is in part mediated by several iron transporters, the expression of these transporters is altered by the iron regulatory gene, HFE. Mutations in the HFE gene are the major cause of the iron overload disorder, hereditary hemochromatosis, one of the prevalent genetic diseases in humans. However, whether or not HFE mutation modifies Mn-induced neurotoxicity has not been evaluated. Therefore, our goal was to define the role of HFE mutation in Mn deposition in the brain and the resultant neurotoxic effects after olfactory Mn exposure. Mice carrying the H67D HFE mutation, which is homologous to the H63D mutation in humans, and their control, wild-type mice, were intranasally instilled with MnCl2 with different doses (0, 0.2, 1.0 and 5.0 mg kg(-1)) daily for 3 days. Mn levels in the blood, liver and brain were determined using inductively-coupled plasma mass spectrometry (ICP-MS). H67D mutant mice showed significantly lower Mn levels in the blood, liver, and most brain regions, especially in the striatum, while mice fed an iron-overload diet did not. Moreover, mRNA expression of ferroportin, an essential exporter of iron and Mn, was up-regulated in the striatum. In addition, the levels of isoprostane, a marker of lipid peroxidation, were increased in the striatum after Mn exposure in wild-type mice, but were unchanged in H67D mice. Together, our results suggest that the H67D mutation provides decreased susceptibility to Mn accumulation in the brain and neurotoxicity induced by inhaled Mn. PMID:27295312

  1. Ammonium accumulation and cell death in a rat 3D brain cell model of glutaric aciduria type I.

    Directory of Open Access Journals (Sweden)

    Paris Jafari

    Full Text Available Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency is an inborn error of metabolism that usually manifests in infancy by an acute encephalopathic crisis and often results in permanent motor handicap. Biochemical hallmarks of this disease are elevated levels of glutarate and 3-hydroxyglutarate in blood and urine. The neuropathology of this disease is still poorly understood, as low lysine diet and carnitine supplementation do not always prevent brain damage, even in early-treated patients. We used a 3D in vitro model of rat organotypic brain cell cultures in aggregates to mimic glutaric aciduria type I by repeated administration of 1 mM glutarate or 3-hydroxyglutarate at two time points representing different developmental stages. Both metabolites were deleterious for the developing brain cells, with 3-hydroxyglutarate being the most toxic metabolite in our model. Astrocytes were the cells most strongly affected by metabolite exposure. In culture medium, we observed an up to 11-fold increase of ammonium in the culture medium with a concomitant decrease of glutamine. We further observed an increase in lactate and a concomitant decrease in glucose. Exposure to 3-hydroxyglutarate led to a significantly increased cell death rate. Thus, we propose a three step model for brain damage in glutaric aciduria type I: (i 3-OHGA causes the death of astrocytes, (ii deficiency of the astrocytic enzyme glutamine synthetase leads to intracerebral ammonium accumulation, and (iii high ammonium triggers secondary death of other brain cells. These unexpected findings need to be further investigated and verified in vivo. They suggest that intracerebral ammonium accumulation might be an important target for the development of more effective treatment strategies to prevent brain damage in patients with glutaric aciduria type I.

  2. Development of quantitative analysis method for stereotactic brain image. Assessment of reduced accumulation in extent and severity using anatomical segmentation

    International Nuclear Information System (INIS)

    Through visual assessment by three-dimensional (3D) brain image analysis methods using stereotactic brain coordinates system, such as three-dimensional stereotactic surface projections and statistical parametric mapping, it is difficult to quantitatively assess anatomical information and the range of extent of an abnormal region. In this study, we devised a method to quantitatively assess local abnormal findings by segmenting a brain map according to anatomical structure. Through quantitative local abnormality assessment using this method, we studied the characteristics of distribution of reduced blood flow in cases with dementia of the Alzheimer type (DAT). Using twenty-five cases with DAT (mean age, 68.9 years old), all of whom were diagnosed as probable Alzheimer's disease based on National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA), we collected I-123 iodoamphetamine SPECT data. A 3D brain map using the 3D-stereotactic surface projections (SSP) program was compared with the data of 20 cases in the control group, who age-matched the subject cases. To study local abnormalities on the 3D images, we divided the whole brain into 24 segments based on anatomical classification. We assessed the extent of an abnormal region in each segment (rate of the coordinates with a Z-value that exceeds the threshold value, in all coordinates within a segment), and severity (average Z-value of the coordinates with a Z-value that exceeds the threshold value). This method clarified orientation and expansion of reduced accumulation, through classifying stereotactic brain coordinates according to the anatomical structure. This method was considered useful for quantitatively grasping distribution abnormalities in the brain and changes in abnormality distribution. (author)

  3. Harmful effects of nicotine.

    Science.gov (United States)

    Mishra, Aseem; Chaturvedi, Pankaj; Datta, Sourav; Sinukumar, Snita; Joshi, Poonam; Garg, Apurva

    2015-01-01

    With the advent of nicotine replacement therapy, the consumption of the nicotine is on the rise. Nicotine is considered to be a safer alternative of tobacco. The IARC monograph has not included nicotine as a carcinogen. However there are various studies which show otherwise. We undertook this review to specifically evaluate the effects of nicotine on the various organ systems. A computer aided search of the Medline and PubMed database was done using a combination of the keywords. All the animal and human studies investigating only the role of nicotine were included. Nicotine poses several health hazards. There is an increased risk of cardiovascular, respiratory, gastrointestinal disorders. There is decreased immune response and it also poses ill impacts on the reproductive health. It affects the cell proliferation, oxidative stress, apoptosis, DNA mutation by various mechanisms which leads to cancer. It also affects the tumor proliferation and metastasis and causes resistance to chemo and radio therapeutic agents. The use of nicotine needs regulation. The sale of nicotine should be under supervision of trained medical personnel. PMID:25810571

  4. Harmful effects of nicotine

    Directory of Open Access Journals (Sweden)

    Aseem Mishra

    2015-01-01

    Full Text Available With the advent of nicotine replacement therapy, the consumption of the nicotine is on the rise. Nicotine is considered to be a safer alternative of tobacco. The IARC monograph has not included nicotine as a carcinogen. However there are various studies which show otherwise. We undertook this review to specifically evaluate the effects of nicotine on the various organ systems. A computer aided search of the Medline and PubMed database was done using a combination of the keywords. All the animal and human studies investigating only the role of nicotine were included. Nicotine poses several health hazards. There is an increased risk of cardiovascular, respiratory, gastrointestinal disorders. There is decreased immune response and it also poses ill impacts on the reproductive health. It affects the cell proliferation, oxidative stress, apoptosis, DNA mutation by various mechanisms which leads to cancer. It also affects the tumor proliferation and metastasis and causes resistance to chemo and radio therapeutic agents. The use of nicotine needs regulation. The sale of nicotine should be under supervision of trained medical personnel.

  5. The occurrence of diffuse axonal injury in the brain:associated with the accumulation and clearance of myelin debris

    Institute of Scientific and Technical Information of China (English)

    Liang Wen; Jun Xu; Tianxiang Zhan; Hao Wang; Xin Huang; Wenchao Liu; Xiaofeng Yang; Renya Zhan

    2014-01-01

    The accumulation of myelin debris may be a major contributor to the inlfammatory response after diffuse axonal injury. In this study, we examined the accumulation and clearance of myelin debris in a rat model of diffuse axonal injury. Oil Red O staining was performed on sections from the cerebral cortex, hippocampus and brain stem to identify the myelin debris. Seven days after diffuse axonal injury, many Oil Red O-stained particles were observed in the cerebral cortex, hippocampus and brain stem. In the cerebral cortex and hippocampus, the amount of myelin debris peaked at 14 days after injury, and decreased signiifcantly at 28 days. In the brain stem, the amount of myelin debris peaked at 7 days after injury, and decreased signiifcantly at 14 and 28 days. In the cortex and hippocampus, some myelin debris could still be observed at 28 days after diffuse axonal injury. Our ifndings suggest that myelin debris may persist in the rat central ner-vous system after diffuse axonal injury, which would hinder recovery.

  6. Vulnerability to nicotine self-administration in adolescent mice correlates with age-specific expression of α4* nicotinic receptors.

    Science.gov (United States)

    Renda, Anthony; Penty, Nora; Komal, Pragya; Nashmi, Raad

    2016-09-01

    The majority of smokers begin during adolescence, a developmental period with a high susceptibility to substance abuse. Adolescents are affected differently by nicotine compared to adults, with adolescents being more vulnerable to nicotine's rewarding properties. It is unknown if the age-dependent molecular composition of a younger brain contributes to a heightened susceptibility to nicotine addiction. Nicotine, the principle pharmacological component of tobacco, binds and activates nicotinic acetylcholine receptors (nAChRs) in the brain. The most prevalent is the widely expressed α4-containing (α4*) subtype which mediates reward and is strongly implicated in nicotine dependence. Exposing different age groups of mice, postnatal day (P) 44-86 days old, to a two bottle-choice oral nicotine self-administration paradigm for five days yielded age-specific consumption levels. Nicotine self-administration was elevated in the P44 group, peaked at P54-60 and was drastically lower in the P66 through P86 groups. We also quantified α4* nAChR expression via spectral confocal imaging of brain slices from α4YFP knock-in mice, in which the α4 nAChR subunit is tagged with a yellow fluorescent protein. Quantitative fluorescence revealed age-specific α4* nAChR expression in dopaminergic and GABAergic neurons of the ventral tegmental area. Receptor expression showed a strong positive correlation with daily nicotine dose, suggesting that α4* nAChR expression levels are age-specific and may contribute to the propensity to self-administer nicotine. PMID:27102349

  7. Anti-nicotine vaccine: current status

    Directory of Open Access Journals (Sweden)

    Vishal Prakash Giri

    2015-12-01

    Full Text Available Tobacco abuse has an enormous impact on health. Nicotine is the main substance responsible for dependence on tobacco-containing products. The vast majority of cigarette smokers who try to quit ultimately fail because of high relapse rates. Clearly, novel approaches are needed for the treatment and prevention of nicotine addiction. Having an efficient vaccine that would generate antibodies to sequester the drug and prevent its access to the brain could go a long way toward helping a motivated addict quit an addiction. [Int J Basic Clin Pharmacol 2015; 4(6.000: 1309-1313

  8. Nicotine and sympathetic neurotransmission.

    Science.gov (United States)

    Haass, M; Kübler, W

    1997-01-01

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

  9. Behavioral and molecular analysis of nicotine-conditioned place preference in zebrafish.

    Directory of Open Access Journals (Sweden)

    Ximena Kedikian

    Full Text Available Studies using mice and rats have demonstrated that nicotine induces a conditioned place preference (CPP, with more effective results obtained by using biased procedures. Zebrafish have also been used as a model system to identify factors influencing nicotine-associated reward by using an unbiased design. Here, we report that zebrafish exhibited putative nicotine biased CPP to an initially aversive compartment (nicotine-paired group. A counterbalanced nicotine-exposed control group did not show a significant preference shift, providing evidence that the preference shift in the nicotine-paired group was not due to a reduction of aversion for this compartment. Zebrafish preference was corroborated by behavioral analysis of several indicators of drug preference, such as time spent in the drug-paired side, number of entries to the drug-paired side, and distance traveled. These results provided strong evidence that zebrafish may actually develop a preference for nicotine, although the drug was administrated in an aversive place for the fish, which was further supported by molecular studies. Reverse transcription-quantitative real-time PCR analysis depicted a significant increase in the expression of α7 and α6 but not α4 and β2 subunits of the nicotinic receptor in nicotine-paired zebrafish brains. In contrast, zebrafish brains from the counterbalanced nicotine group showed no significant changes. Moreover, CREB phosphorylation, an indicator of neural activity, accompanied the acquisition of nicotine-CPP. Our studies offered an incremental value to the drug addiction field, because they further describe behavioral features of CPP to nicotine in zebrafish. The results suggested that zebrafish exposed to nicotine in an unfriendly environment can develop a preference for that initially aversive place, which is likely due to the rewarding effect of nicotine. Therefore, this model can be used to screen exogenous and endogenous molecules involved in

  10. Mechanism-based medication development for the treatment of nicotine dependence

    Institute of Scientific and Technical Information of China (English)

    Zheng-xiong XI; Krista SPILLER; Eliot L GARDNER

    2009-01-01

    Tobacco use is a global problem with serious health consequences. Though some treatment options exist, there remains a great need for new effective pharmacotherapies to aid smokers in maintaining long-term abstinence. In the present article, we first discuss the neural mechanisms underlying nicotine reward, and then review various mechanism-based pharmacological agents for the treatment of nicotine dependence. An oversimplified hypothesis of addiction to tobacco is that nicotine is the major addictive component of tobacco. Nicotine binds to a4β2 and a7 nicotinic acetylcholine receptors (nAChRs) located on dopaminergic, glutamatergic and GABAergic neurons in the mesolimbic dopamine (DA) system, which causes an increase in extracellular DA in the nucleus accumbens (NAc). That increase in DA reinforces tobacco use, particularly during the acquisition phase. Enhanced glutamate transmission to DA neurons in the ventral tegmental area appears to play an important role in this process. In addition, chronic nicotine treatment increases endocannabinoid levels in the mesolimbic DA system, which indirectly modulates NAc DA release and nicotine reward. Accordingly, pharmacological agents that target brain acetylcholine, DA, glutamate, GABA, or endocannabonoid signaling systems have been proposed to interrupt nicotine action. Furthermore, pharmacokinetic strategies that alter plasma nicotine availability, metabolism and clearance also significantly alter nicotine's action in the brain. Progress using these pharmacodynamic and pharmacokinetic agents is reviewed. For drugs in each category, we discuss the mechanistic rationale for their potential anti-nicotine efficacy, major findings in preclinical and clinical studies, and future research directions.

  11. In vivo imaging of nicotinic receptor upregulation following chronic (-)-nicotine treatment in baboon using SPECT

    International Nuclear Information System (INIS)

    To quantify changes in neuronal nAChR binding in vivo, quantitative dynamic SPECT studies were performed with 5-[123I]-iodo-A-85380 in baboons pre and post chronic treatment with (-)-nicotine or saline control. Infusion of (-)-nicotine at a dose of 2.0 mg/kg/24h for 14 days resulted in plasma (-)-nicotine levels of 27.3 ng/mL. This is equivalent to that found in an average human smoker (20 cigarettes a day). In the baboon brain the regional distribution of 5-[123I]-iodo-A-85380 was consistent with the known densities of nAChRs (thalamus > frontal cortex > cerebellum). Changes in nAChR binding were estimated from the volume of distribution (Vd ) and binding potential (BP) derived from 3-compartment model fits. In the (-)-nicotine treated animal Vd was significantly increased in the thalamus (52%) and cerebellum (50%) seven days post cessation of (-)-nicotine treatment, suggesting upregulation of nAChRs. The observed 33% increase in the frontal cortex failed to reach significance. A significant increase in BP was seen in the thalamus. In the saline control animal no changes were observed in Vd or BP under any experimental conditions. In this preliminary study, we have demonstrated for the first time in vivo upregulation of neuronal nAChR binding following chronic (-)-nicotine treatment

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

    International Nuclear Information System (INIS)

    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. - Graphical abstract: Nicotine inhibits melanogenesis and induces oxidative stress in HEMn-LP melanocytes. - Highlights: • Nicotine induces concentration-dependent loss in melanocytes viability. • Nicotine in non-cytotoxic concentrations inhibits melanogenesis. • Nicotine in higher concentrations induces oxidative stress

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

    Energy Technology Data Exchange (ETDEWEB)

    Delijewski, Marcin; Beberok, Artur; Otręba, Michał; Wrześniok, Dorota; Rok, Jakub; Buszman, Ewa, E-mail: ebuszman@sum.edu.pl

    2014-10-15

    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 EC{sub 50} 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. - Graphical abstract: Nicotine inhibits melanogenesis and induces oxidative stress in HEMn-LP melanocytes. - Highlights: • Nicotine induces concentration-dependent loss in melanocytes viability. • Nicotine in non-cytotoxic concentrations inhibits melanogenesis. • Nicotine in higher concentrations induces oxidative stress.

  14. Neurotensin Agonist Attenuates Nicotine Potentiation to Cocaine Sensitization

    Directory of Open Access Journals (Sweden)

    Paul Fredrickson

    2014-01-01

    Full Text Available 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.

  15. In vivo positron emission tomography studies on the novel nicotinic receptor agonist [11C]MPA compared with [11C]ABT-418 and (S)(-)[11C]nicotine in Rhesus monkeys

    International Nuclear Information System (INIS)

    The novel 11C-labeled nicotinic agonist (R,S)-1-[11C]methyl-2(3-pyridyl)azetidine ([11C]MPA) was evaluated as a positron emission tomography (PET) ligand for in vivo characterization of nicotinic acetylcholine receptors in the brain of Rhesus monkeys in comparison with the nicotinic ligands (S)-3-methyl-5-(1-[11C]methyl-2-pyrrolidinyl)isoxazol ([11C]ABT-418) and (S)(-)[11C]nicotine. The nicotinic receptor agonist [11C]MPA demonstrated rapid uptake into the brain to a similar extent as (S)(-) [11C]nicotine and [11C]ABT-418. When unlabeled (S)(-)nicotine (0.02 mg/kg) was administered 5 min before the radioactive tracers, the uptake of [11C]MPA was decreased by 25% in the thalamus, 19% in the temporal cortex, and 11% in the cerebellum, whereas an increase was found for the uptake of (S)(-)[11C]nicotine and [11C]ABT-418. This finding indicates specific binding of [11C]MPA to nicotinic receptors in the brain in a simple classical displacement study. [11C]MPA seems to be a more promising radiotracer than (S)(-)[11C]nicotine or [11C]ABT-418 for PET studies to characterize nicotinic receptors in the brain

  16. Nicotinic receptors in addiction pathways.

    Science.gov (United States)

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

    2013-04-01

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

  17. Ethanol-nicotine interactions in long-sleep and short-sleep mice

    Energy Technology Data Exchange (ETDEWEB)

    de Fiebre, C.M.; Marks, M.J.; Collins, A.C. (Univ. of Colorado, Boulder (USA))

    1990-05-01

    The possibility that common genetic factors regulate initial sensitivities to ethanol and nicotine as well as the development of cross-tolerance between these agents was explored using the long-sleep (LS) and short-sleep (SS) mice. The LS mice proved to be more sensitive to an acute challenge with nicotine than were the SS mice. Segregation analysis (F1, F2, backcross) indicated that ethanol sensitivity and nicotine sensitivity segregate together. Acute pretreatment with nicotine did not significantly affect sensitivity to ethanol, but ethanol pretreatment altered nicotine responsiveness. The LS mice develop more tolerance to nicotine and ethanol than do the SS and they also develop more cross-tolerance. These genetically determined differences in initial sensitivities, and tolerance and cross-tolerance development are not readily explained by differences in brain nicotinic receptor numbers.

  18. TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

    OpenAIRE

    McColl, Alison; Thomson, Carolyn A.; Nerurkar, Louis; Graham, Gerard J.; Cavanagh, Jonathan

    2016-01-01

    Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding t...

  19. TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

    OpenAIRE

    McColl, Alison; Thomson, Carolyn A.; Nerurkar, Louis; Graham, Gerard J.; Cavanagh, Jonathan

    2016-01-01

    Background The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that i...

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

    OpenAIRE

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

    2014-01-01

    We tested the hypothesis that nicotine, which acts peripherally to promote coughing, might inhibit reflex cough at a central site. Nicotine was administered via the vertebral artery [intra-arterial (ia)] to the brain stem circulation and by microinjections into a restricted area of the caudal ventral respiratory column in 33 pentobarbital anesthetized, spontaneously breathing cats. The number of coughs induced by mechanical stimulation of the tracheobronchial airways; amplitudes of the diaphr...

  1. The Yin and Yang of nicotine: harmful during development, beneficial in adult patient populations

    Directory of Open Access Journals (Sweden)

    Danielle S Counotte

    2012-10-01

    Full Text Available Nicotine has remarkably diverse effects on the brain. Being the main active compound in tobacco, nicotine can aversively affect brain development. However, it has the ability to act positively by restoring attentional capabilities in smokers. Here, we focus on nicotine exposure during the prenatal and adolescent developmental periods and specifically, we will review the long-lasting effects of nicotine on attention, both in humans and animal models. We discuss the reciprocal relation of the beneficial effects of nicotine, improving attention in smokers and in patients with neuropsychiatric diseases, such as schizophrenia and attention deficit/hyperactivity disorder, versus nicotine-related attention deficits already caused during adolescence. Given the need for research on the mechanisms of nicotine’s cognitive actions, we discuss some of the recent work performed in animals.

  2. Synthesis of 4,4-ditritio-(+)-nicotine: comparative binding and distribution studies with natural enantiomer

    International Nuclear Information System (INIS)

    The preparation of 4,4-ditritio-(+)-nicotine (Vb) (specific activity 10.3 Ci/mmole)from (+)-nicotine (Ib) via (-) 4,4-dibromocotinine (IIIb) is described. Although Ib is 10-30 times less potent than (-)-nicotine (Ia) in the CNS, its binding affinity for the crude mitochondrial or nuclear fraction of whole rat brain is only three times less than that of Ia. However, distribution studies showed that the maximum brain levels of (-)-[3H] nicotine are nearly twice those of (+)-[3H]-nicotine following administration of a 2-micrograms/kg dose. Binding affinity and disposition of the stereoisomers account for a portion of the pharmacological stereospecificity of nicotine

  3. Delta-9-tetrahydrocannabinol accumulation, metabolism and cell-type-specific adverse effects in aggregating brain cell cultures

    International Nuclear Information System (INIS)

    Despite the widespread use of Cannabis as recreational drug or as medicine, little is known about its toxicity. The accumulation, metabolism and toxicity of THC were analyzed 10 days after a single treatment, and after repeated exposures during 10 days. Mixed-cell aggregate cultures of fetal rat telencephalon were used as in vitro model, as well as aggregates enriched either in neurons or in glial cells. It was found that THC accumulated preferentially in neurons, and that glia-neuron interactions decreased THC accumulation. The quantification of 11-OH-THC and of THC-COOH showed that brain aggregates were capable of THC metabolism. No cell-type difference was found for the metabolite 11-OH-THC, whereas the THC-COOH content was higher in mixed-cell cultures. No cell death was found at THC concentrations of 2 μM in single treatment and of 1 μM and 2 μM in repeated treatments. Neurons, and particularly GABAergic neurons, were most sensitive to THC. Only the GABAergic marker was affected after the single treatment, whereas the GABAergic, cholinergic and astrocytic markers were decreased after the repeated treatments. JWH 015, a CB2 receptor agonist, showed effects similar to THC, whereas ACEA, a CB1 receptor agonist, had no effect. The expression of the cytokine IL-6 was upregulated 48 h after the single treatment with 5 μM of THC or JWH 015, whereas the expression of TNF-α remained unchanged. These results suggest that the adverse effects of THC were related either to THC accumulation or to cannabinoid receptor activation and associated with IL-6 upregulation

  4. Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors

    OpenAIRE

    Melis, Miriam; Pillolla, Giuliano; Luchicchi, Antonio; Muntoni, Anna Lisa; Yasar, Sevil; Goldberg, Steven R.; Pistis, Marco

    2008-01-01

    Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological ...

  5. Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains.

    Science.gov (United States)

    Kametani, Fuyuki; Obi, Tomokazu; Shishido, Takeo; Akatsu, Hiroyasu; Murayama, Shigeo; Saito, Yuko; Yoshida, Mari; Hasegawa, Masato

    2016-01-01

    TDP-43 is the major disease-associated protein involved in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions linked to TDP-43 pathology (FTLD-TDP). Abnormal phosphorylation, truncation and cytoplasmic mis-localization are known to be the characteristics for the aggregated forms of TDP-43, and gain of toxic abnormal TDP-43 or loss of function of physiological TDP-43 have been suggested as the cause of neurodegeneration. However, most of the post-translational modifications or truncation sites in the abnormal TDP-43 in brains of patients remain to be identified by protein chemical analysis. In this study, we carried out a highly sensitive liquid chromatography-mass spectrometry analysis of Sarkosyl-insoluble pathological TDP-43 from brains of ALS patients and identified several novel phosphorylation sites, deamidation sites, and cleavage sites. Almost all modifications were localized in the Gly-rich C-terminal half. Most of the cleavage sites identified in this study are novel and are located in N-terminal half, suggesting that these sites may be more accessible to proteolytic enzymes. The data obtained in this study provide a foundation for the molecular mechanisms of TDP-43 aggregation and ALS pathogenesis. PMID:26980269

  6. Neuronal Nicotinic Acetylcholine Receptors: Neuroplastic Changes underlying Alcohol and Nicotine Addictions

    Directory of Open Access Journals (Sweden)

    Allison Anne Feduccia

    2012-08-01

    Full Text Available 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.

  7. Does brain drain cause human capital accumulation%人才外流促进人力资本积累

    Institute of Scientific and Technical Information of China (English)

    王德劲

    2011-01-01

    在VAR模型框架内,检验了我国人力资本与高教育移民率之间的Granger因果关系,估计了两者之间的传递函数模型,证实了人才外流促进人力资本积累的“正”经济效应的存在,并分析了移民率变化对人力资本存量增长的传递机制。%The Granger causality between human capital and immigrants with higher eduction is tested and measured in the framenork of VAR model system, and the transfer function model between two of them is estimated. The positive effect that brain drain induces human capital accumulation is confirmed, and its transfer mechanism is analyzed.

  8. The pattern of amyloid accumulation in the brains of adults with Down syndrome

    Science.gov (United States)

    Annus, Tiina; Wilson, Liam R.; Hong, Young T.; Acosta–Cabronero, Julio; Fryer, Tim D.; Cardenas–Blanco, Arturo; Smith, Robert; Boros, Istvan; Coles, Jonathan P.; Aigbirhio, Franklin I.; Menon, David K.; Zaman, Shahid H.; Nestor, Peter J.; Holland, Anthony J.

    2016-01-01

    Introduction Adults with Down syndrome (DS) invariably develop Alzheimer's disease (AD) neuropathology. Understanding amyloid deposition in DS can yield crucial information about disease pathogenesis. Methods Forty-nine adults with DS aged 25–65 underwent positron emission tomography with Pittsburgh compound–B (PIB). Regional PIB binding was assessed with respect to age, clinical, and cognitive status. Results Abnormal PIB binding became evident from 39 years, first in striatum followed by rostral prefrontal-cingulo-parietal regions, then caudal frontal, rostral temporal, primary sensorimotor and occipital, and finally parahippocampal cortex, thalamus, and amygdala. PIB binding was related to age, diagnostic status, and cognitive function. Discussion PIB binding in DS, first appearing in striatum, began around age 40 and was strongly associated with dementia and cognitive decline. The absence of a substantial time lag between amyloid accumulation and cognitive decline contrasts to sporadic/familial AD and suggests this population's suitability for an amyloid primary prevention trial. PMID:26362596

  9. Triethyllead treatment of cultured brain cells. Effect on accumulation of radioactive precursors in galactolipids

    Energy Technology Data Exchange (ETDEWEB)

    Grundt, I.K.; Ammitzboll, T.; Clausen, J.

    1981-02-01

    Cultured cells from chick embryo brains were studied for their sensitivity to triethyllead. Triethyllead chloride (3.16 microM) was added to the nutrient medium and incubated for 48 hr with the cells. Morphological changes in light microscope and radioactive labeling of galactolipids were assayed. Triethyllead treatment reduced the number of neuronal cells with processes. Morphological changes were not observed in glial cells. The (/sup 35/S)sulfate labeling of sulfatides was reduced to 50%. The (/sup 3/H)serine labeling of cerebrosides with alpha-hydroxy fatty acids was not influenced, while the (/sup 3/H)serine labeling of cerebrosides with nonhydroxy fatty acids was inhibited 40% in one- and two- but not in three-week-old cultures. The results indicate that the nerve cell response to triethyllead in cultures is selective, since the neurons are more sensitive than the glia cells and the labeling of sulfatides is more sensitive than that of cerebrosides.

  10. Neuronal nicotinic acetylcholine receptors: Common molecular substrates of nicotine and alcohol dependence

    Directory of Open Access Journals (Sweden)

    AndrewR.Tapper

    2013-04-01

    Full Text Available Alcohol and nicotine are often co-abused. As many as 80-95% of alcoholics are also smokers, suggesting that ethanol and nicotine, the primary addictive component of tobacco smoke, may functionally interact in the central nervous system and/or share a common mechanism of action. While nicotine initiates dependence by binding to and activating neuronal nicotinic acetylcholine receptors (nAChRs, ligand-gated cation channels normally activated by endogenous acetylcholine (ACh, ethanol is much less specific with the ability to modulate multiple gene products including those encoding voltage-gated ion channels, and excitatory/inhibitory neurotransmitter receptors. However, emerging data indicate that ethanol interacts with nAChRs, both directly and indirectly, in the mesocorticolimbic dopaminergic (DAergic reward circuitry to affect brain reward systems. Like nicotine, ethanol activates DAergic neurons of the ventral tegmental area (VTA which project to the nucleus accumbens (NAc. Blockade of VTA nAChRs reduces ethanol-mediated activation of DAergic neurons, NAc DA release, consumption, and operant responding for ethanol in rodents. Thus, ethanol may increase ACh release into the VTA driving activation of DAergic neurons through nAChRs. In addition, ethanol potentiates distinct nAChR subtype responses to ACh and nicotine in vitro and in DAergic neurons. The smoking cessation therapeutic and nAChR partial agonist, varenicline, reduces alcohol consumption in heavy drinking smokers and rodent models of alcohol consumption. Finally, single nucleotide polymorphisms in nAChR subunit genes are associated with alcohol dependence phenotypes and smoking behaviors in human populations. Together, results from preclinical, clinical, and genetic studies indicate that nAChRs may have an inherent role in the abusive properties of ethanol, as well as in nicotine and alcohol co-dependence.

  11. Neuronal nicotinic acetylcholine receptors serve as sensitive targets that mediate β-amyloid neurotoxicity

    Institute of Scientific and Technical Information of China (English)

    Qiang LIU; Jie WU

    2006-01-01

    Alzheimer's disease (AD) is the most common form of brain dementia characterized by the accumulation of β-amyloid peptides (Aβ) and loss of forebrain cholinergic neurons. Aβ accumulation and aggregation are thought to contribute to cholinergic neuronal degeneration, in turn causing learning and memory deficits, but the specific targets that mediate Aβ neurotoxicity remain elusive. Recently, accumlating lines of evidence have demonstrated that Aβ directly modulates the function of neuronal nicotinic acetylcholine receptors (nAChRs), which leads to the new hypothesis that neuronal nAChRs may serve as important targets that mediate Aβ neurotoxicity. In this review, we summarize current studies performed in our laboratory and in others to address the question of how Aβ modulates neuronal nAChRs, especially nAChR subunit function.

  12. Effects of nicotine on regional cerebral glucose metabolism in awake resting tobacco smokers.

    Science.gov (United States)

    Domino, E F; Minoshima, S; Guthrie, S K; Ohl, L; Ni, L; Koeppe, R A; Cross, D J; Zubieta, J

    2000-01-01

    Eleven healthy tobacco smoking adult male volunteers of mixed race were tobacco abstinent overnight for this study. In each subject, positron emission tomographic images of regional cerebral metabolism of glucose with [18F]fluorodeoxyglucose were obtained in two conditions in the morning on different days: about 3min after approximately 1-2mg of nasal nicotine spray and after an equivalent volume of an active placebo spray of oleoresin of pepper in a random counterbalanced design. A Siemens/CTI 931/08-12 scanner with the capability of 15 horizontal brain slices was used. The images were further converted into a standard uniform brain format in which the mean data of all 11 subjects were obtained. Images were analysed in stereotactic coordinates using pixel-wise t statistics and a smoothed Gaussian model. Peak plasma nicotine levels varied three-fold and the areas under the curve(0-30min) varied seven-fold among the individual subjects. Nicotine caused a small overall reduction in global cerebral metabolism of glucose but, when the data were normalized, several brain regions showed relative increases in activity. Cerebral structures specifically activated by nicotine (nicotine minus pepper, Z score >4.0) included: left inferior frontal gyrus, left posterior cingulate gyrus and right thalamus. The visual cortex, including the right and left cuneus and left lateral occipito-temporal gyrus fusiformis, also showed an increase in regional cerebral metabolism of glucose with Z scores >3. 6. Structures with a decrease in regional cerebral metabolism of glucose (pepper minus nicotine) were the left insula and right inferior occipital gyrus, with Z scores >3.5. Especially important is the fact that the thalamus is activated by nicotine. This is consistent with the high density of nicotinic cholinoceptors in that brain region. However, not all brain regions affected by nicotine are known to have many nicotinic cholinoceptors. The results are discussed in relation to the

  13. A reduced cerebral metabolic ratio in exercise reflects metabolism and not accumulation of lactate within the human brain

    DEFF Research Database (Denmark)

    Dalsgaard, Mads K; Quistorff, Bjørn; Danielsen, Else R;

    2003-01-01

    During maximal exercise lactate taken up by the human brain contributes to reduce the cerebral metabolic ratio, O(2)/(glucose + 1/2 lactate), but it is not known whether the lactate is metabolized or if it accumulates in a distribution volume. In one experiment the cerebral arterio......-venous differences (AV) for O(2), glucose (glc) and lactate (lac) were evaluated in nine healthy subjects at rest and during and after exercise to exhaustion. The cerebrospinal fluid (CSF) was drained through a lumbar puncture immediately after exercise, while control values were obtained from six other healthy...... young subjects. In a second experiment magnetic resonance spectroscopy ((1)H-MRS) was performed after exhaustive exercise to assess lactate levels in the brain (n = 5). Exercise increased the AV(O2) from 3.2 +/- 0.1 at rest to 3.5 +/- 0.2 mM (mean +/-s.e.m.; P < 0.05) and the AV(glc) from 0.6 +/- 0.0 to...

  14. Chronic Nicotine Exposure Induces a Long-Lasting and Pathway-Specific Facilitation of LTP in the Amygdala

    Science.gov (United States)

    Huang, Yan-You; Kandel, Eric R.; Levine, Amir

    2008-01-01

    Nicotine, in the form of tobacco, is the most commonly used drug of abuse. In addition to its rewarding properties, nicotine also affects many cognitive and emotional processes that involve several brain regions, including hippocampus and amygdala. Long-term changes in synaptic strength in these brain regions after drug exposure may be importantly…

  15. The role of alpha4 containing nicotinic acetylcholine receptors in dopamine neurons

    OpenAIRE

    McGranahan, Tresa Michelle

    2011-01-01

    Nicotine is the primary psychoactive substance in tobacco and it exerts its effects by interaction with various subtypes of nicotinic acetylcholine receptors (nAChRs) in the brain. One of the major subtypes expressed in brain, the alpha4beta2-nAChR, endogenously modulates neuronal excitability and, thereby, modifies certain normal, as well as nicotine-induced, behaviors. Although alpha4- containing nAChRs are widely expressed across the brain, a major focus has been on their roles within midb...

  16. Neurocognitive Insights in Nicotine Addiction

    NARCIS (Netherlands)

    M. Luijten (Maartje)

    2012-01-01

    textabstractIn the Netherlands, 27% of the population is currently smoking. Nicotine is among the most addictive substances of abuse. Thirty-two percent of the people who tried smoking develop nicotine dependence within ten year. This percentage is higher for nicotine than for other substances of ab

  17. Tribute to: Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area [William Corrigall, Kathleen Coen and Laurel Adamson, Brain Res. 653 (1994) 278-284].

    Science.gov (United States)

    Leri, Francesco; Vaccarino, Franco J

    2016-08-15

    In this paper, Dr. Corrigall and collaborators described elegant experiments designed to elucidate the neurobiology of nicotine reinforcement. The nicotinic receptor antagonist dihydro-β-erythroidine (DHβE) was infused in the ventral tegmental area (VTA) or nucleus accumbens (NAC) of rats trained to self-administer nicotine intravenously. Additionally, DHβE was infused in the VTA of rats trained to self-administer food or cocaine, and nicotine self-administration was assessed in rats with lesions to the peduculopontine tegmental nucleus (PPT). A number of key themes emerged from this fundamental study that remain relevant today. The primary finding was that infusions of DHβE in the VTA, but not in the NAC, lowered nicotine self-administration, suggesting that nicotinic receptors in VTA are involved in the reinforcing action of nicotine. This conclusion has been confirmed by subsequent findings, and the nature of the nicotinic receptors has also been elucidated. The authors also reported that DHβE in the VTA had no effect on food or cocaine self-administration, and that lesions to the PPT did not alter nicotine self-administration. Since this initial investigation, the question of whether nicotinic receptors in the VTA are necessary for the reinforcing action of other stimuli, and by which mechanisms, has been extensively explored. Similarly, many groups have further investigated the role of mesopontine cholinergic nuclei in reinforcement. This paper not only contributed in important ways to our understanding of the neurochemical basis of nicotine reinforcement, but was also a key catalyst that gave rise to several research themes central to the neuropharmacology of substance abuse. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID:26867702

  18. Radioiodination of nicotine with specific activity high enough for mapping nicotinic acetylcholine receptors

    International Nuclear Information System (INIS)

    A novel radiochemical method is presented to synthesize 5-[123I/125I/131I]-DL-nicotine by radioiodination of 5-bromonicotine. Radioiodination of the precursur 5-DL-bromonicotine was achieved using a copper (I)-assisted nucleophilic exchange reaction in the presence of reducing agent. The reaction conditions were optimized by varying pH, concentration of Sn(II) salt, ascorbic acid, Cu(I)chloride and reaction temperature. After purification by high-performance liquid chromatography the radiochemical purity of the product exceeded 98%, with a radiochemical yield of 55% and a specific activity ≥5 GBq/μmol. Specific binding of the iodinated nicotine was demonstrated in rate brain by autoradiography. The radioactivity from the specific structures was displaced by an excess of non-radioactive nicotine (10-3 M) with KD and Bmax of 13.1±7.8 nM and 22±2.7 fmol/mg protein and unspecific binding of about 40%. The in vivo distribution of 5-[131I]iodonicotine was determined in 20 female Wistar rats at various time intervals of 15 s to 90 min post injection (p.i.) by well counting and autoradiography. Brain activity peaked within 0.5 min p.i., and then showed a biexponential washout. Initially, activity within the cerebral cortex exceeded that of the cerebellum by a factor of 1.5-2.0. It was also increased in the striatum and thalamus. However, as soon as 15 min p.i. activity was almost homogeneously distributed. In conclusion, synthesis of 5-iodo-DL-nicotine (labelled with 131I, 125I or 123I, respectively) with appropriately high specific activity for receptor studies was achieved and specific binding to nicotine receptors in rat brain was demonstrated; following intravenous injection, however, there is considerable unspecific binding, obviously due to highly flow-dependent tissue retention. (orig.)

  19. Discriminability of personality profiles in isolated and Co-morbid marijuana and nicotine users.

    Science.gov (United States)

    Ketcherside, Ariel; Jeon-Slaughter, Haekyung; Baine, Jessica L; Filbey, Francesca M

    2016-04-30

    Specific personality traits have been linked with substance use disorders (SUDs), genetic mechanisms, and brain systems. Thus, determining the specificity of personality traits to types of SUD can advance the field towards defining SUD endophenotypes as well as understanding the brain systems involved for the development of novel treatments. Disentangling these factors is particularly important in highly co morbid SUDs, such as marijuana and nicotine use, so treatment can occur effectively for both. This study evaluated personality traits that distinguish isolated and co-morbid use of marijuana and nicotine. To that end, we collected the NEO Five Factor Inventory in participants who used marijuana-only (n=59), nicotine-only (n=27), both marijuana and nicotine (n=28), and in non-using controls (n=28). We used factor analyses to identify personality profiles, which are linear combinations of the five NEO Factors. We then conducted Receiver Operating Characteristics (ROC) curve analysis to test accuracy of the personality factors in discriminating isolated and co-morbid marijuana and nicotine users from each other. ROC curve analysis distinguished the four groups based on their NEO personality patterns. Results showed that NEO Factor 2 (openness, extraversion, agreeableness) discriminated marijuana and marijuana+nicotine users from controls and nicotine-only users with high predictability. Additional ANOVA results showed that the openness dimension discriminated marijuana users from nicotine users. These findings suggest that personality dimensions distinguish marijuana users from nicotine users and should be considered in prevention strategies. PMID:27086256

  20. Nicotine induces dendritic spine remodeling in cultured hippocampal neurons.

    Science.gov (United States)

    Oda, Akira; Yamagata, Kanato; Nakagomi, Saya; Uejima, Hiroshi; Wiriyasermkul, Pattama; Ohgaki, Ryuichi; Nagamori, Shushi; Kanai, Yoshikatsu; Tanaka, Hidekazu

    2014-01-01

    Cholinergic neurons in the CNS are involved in synaptic plasticity and cognition. Both muscarinic and nicotinic acetylcholine receptors (nAChRs) influence plasticity and cognitive function. The mechanism underlying nAChR-induced plasticity, however, has remained elusive. Here, we demonstrate morphological changes in dendritic spines following activation of α4β2* nAChRs, which are expressed on glutamatergic pre-synaptic termini of cultured hippocampal neurons. Exposure of the neurons to nicotine resulted in a lateral enlargement of spine heads. This was abolished by dihydro-β-erythroidine, an antagonist of α4β2* nAChRs, but not by α-bungarotoxin, an antagonist of α7 nAChRs. Tetanus toxin or a mixture of 2-amino-5-phosphonovaleric acid and 6-cyano-7-nitroquinoxaline-2,3-dione, antagonists of NMDA- and AMPA-type glutamate receptors, blocked the nicotine-induced spine remodeling. In addition, nicotine exerted full spine-enlarging response in the post-synaptic neuron whose β2 nAChR expression was knocked down. Finally, pre-treatment with nicotine enhanced the Ca(2+)-response of the neurons to glutamate. These data suggest that nicotine influences the activity of glutamatergic neurotransmission through the activation of pre-synaptic α4β2 nAChRs, resulting in the modulation of spinal architecture and responsiveness. The present findings may represent one of the cellular mechanisms underlying cholinergic tuning of brain function. Activation of nicotinic acetylcholine receptors (nAChRs) in brain influences plasticity and cognition. Here, activation of α4β2* nAChRs, which are expressed on glutamatergic presynaptic termini, results in the enlargement of dendritic spines through the modulation of the glutamatergic neurotransmission. The remodeled spinal architecture might be responsible for the change in responsiveness of neural circuitry, leading to cholinergic tuning of brain function. PMID:24117996

  1. Growth and development, nicotine concentrations and sources of nicotine-n in flue-cured tobacco plants influenced by basal n fertilization time and n fertilizer (15N)

    International Nuclear Information System (INIS)

    A field experiment with 15N isotope tracing micro-plots was carried out to study the effects of basal N fertilizer application time (15 d, 30 d before the transplanting) of flue-cured tobacco (FCT) seedlings and nitrogen fertilization (with N and without N) on growth and development, nicotine concentrations and sources of nicotine N of FCT in Laowan (N 31 degree 27', E 111 degree 14', 1 130 m above sea level), a main tobacco production area of Xiangfan city, Hubei province. The results showed that both dry matter accumulation and nicotine concentrations of different parts of FCT increased with growing of plants. The concentrations of nicotine decreased with the ascending of leaf position before topping period, but just opposite after the removal of apex. The proportion of nicotine N from fertilizer to total nicotine N decreased with growing of FCT plants and the rising of leaf position. Applying N fertilizer significantly increased dry matter accumulation of shoot and the nicotine concentrations of different poisional tobacco leaves by 2.1-2.7 fold and 0.1-0.7 fold respectively. Compared with the basal fertilization time 15 d before transplanting, applying basal fertilizer 30 d before transplanting increased the dry matter accumulation and nicotine concentrations of flue-cured tobacco by 2.2%-8.0% and 6.3%-18.5% respectively. There was no significant effects of basal N fertilization time on the proportion of nicotine-N from fertilizer in organs of FCT plants at mature stage. These results suggested that properly putting forward the basal N fertilization time before transplanting make for decrease of nicotine concentrations and improvement of quality of FCT leaves, so as to improve its industrial utilities. (authors)

  2. Nicotine consumption and schizotypy in first-degree relatives of individuals with schizophrenia and non-psychiatric controls

    OpenAIRE

    Esterberg, Michelle L.; Jones, Erin M.; Compton, Michael T.; Walker, Elaine F.

    2007-01-01

    Individuals with schizophrenia have very high rates of cigarette smoking, and much has been discovered about the influence of nicotine on brain functioning in schizophrenia. However, less is understood about the relationship between nicotine consumption and milder phenotypes related to schizophrenia, specifically schizotypy. This study examined the relationship between nicotine consumption and schizotypy in two unmedicated samples that included first-degree relatives and non-psychiatric contr...

  3. Localized low-level re-expression of high-affinity mesolimbic nicotinic acetylcholine receptors restores nicotine-induced locomotion but not place conditioning.

    Science.gov (United States)

    Mineur, Y S; Brunzell, D H; Grady, S R; Lindstrom, J M; McIntosh, J M; Marks, M J; King, S L; Picciotto, M R

    2009-04-01

    High-affinity, beta2-subunit-containing (beta2*) nicotinic acetylcholine receptors (nAChRs) are essential for nicotine reinforcement; however, these nAChRs are found on both gamma-aminobutyric acid (GABA) and dopaminergic (DA) neurons in the ventral tegmental area (VTA) and also on terminals of glutamatergic and cholinergic neurons projecting from the pedunculopontine tegmental area and the laterodorsal tegmental nucleus. Thus, systemic nicotine administration stimulates many different neuronal subtypes in various brain nuclei. To identify neurons in which nAChRs must be expressed to mediate effects of systemic nicotine, we investigated responses in mice with low-level, localized expression of beta2* nAChRs in the midbrain/VTA. Nicotine-induced GABA and DA release were partially rescued in striatal synaptosomes from transgenic mice compared with tissue from beta2 knockout mice. Nicotine-induced locomotor activation, but not place preference, was rescued in mice with low-level VTA expression, suggesting that low-level expression of beta2* nAChRs in DA neurons is not sufficient to support nicotine reward. In contrast to control mice, transgenic mice with low-level beta2* nAChR expression in the VTA showed no increase in overall levels of cyclic AMP response element-binding protein (CREB) but did show an increase in CREB phosphorylation in response to exposure to a nicotine-paired chamber. Thus, CREB activation in the absence of regulation of total CREB levels during place preference testing was not sufficient to support nicotine place preference in beta2 trangenic mice. This suggests that partial activation of high-affinity nAChRs in VTA might block the rewarding effects of nicotine, providing a potential mechanism for the ability of nicotinic partial agonists to aid in smoking cessation. PMID:19077117

  4. Modeling nicotine addiction in rats.

    Science.gov (United States)

    Caille, Stephanie; Clemens, Kelly; Stinus, Luis; Cador, Martine

    2012-01-01

    Among the human population, 15% of drug users develop a pathological drug addiction. This figure increases substantially with nicotine, whereby more than 30% of those who try smoking develop a nicotine addiction. Drug addiction is characterized by compulsive drug-seeking and drug-taking behaviors (craving), and loss of control over intake despite impairment in health, social, and occupational functions. This behavior can be accurately modeled in the rat using an intravenous self-administration (IVSA) paradigm. Initial attempts at establishing nicotine self-administration had been problematic, yet in recent times increasingly reliable models of nicotine self-administration have been developed. The present article reviews different characteristics of the nicotine IVSA model that has been developed to examine nicotine reinforcing and motivational properties in rats. PMID:22231818

  5. Brain

    Science.gov (United States)

    ... will return after updating. Resources Archived Modules Updates Brain Cerebrum The cerebrum is the part of the ... the outside of the brain and spinal cord. Brain Stem The brain stem is the part of ...

  6. Nicotinic acetylcholine receptors mediate lung cancer growth

    Directory of Open Access Journals (Sweden)

    PaulDGardner

    2013-09-01

    Full Text Available Ion channels modulate ion flux across cell membranes, activate signal transduction pathways, and influence cellular transport – vital biological functions that are inexorably linked to cellular processes that go awry during carcinogenesis. Indeed, deregulation of ion channel function has been implicated in cancer-related phenomena such as unrestrained cell proliferation and apoptotic evasion. As the prototype for ligand-gated ion channels, nicotinic acetylcholine receptors (nAChRs have been extensively studied in the context of neuronal cells but accumulating evidence also indicate a role for nAChRs in carcinogenesis. Recently, variants in the nAChR genes CHRNA3, CHRNA5, and CHRNB4 have been implicated in nicotine dependence and lung cancer susceptibility. Here, we silenced the expression of these three genes to investigate their function in lung cancer. We show that these genes are necessary for the viability of small cell lung carcinomas (SCLC, the most aggressive type of lung cancer. Furthermore, we show that nicotine promotes SCLC cell viability whereas an α3β4-selective antagonist, α-conotoxin AuIB, inhibits it. Our findings posit a mechanism whereby signaling via α3/α5/β4-containing nAChRs promotes lung carcinogenesis.

  7. The psychobiology of nicotine dependence

    OpenAIRE

    D. J. K. Balfour

    2008-01-01

    There is abundant evidence to show that nicotine is the principal addictive component of tobacco smoke. The results of laboratory studies have shown that nicotine has many of the behavioural and neurobiological properties of a drug of dependence. This article focuses on the evidence that nicotine has the rewarding and reinforcing properties typical of an addictive drug and that these properties are mediated, in part, by its effects on mesolimbic dopamine neurones. However, in many experimenta...

  8. 人才外流、空间外溢与人力资本积累%Brain Drain,Spatial Spill-over and Human Capital Accumulation

    Institute of Scientific and Technical Information of China (English)

    陈晓毅

    2013-01-01

      Based on Chinese provincial panel data from 2000 to 2010,the effect of brain drain on Chinese human capital ac-cumulation is studied by spatial econometric models. The results show that investment in education is helpful to humman capi-tal accumulation. Chinese brain drain significantly improve humman capital by education incentive, talents recruitment, Mi-grants’ remittances. There exists noticeable spaial spillover in the human capital accumulation in regions. So we should treat brain drain more rationally. We can use the positive effect of brain drain and the spaial spillover in the human capital accu-mulation to decrease the human capital inequality between regions.%  采用2000—2010年中国31个地区的面板数据,利用空间面板计量模型就人才外流对人力资本积累的影响进行实证研究。结果显示,教育投资有利于人力资本积累;我国人才外流对人力资本积累有显著的促进作用,其作用机制在于:教育激励、人才回流和海外汇款;地区间人力资本积累存在空间外溢性。因此,应当对人才外流持理性态度,充分发挥人才外流对人力资本积累的正效益,利用人力资本积累的空间外溢性,缩小地区间人力资本水平的差距。

  9. The future of nicotine replacement.

    Science.gov (United States)

    Russell, M A

    1991-05-01

    Following in the wake of progress forged by nicotine chewing gum, a new generation of nicotine replacement products will soon be available as aids to giving up smoking. These range from nicotine skin patches, which take 6-8 hrs to give very flat steady-state peak blood levels, to nicotine vapour inhalers which mimic the transient high-nicotine boli that follow within a few seconds of each inhaled puff of cigarette smoke. Other products undergoing clinical trials include a nasal nicotine spray and nicotine lozenges. It is argued here that it is not so much the efficacy of new nicotine delivery systems as temporary aids to cessation, but their potential as long-term alternatives to tobacco that makes the virtual elimination of tobacco a realistic future target. Their relative safety compared with tobacco is discussed. A case is advanced for selected nicotine replacement products to be made as palatable and acceptable as possible and actively promoted on the open market to enable them to compete with tobacco products. They will also need health authority endorsement, tax advantages and support from the anti-smoking movement if tobacco use is to be gradually phased out altogether. PMID:1859935

  10. Nicotine effects on regional cerebral blood flow in awake, resting tobacco smokers.

    Science.gov (United States)

    Domino, E F; Minoshima, S; Guthrie, S; Ohl, L; Ni, L; Koeppe, R A; Zubieta, J K

    2000-12-01

    The hypothesis for this research was that regional cerebral blood flow (rCBF) would increase following nasal nicotine administration to overnight abstinent tobacco smokers in relationship to the known brain distribution of nicotinic cholinergic receptors (nAChRs). Nine male and nine female healthy adult smokers were studied. They abstained overnight from tobacco products for 10 or more hours prior to study the next morning. Nicotine nasal spray was given in doses of 1-2.5 mg total with half in each nostril while the subject was awake and resting in a supine position. Oleoresin of pepper solution in a similar volume was used as an active placebo to control for the irritating effects of nicotine. Both substances were given single blind to the subjects. Positron emission tomography (PET) with H(2)(15)O was used to measure rCBF. The data from each subject volunteer were normalized to global activity to better assess regional brain changes. Both nasal nicotine and pepper spray produced similar increases in CBF in somesthetic area II, consistent with the irritant effects of both substances. The mean rCBF effects of nasal pepper were subtracted from those of nasal nicotine to determine the actions of nicotine alone. The latter produced increases in rCBF in the thalamus, pons, Brodman area 17 of the visual cortex, and cerebellum. Some brain areas that contain a large number of nAChRs, such as the thalamus, showed an increase in CBF. Other areas that have few nAChRs, such as the cerebellum, also showed an increase in relative CBF. The hippocampal/parahippocampal areas showed greater regional decreases (left) and lesser increases (right) in CBF that correlated with the increase in plasma arterial nicotine concentrations. The results obtained indicate complex primary and secondary effects of nicotine in which only some regional brain CBF changes correlate with the known distribution of nAChR. No gender differences were noted. PMID:11020234

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

    Science.gov (United States)

    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.

  12. Specific accumulation of {sup 18}F-deoxyglucose in three-dimensional long-term cultures of human and rodent brain tissue

    Energy Technology Data Exchange (ETDEWEB)

    Hocke, C.; Prante, O.; Kuwert, T. [Clinic of Nuclear Medicine, Univ. of Erlangen-Nuernberg (Germany); Bluemcke, I.; Jeske, I. [Dept. of Neuropathology, Univ. of Erlangen-Nuernberg (Germany); Romstoeck, J. [Dept. of Neurosurgery, Univ. of Erlangen-Nuernberg (Germany); Stefan, H. [Dept. of Neurology, Univ. of Erlangen-Nuernberg (Germany)

    2007-07-01

    Aim: Organotypic slice cultures (OSC) of human brain specimens represent an intriguing experimental model for translational studies addressing, e.g., stem cell transplantation in neurodegenerative diseases or targeting invasion by malignant glioma ex vivo. However, long-term viability and phenomena of structural reorganization of human OSC remain to be further characterized. Here, we report the use of {sup 18}F-deoxyglucose (FDG) for evaluating the viability of brain slice preparations obtained either from postnatal rats or human hippocampal specimens. Methods: Anatomically well preserved human hippocampi obtained from epilepsy surgery and rat hippocampus slice cultures obtained from six day old Wistar rats were dissected into horizontal slices. The slices were incubated with FDG in phosphate buffered saline up to 1 h, either with or without supplementation of glucose at a concentration of 2.5 mg/ml. Radioactivity within the medium or slice cultures was measured using a gamma-counter. In addition, distribution of radioactivity was autoradiographically visualized and quantified as counts per mm{sup 2}. Results: In rat hippocampal slices, FDG accumulated with 1 300 000 {+-} 68 000 counts/mm{sup 2}, whereas the incorporation of the radioactive label in human slices was in the order of 1 500 000 {+-} 370 000 counts/mm{sup 2}. The elevation of glucose concentration within the medium led to a significant three-fold decrease of FDG accumulation in rat slices and to a 2.4-fold decrease in human specimens. Conclusions: FDG accumulated in organotypic brain cultures of human or rodent origin. FDG is thus suited to investigate the viability of OSC. Furthermore, these preparations open new ways to study the factors governing cerebral FDG uptake in brain tissue ex vivo. (orig.)

  13. Extraosseous accumulation of bone scanning agents in malignant brain tumors. Comparison to semi-quantitative evaluation with 99mTc SPECT/201Tl SPECT and histological findings

    International Nuclear Information System (INIS)

    Although 201Tl chloride (Tl) SPECT has been used in the differential diagnosis between recurrence of malignant brain tumor and necrosis after treatment, it is not generally recognized as a definite modality to distinguish them. We conducted a preliminary study using Tl SPECT and 99mTc-MDP or 99mTc-HMDP (Tc) SPECT because it has been said that extraosseous accumulation was caused by calcium deposits in necrotic tissues. In our study, for the purposes of clarifying the mechanism of extraosseous uptake and the correlation between extraosseous accumulation of bone-scanning agent and tumor viability in malignant brain tumors, we compared whether Tc uptake was correlated with the histopathological findings and further performed semi-quantitative evaluation between Tc SPECT and Tl SPECT. The correlation coefficients between the ratio of tumor to normal skull count obtained from Tc SPECT (Tc-T/N) and those of tumor to normal brain count (T/N) and to normal scalp count (T/S) both obtained from Tl SPECT were calculated. Using contrast enhanced CT (CE-CT) or contrast enhanced MRI (CE-MRI), 8 of 10 cases showed intensely ring-enhanced tumor with necrotic lesion. Histopathologically, 7 of 8 cases whose tumor had been resected before treatment had necrosis with increased vascularity or bleeding. Of the remaining 2 cases one case, malignant lymphoma had only hypervascularity by biopsy, while the other one was excluded for resection after treatment. Three of these 8 cases whose CE-CT or CE-MRI showed necrotic lesions exhibited Tc and Tl accumulations in the area corresponding to necrosis. In contrast, 2 showed no Tc nor Tl uptake. Tc-T/N had no significant correlation with any of early-, delayed-T/N or T/S. In conclusion, there was no significant correlation between Tc and Tl uptakes by malignant brain tumors in semi-quantitative evaluation. (author)

  14. The psychobiology of nicotine dependence

    Directory of Open Access Journals (Sweden)

    D. J. K. Balfour

    2008-12-01

    Full Text Available There is abundant evidence to show that nicotine is the principal addictive component of tobacco smoke. The results of laboratory studies have shown that nicotine has many of the behavioural and neurobiological properties of a drug of dependence. This article focuses on the evidence that nicotine has the rewarding and reinforcing properties typical of an addictive drug and that these properties are mediated, in part, by its effects on mesolimbic dopamine neurones. However, in many experimental models of dependence, nicotine has relatively weak reinforcing properties that do not appear to explain adequately the powerful addiction to tobacco smoke experienced by many habitual smokers. Some of the reasons for this conundrum will be covered herein. This article focuses on the hypothesis that sensory stimuli and other pharmacologically active components in tobacco smoke play a pivotal role in the addiction to nicotine when it is inhaled in tobacco smoke. The article will discuss the evidence that dependence upon tobacco smoke reflects a complex interaction between nicotine and the components of the smoke, which are mediated by complementary effects of nicotine on the dopamine projections to the shell and core subdivisions of the accumbens. It will also discuss the extent to which the complexity of the dependence explains why nicotine replacement therapy does not provide a completely satisfying aid to smoking cessation and speculate on the properties treatments should exhibit if they are to provide a better treatment for tobacco dependence than those currently available.

  15. Effects of Nicotine on the Neurophysiological and Behavioral Effects of Ketamine in Humans

    Directory of Open Access Journals (Sweden)

    Daniel H Mathalon

    2014-01-01

    Full Text Available Background: N-methyl-D-aspartate (NMDA receptor hypofunction has been implicated in the pathophysiology of schizophrenia and its associated neurocognitive impairments. The high rate of cigarette smoking in schizophrenia raises questions about how nicotine modulates putative NMDA receptor hypofunction in the illness. Accordingly, we examined the modulatory effects of brain nicotinic acetylcholine receptor (nAChR stimulation on NMDA receptor hypofunction by examining the interactive effects of nicotine, a nAChR agonist, and ketamine, a noncompetitive NMDA receptor antagonist, on behavioral and neurophysiological measures in healthy human volunteers.Methods: From an initial sample of 17 subjects (age range 18 - 55 years, 8 subjects successfully completed 4 test sessions, each separated by at least 3 days, during which they received ketamine or placebo and two injections of nicotine or placebo in a double-blind, counterbalanced manner. Schizophrenia-like effects (PANSS, perceptual alterations (CADSS, subjective effects (VAS and auditory event-related brain potentials (mismatch negativity, P300 were assessed during each test session.Results: Consistent with existing studies, ketamine induced transient schizophrenia-like behavioral effects. P300 was reduced and delayed by ketamine regardless of whether it was elicited by a target or novel stimulus, while nicotine only reduced the amplitude of P3a. Nicotine did not rescue P300 from the effects of ketamine; the interactions of ketamine and nicotine were not significant. While nicotine significantly reduced MMN amplitude, ketamine did not. Conclusion: Nicotine failed to modulate ketamine-induced schizophrenia-like effects in this preliminary study. Interestingly, ketamine reduced P3b amplitude and nicotine reduced P3a amplitude, suggesting independent roles of NMDA receptor and nAChR in the generation of P3b and P3a, respectively.

  16. Oxidative mechanisms contributing to the developmental neurotoxicity of nicotine and chlorpyrifos

    International Nuclear Information System (INIS)

    Nicotine and chlorpyrifos are developmental neurotoxicants that, despite their differences in structure and mechanism of action, share many aspects for damage to the developing brain. Both are thought to generate oxidative radicals; in the current study, we evaluated their ability to produce lipid peroxidation in two in vitro models of neural cell development (PC12 and SH-SY5Y cells) and for nicotine, with treatment of adolescent rats in vivo. Nicotine and chlorpyrifos, in concentrations relevant to human exposures, elicited an increase in thiobarbituric-acid-reactive species (TBARS) in undifferentiated cells, an effect that was prevented by addition of the antioxidant, Vitamin E. Initiating differentiation with nerve growth factor, which enhances nicotinic acetylcholine receptor expression, increased the TBARS response to nicotine but not chlorpyrifos, suggesting that the two agents act by different originating mechanisms to converge on the endpoint of oxidative damage. Furthermore, nicotine protected the cells from oxidative damage evoked by chlorpyrifos and similarly blocked the antimitotic effect of chlorpyrifos. Treatment of adolescent rats with nicotine elicited increases in TBARS in multiple brain regions when given in doses that simulate plasma nicotine concentrations found in smokers or at one-tenth the dose. Our results indicate that nicotine and chlorpyrifos elicit oxidative damage to developing neural cells both in vitro and in vivo, a mechanism that explains some of the neurodevelopmental endpoints that are common to the two agents. The balance between neuroprotectant and neurotoxicant actions of nicotine may be particularly important in situations where exposure to tobacco smoke is combined with other prooxidant insults

  17. The effect of nicotine on striatal dopamine release in man: A [11C]raclopride PET study.

    Science.gov (United States)

    Montgomery, Andrew J; Lingford-Hughes, Anne R; Egerton, Alice; Nutt, David J; Grasby, Paul M

    2007-08-01

    In common with many addictive substances and behaviors nicotine activates the mesolimbic dopaminergic system. Brain microdialysis studies in rodents have consistently shown increases in extrasynaptic DA levels in the striatum after administration of nicotine but PET experiments in primates have given contradicting results. A recent PET study assessing the effect of smoking in humans showed no change in [(11)C]raclopride binding in the brain, but did find that "hedonia" correlated with a reduction in [(11)C]raclopride binding suggesting that DA may mediate the positive reinforcing effects of nicotine. In this experiment we measured the effect of nicotine, administered via a nasal spray, on DA release using [(11)C]raclopride PET, in 10 regular smokers. There was no overall change in [(11)C]raclopride binding after nicotine administration in any of the striatal regions examined. However, the individual change in [(11)C]raclopride binding correlated with change in subjective measures of "amused" and "happiness" in the associative striatum (AST) and sensorimotor striatum (SMST). Nicotine concentration correlated negatively with change in BP in the limbic striatum. Nicotine had significant effects on cardiovascular measures including pulse rate, systolic blood pressure (BPr), and diastolic BPr. Baseline [(11)C]raclopride binding potential (BP) in the AST correlated negatively with the Fagerström score, an index of nicotine dependence. These results support a role for the DA system in nicotine addiction, but reveal a more complex relationship than suggested by studies in animals. PMID:17492764

  18. The effect of experimentally-induced renal failure on accumulation of bupropion and its major basic metabolites in plasma and brain of guinea pigs.

    Science.gov (United States)

    DeVane, C L; Laizure, S C; Cameron, D F

    1986-01-01

    Dosage regimen adjustments because of poor renal function are often assumed to be unnecessary for extensively metabolized antidepressants. This assumption is being increasingly questioned in recognition of the role of active drug metabolites. The purpose of this study was to assess the steady-state accumulation of the new antidepressant bupropion and its three major basic metabolites in guinea pigs, with and without experimentally-induced renal failure. Two groups of guinea pigs were treated by intraperitoneal (IP) implantation of mini-osmotic pumps containing bupropion hydrochloride. Immediately after surgery, one group of animals received an injection of uranyl nitrate. After 4 days, all animals were sacrificed by decapitation following blood removal by cardiac puncture. Analysis of plasma and brain samples by high performance liquid chromatography (HPLC) for concentrations of bupropion (BUP) and its major basic metabolites, the erythro-amino alcohol (EB), the threo-amino alcohol (TB) and the hydroxy metabolite (HB) revealed greater accumulation of BUP, TB, and HB in plasma and brain of the animals with renal failure compared to controls. No difference was found between groups in the concentrations of the EB metabolite. As the guinea pig shows a BUP and metabolite plasma concentration profile similar to that seen in human studies, these results suggest that further studies of bupropion and its major metabolites are warranted in patients with impaired renal function to assess possible excessive drug and metabolite accumulation. PMID:3092270

  19. Interaction of Nicotine and Bovine Serum Albumin

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The binding of nicotine to bovine serum albumin (BSA) was studied by UV absorption, fluorescence, and 1H NMR methods. With the addition of nicotine, the absorption band of BSA at about 210 nm decreased gradually, moved to longer wavelengths, and narrowed. BSA fluorescence of tryptophan residue was quenched by nicotine. The 1H NMR peaks of nicotine moved to downfield by the addition of BSA. The experimental results showed that nicotine was capable of binding with BSA to form a 1:1 complex. BSA's high selectivity for nicotine binding suggests a unique role for this protein in the detoxification and/or transport of nicotine.

  20. [Nicotinic acid and nicotinamide].

    Science.gov (United States)

    Kobayashi, M; Shimizu, S

    1999-10-01

    Nicotinic acid and nicotinamide are called niacin. They are the antipellagra vitamin essential to many animals for growth and health. In human being, niacin is believed necessary together with other vitamins for the prevention and cure of pellagra. Niacin is widely distributed in nature; appreciable amounts are found in liver, fish, yeast and cereal grains. Nicotinamide is a precursor of the coenzyme NAD and NADP. Some of the most understood metabolic processes that involve niacin are glycolysis, fatty acid synthesis and respiration. Niacin is also related to the following diseases: Hartnup disease; blue diaper syndrome; tryptophanuria; hydroxykynureninuria; xanthurenic aciduria; Huntington's disease. PMID:10540864

  1. Neural and behavioural changes in male periadolescent mice after prolonged nicotine-MDMA treatment.

    Science.gov (United States)

    Adeniyi, Philip A; Ishola, Azeez O; Laoye, Babafemi J; Olatunji, Babawale P; Bankole, Oluwamolakun O; Shallie, Philemon D; Ogundele, Olalekan M

    2016-02-01

    The interaction between MDMA and Nicotine affects multiple brain centres and neurotransmitter systems (serotonin, dopamine and glutamate) involved in motor coordination and cognition. In this study, we have elucidated the effect of prolonged (10 days) MDMA, Nicotine and a combined Nicotine-MDMA treatment on motor-cognitive neural functions. In addition, we have shown the correlation between the observed behavioural change and neural structural changes induced by these treatments in BALB/c mice. We observed that MDMA (2 mg/Kg body weight; subcutaneous) induced a decline in motor function, while Nicotine (2 mg/Kg body weight; subcutaneous) improved motor function in male periadolescent mice. In combined treatment, Nicotine reduced the motor function decline observed in MDMA treatment, thus no significant change in motor function for the combined treatment versus the control. Nicotine or MDMA treatment reduced memory function and altered hippocampal structure. Similarly, a combined Nicotine-MDMA treatment reduced memory function when compared with the control. Ultimately, the metabolic and structural changes in these neural systems were seen to vary for the various forms of treatment. It is noteworthy to mention that a combined treatment increased the rate of lipid peroxidation in brain tissue. PMID:26088184

  2. Exposure to nicotine increases nicotinic acetylcholine receptor density in the reward pathway and binge ethanol consumption in C57BL/6J adolescent female mice.

    Science.gov (United States)

    Locker, Alicia R; Marks, Michael J; Kamens, Helen M; Klein, Laura Cousino

    2016-05-01

    Nearly 80% of adult smokers begin smoking during adolescence. Binge alcohol consumption is also common during adolescence. Past studies report that nicotine and ethanol activate dopamine neurons in the reward pathway and may increase synaptic levels of dopamine in the nucleus accumbens through nicotinic acetylcholine receptor (nAChR) stimulation. Activation of the reward pathway during adolescence through drug use may produce neural alterations affecting subsequent drug consumption. Consequently, the effect of nicotine exposure on binge alcohol consumption was examined along with an assessment of the neurobiological underpinnings that drive adolescent use of these drugs. Adolescent C57BL/6J mice (postnatal days 35-44) were exposed to either water or nicotine (200μg/ml) for ten days. On the final four days, ethanol intake was examined using the drinking-in-the-dark paradigm. Nicotine-exposed mice consumed significantly more ethanol and displayed higher blood ethanol concentrations than did control mice. Autoradiographic analysis of nAChR density revealed higher epibatidine binding in frontal cortical regions in mice exposed to nicotine and ethanol compared to mice exposed to ethanol only. These data show that nicotine exposure during adolescence increases subsequent binge ethanol consumption, and may affect the number of nAChRs in regions of the brain reward pathway, specifically the frontal cortex. PMID:26428091

  3. Neurochemical and behavioural interactions between ibogaine and nicotine in the rat.

    OpenAIRE

    Benwell, M. E.; Holtom, P. E.; Moran, R.J.; Balfour, D. J.

    1996-01-01

    1. In vivo brain microdialysis has been employed to investigate the effects of ibogaine on nicotine-induced changes in dopamine overflow in the nucleus accumbens (NAc) of freely moving rats. The effects of the compound on locomotor responses to nicotine and behaviour in the elevated plus-maze were also examined. 2. No changes were observed in the dopamine overflow or the locomotor activity of the animals following the administration of ibogaine (40 mg kg-1, i.p.). However, ibogaine, administe...

  4. The ''in vivo'' distribution of carbon 11 labeled-nicotine in animals. A method suitable for use in man

    International Nuclear Information System (INIS)

    A method is described to label nicotine with carbon 11. A hundred millicuries can be obtained, in 45 minutes, with a high specific activity. This labeling of nicotine has allowed an ''in vivo'' study of the distribution of this very toxic drug in animals. Five minutes after injection in rabbits or monkeys, it was shown with a gamma camera or with a positron camera that the radioactivity was very rapidly distributed throughout the tissues especially in brain, lungs and kidneys. 11C-nicotine readily penetrates the blood-brain barrier and the brain radioactivity decreases very sharply with time. The eyes however retained activity, possibly in the retina. Unfortunately the monkey is not the ideal subject for 11C-nicotine brain study because: the brain is small, considering the resolution of the cameras and the cerebral lobes are also quite overlaped in this animal; Japanese authors have shown that compared with dogs the nicotine brain uptake is lower, due to the high affinity of nicotine for skeletal muscle which occupies approximately forty to fifty % of the body weight of the monkey. Also in monkeys, the nicotine destruction is faster than in dogs because there is a higher enzyme nicotine metabolizing activity in the liver of this animal. The differences observed between various animals studies using nicotine indicate that we should not draw any firm conclusions about the behaviour of this drug in humans. In order to do so, examinations must be conducted in man and the method described in spite of its limitations provides a means for such a study

  5. Accumulation of 14C-5,6-dihydroxytryptamine-melanin in intrathecal and subependymal phagocytes of the rat CNS and possible routes of their elimination from brain

    International Nuclear Information System (INIS)

    14C-5,6-DHT-Melanin, a labelled synthetic polymer resembling the naturally occurring melanin formed in brain by autoxidation of dopamine, was injected into the left lateral ventricle of adult rats, and its fate followed by autoradiography and by transmission electron microscopy of structures identified as labelled in preceding light micrographs, and by EM-autoradiography. Shortly after injection, melanin particles (easily identified in the em because of their size, structure and electron opacity) were seen ingested by supraependymal and epiplexus cells, by cells residing in the piaarachnoid, i.e. free subarachnoidal cells and perivascular cells, and by subependymally located microglia-like cells with intraventricular processes. Up to day four, an increase in the number of labelled phagocytes in the CSF was noted which transformed into typical reactive macrophages. Beyond this time, many intraventricular melanin-loaded phagocytes formed rounded clusters; cells of such clusters were subsequently found to invade the brain parenchyma by penetrating the ependymal lining and to accumulate in the perivascular space of brain vessels. 14C-Melanin-storing macrophages were found in the marginal sinus of the deep jugular lymph nodes suggesting emigration of CNS-derived phagocytes via lymphatics or prelymphatics that contact the subarachnoidal space compartment. This does not exclude the possibility that some of the macrophages leave the brain via the systemic circulation by penetrating the vascular endothelium; these may be disposed of in peripheral organs other than the lymph nodes

  6. Difference in 201TlCl accumulation mechanism in brain tumors. A comparison of their Na+-K+ ATPase activities

    International Nuclear Information System (INIS)

    The accumulation levels of 201TlCl and Na+ -K+ ATPase activity in tumor tissue were compared among glioblastoma, benign glioma and meningioma to study the difference in the mechanism of 201TlCl accumulation. The subjects were 19 cases comprised of 6 glioblastoma, 2 oligodendroglioma, 1 fibrillary astrocytoma, 1 pilocytic astrocytoma and 9 meningioma. Preoperative 201TlCl SPECT was performed in all the cases, and Thallium Index (TL index) was calculated by a ratio of 201TlCl in the tumor area and the contralateral area. In addition, cell membrane was extracted from the tumor tissue collected intraoperatively to determine Na+ -K+ ATPase activity. No statistically significant difference in TL index was noted between the glioblastoma group (6.97±2.67) and the meningioma group (5.87±1.99). This fact showed that there was no difference in the accumulation level of 201TlCl between the two groups. On the other hand, the glioblastoma group indicated a higher value of Na+ -K+ ATPase activity (49.13±43.76 μmole/hour/mg protein) than the meningioma group (7.73±13.84 μmol/hour/mg protein) (p+ -K+ ATPase activity in 201TlCl accumulation in glioblastoma and the influences of other accumulation mechanism than Na+ -K+ ATPase activity such as the volume of intratumoral vascular bed in meningioma. (author)

  7. Neurons in the brain of the male cynomolgus monkey accumulate /sup 3/H-medroxyprogesterone acetate (MPA)

    Energy Technology Data Exchange (ETDEWEB)

    Michael, R.P.; Bonsall, R.W.; Rees, H.D.

    1986-03-01

    MPA is a synthetic progestin with androgen-depleting activity. It is used clinically to reduce sexual motivation and aggression in male sex offenders. The mechanisms for its behavioral effects are not known. The authors used steroid autoradiography to help identify sites where MPA may act in the brain of male primates. Twenty-four hours after castration, two adult male cynomolgus macaques, weighing 4.9 and 6.6 kg, were administered 5 mCi /sup 3/H-MPA (NEN, 47.7 Ci/mmol) i.v., and were killed 1 h later. Left sides of the brains and samples of pituitary glands were frozen and 4-micron sections were cut and processed for thaw-mount autoradiography. Radioactivity was concentrated in the nuclei of many neutrons in the ventromedial hypothalamic nucleus (n.), arcuate n., medial preoptic n., and anterior hypothalamic area. Virtually no labeled cells were seen in the bed n. of stria terminalis, lateral septal n., amygdala, or pituitary gland. Right sides of the brains were analyzed by HPLC which demonstrated that 98% of the radioactivity in cell nuclei from the hypothalamus was in the form of unmetabolized /sup 3/H-MPA. The distribution of labelling in the brain following /sup 3/H-MPA administration resembled that previously seen following /sup 3/H-ORG 2058 in female cynomolgus monkeys. These data indicate that MPA has a circumscribed localization in the brain.

  8. Pharmacodynamics of nicotine: implications for rational treatment of nicotine addiction.

    Science.gov (United States)

    Benowitz, N L

    1991-05-01

    Rational treatment of the pharmacologic aspects of tobacco addiction includes nicotine substitution therapy. Understanding the pharmacodynamics of nicotine and its role in the addiction process provides a basis for rational therapeutic intervention. Pharmacodynamic considerations are discussed in relation to the elements of smoking cessation therapy: setting objectives, selecting appropriate medication and dosing form, selecting the optimal doses and dosage regimens, assessing therapeutic outcome, and adjusting therapy to optimize benefits and minimize risks. PMID:1859911

  9. Belief about Nicotine Modulates Subjective Craving and Insula Activity in Deprived Smokers

    Science.gov (United States)

    Gu, Xiaosi; Lohrenz, Terry; Salas, Ramiro; Baldwin, Philip R.; Soltani, Alireza; Kirk, Ulrich; Cinciripini, Paul M.; Montague, P. Read

    2016-01-01

    Little is known about the specific neural mechanisms through which cognitive factors influence craving and associated brain responses, despite the initial success of cognitive therapies in treating drug addiction. In this study, we investigated how cognitive factors such as beliefs influence subjective craving and neural activities in nicotine-addicted individuals using model-based functional magnetic resonance imaging (fMRI) and neuropharmacology. Deprived smokers (N = 24) participated in a two-by-two balanced placebo design, which crossed beliefs about nicotine (told “nicotine” vs. told “no nicotine”) with the nicotine content in a cigarette (nicotine vs. placebo) which participants smoked immediately before performing a fMRI task involving reward learning. Subjects’ reported craving was measured both before smoking and after the fMRI session. We found that first, in the presence of nicotine, smokers demonstrated significantly reduced craving after smoking when told “nicotine in cigarette” but showed no change in craving when told “no nicotine.” Second, neural activity in the insular cortex related to craving was only significant when smokers were told “nicotine” but not when told “no nicotine.” Both effects were absent in the placebo condition. Third, insula activation related to computational learning signals was modulated by belief about nicotine regardless of nicotine’s presence. These results suggest that belief about nicotine has a strong impact on subjective craving and insula responses related to both craving and learning in deprived smokers, providing insights into the complex nature of belief–drug interactions. PMID:27468271

  10. Sodium MRI in Multiple Sclerosis is Compatible with Intracellular Sodium Accumulation and Inflammation-Induced Hyper-Cellularity of Acute Brain Lesions

    Science.gov (United States)

    Biller, Armin; Pflugmann, Isabella; Badde, Stephanie; Diem, Ricarda; Wildemann, Brigitte; Nagel, Armin M.; Jordan, J.; Benkhedah, Nadia; Kleesiek, Jens

    2016-01-01

    The cascade of inflammatory pathogenetic mechanisms in multiple sclerosis (MS) has no specific conventional MRI correlates. Clinicians therefore stipulate improved imaging specificity to define the pathological substrates of MS in vivo including mapping of intracellular sodium accumulation. Based upon preclinical findings and results of previous sodium MRI studies in MS patients we hypothesized that the fluid-attenuated sodium signal differs between acute and chronic lesions. We acquired brain sodium and proton MRI data of N = 29 MS patients; lesion type was defined by the presence or absence of contrast enhancement. N = 302 MS brain lesions were detected, and generalized linear mixed models were applied to predict lesion type based on sodium signals; thereby controlling for varying numbers of lesions among patients and confounding variables such as age and medication. Hierarchical model comparisons revealed that both sodium signals average tissue (χ2(1) = 27.89, p < 0.001) and fluid-attenuated (χ2(1) = 5.76, p = 0.016) improved lesion type classification. Sodium MRI signals were significantly elevated in acute compared to chronic lesions compatible with intracellular sodium accumulation in acute MS lesions. If confirmed in further studies, sodium MRI could serve as biomarker for diagnostic assessment of MS, and as readout parameter in clinical trials promoting attenuation of chronic inflammation. PMID:27507776

  11. Sodium MRI in Multiple Sclerosis is Compatible with Intracellular Sodium Accumulation and Inflammation-Induced Hyper-Cellularity of Acute Brain Lesions.

    Science.gov (United States)

    Biller, Armin; Pflugmann, Isabella; Badde, Stephanie; Diem, Ricarda; Wildemann, Brigitte; Nagel, Armin M; Jordan, J; Benkhedah, Nadia; Kleesiek, Jens

    2016-01-01

    The cascade of inflammatory pathogenetic mechanisms in multiple sclerosis (MS) has no specific conventional MRI correlates. Clinicians therefore stipulate improved imaging specificity to define the pathological substrates of MS in vivo including mapping of intracellular sodium accumulation. Based upon preclinical findings and results of previous sodium MRI studies in MS patients we hypothesized that the fluid-attenuated sodium signal differs between acute and chronic lesions. We acquired brain sodium and proton MRI data of N = 29 MS patients; lesion type was defined by the presence or absence of contrast enhancement. N = 302 MS brain lesions were detected, and generalized linear mixed models were applied to predict lesion type based on sodium signals; thereby controlling for varying numbers of lesions among patients and confounding variables such as age and medication. Hierarchical model comparisons revealed that both sodium signals average tissue (χ(2)(1) = 27.89, p < 0.001) and fluid-attenuated (χ(2)(1) = 5.76, p = 0.016) improved lesion type classification. Sodium MRI signals were significantly elevated in acute compared to chronic lesions compatible with intracellular sodium accumulation in acute MS lesions. If confirmed in further studies, sodium MRI could serve as biomarker for diagnostic assessment of MS, and as readout parameter in clinical trials promoting attenuation of chronic inflammation. PMID:27507776

  12. Nicotine Reduces Antipsychotic-Induced Orofacial Dyskinesia in Rats

    OpenAIRE

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

    2012-01-01

    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 ...

  13. A common biological basis of obesity and nicotine addiction

    OpenAIRE

    Thorgeirsson, T E; Gudbjartsson, D.F.; Sulem, P.; Besenbacher, S.; Styrkarsdottir, U.; Thorleifsson, G.; Walters, G. B.; Furberg, H.; Sullivan, P. F.; Marchini, J; McCarthy, M. I.; Steinthorsdottir, V.; Thorsteinsdottir, U.; Stefansson, K.

    2013-01-01

    Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs i...

  14. Regional specificity of manganese accumulation and clearance in the mouse brain: implications for manganese-enhanced MRI.

    Science.gov (United States)

    Grünecker, B; Kaltwasser, S F; Zappe, A C; Bedenk, B T; Bicker, Y; Spoormaker, V I; Wotjak, C T; Czisch, M

    2013-05-01

    Manganese-enhanced MRI has recently become a valuable tool for the assessment of in vivo functional cerebral activity in animal models. As a result of the toxicity of manganese at higher dosages, fractionated application schemes have been proposed to reduce the toxic side effects by using lower concentrations per injection. Here, we present data on regional-specific manganese accumulation during a fractionated application scheme over 8 days of 30 mg/kg MnCl2 , as well as on the clearance of manganese chloride over the course of several weeks after the termination of the whole application protocol supplying an accumulative dose of 240 mg/kg MnCl2 . Our data show most rapid accumulation in the superior and inferior colliculi, amygdala, bed nucleus of the stria terminalis, cornu ammonis of the hippocampus and globus pallidus. The data suggest that no ceiling effects occur in any region using the proposed application protocol. Therefore, a comparison of basal neuronal activity differences in different animal groups based on locally specific manganese accumulation is possible using fractionated application. Half-life times of manganese clearance varied between 5 and 7 days, and were longest in the periaqueductal gray, amygdala and entorhinal cortex. As the hippocampal formation shows one of the highest T1 -weighted signal intensities after manganese application, and manganese-induced memory impairment has been suggested, we assessed hippocampus-dependent learning as well as possible manganese-induced atrophy of the hippocampal volume. No interference of manganese application on learning was detected after 4 days of Mn(2+) application or 2 weeks after the application protocol. In addition, no volumetric changes induced by manganese application were found for the hippocampus at any of the measured time points. For longitudinal measurements (i.e. repeated manganese applications), a minimum of at least 8 weeks should be considered using the proposed protocol to allow for

  15. Functional connectivity analysis of resting-state fMRI networks in nicotine dependent patients

    Science.gov (United States)

    Smith, Aria; Ehtemami, Anahid; Fratte, Daniel; Meyer-Baese, Anke; Zavala-Romero, Olmo; Goudriaan, Anna E.; Schmaal, Lianne; Schulte, Mieke H. J.

    2016-03-01

    Brain imaging studies identified brain networks that play a key role in nicotine dependence-related behavior. Functional connectivity of the brain is dynamic; it changes over time due to different causes such as learning, or quitting a habit. Functional connectivity analysis is useful in discovering and comparing patterns between functional magnetic resonance imaging (fMRI) scans of patients' brains. In the resting state, the patient is asked to remain calm and not do any task to minimize the contribution of external stimuli. The study of resting-state fMRI networks have shown functionally connected brain regions that have a high level of activity during this state. In this project, we are interested in the relationship between these functionally connected brain regions to identify nicotine dependent patients, who underwent a smoking cessation treatment. Our approach is on the comparison of the set of connections between the fMRI scans before and after treatment. We applied support vector machines, a machine learning technique, to classify patients based on receiving the treatment or the placebo. Using the functional connectivity (CONN) toolbox, we were able to form a correlation matrix based on the functional connectivity between different regions of the brain. The experimental results show that there is inadequate predictive information to classify nicotine dependent patients using the SVM classifier. We propose other classification methods be explored to better classify the nicotine dependent patients.

  16. Ammonium accumulation and cell death in a rat 3D brain cell model of glutaric aciduria type I.

    OpenAIRE

    Paris Jafari; Olivier Braissant; Petra Zavadakova; Hugues Henry; Luisa Bonafé; Diana Ballhausen

    2013-01-01

    Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency) is an inborn error of metabolism that usually manifests in infancy by an acute encephalopathic crisis and often results in permanent motor handicap. Biochemical hallmarks of this disease are elevated levels of glutarate and 3-hydroxyglutarate in blood and urine. The neuropathology of this disease is still poorly understood, as low lysine diet and carnitine supplementation do not always prevent brain damage, even in early-treated...

  17. Recurrent exposure to nicotine differentiates human bronchial epithelial cells via epidermal growth factor receptor activation

    International Nuclear Information System (INIS)

    Cigarette smoking is the major preventable cause of lung cancer in developed countries. Nicotine (3-(1-methyl-2-pyrrolidinyl)-pyridine) is one of the major alkaloids present in tobacco. Besides its addictive properties, its effects have been described in panoply of cell types. In fact, recent studies have shown that nicotine behaves as a tumor promoter in transformed epithelial cells. This research focuses on the effects of acute repetitive nicotine exposure on normal human bronchial epithelial cells (NHBE cells). Here we show that treatment of NHBE cells with recurrent doses of nicotine up to 500 μM triggered cell differentiation towards a neuronal-like phenotype: cells emitted filopodia and expressed neuronal markers such as neuronal cell adhesion molecule, neurofilament-M and the transcription factors neuronal N and Pax-3. We also demonstrate that nicotine treatment induced NF-kB translocation to the nucleus, phosphorylation of the epidermal growth factor receptor (EGFR), and accumulation of heparin binding-EGF in the extracellular medium. Moreover, addition of AG1478, an inhibitor of EGFR tyrosine phosphorylation, or cetuximab, a monoclonal antibody that precludes ligand binding to the same receptor, prevented cell differentiation by nicotine. Lastly, we show that differentiated cells increased their adhesion to the extracellular matrix and their protease activity. Given that several lung pathologies are strongly related to tobacco consumption, these results may help to better understand the damaging consequences of nicotine exposure

  18. Targeting nicotine addiction: the possibility of a therapeutic vaccine

    Directory of Open Access Journals (Sweden)

    Escobar-Chávez JJ

    2011-04-01

    Full Text Available José Juan Escobar-Chávez1, Clara Luisa Domínguez-Delgado2, Isabel Marlen Rodríguez-Cruz21Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán-Universidad Nacional Autónoma de México, Cuautitlán Izcalli, Estado de México, México; 2División de Estudios de Posgrado (Tecnología Farmacéutica, Facultad de Estudios Superiores Cuautitlán-Universidad Nacional Autónoma de México, Cuautitlán Izcalli, Estado de México, MéxicoAbstract: Cigarette smoking is the primary cause of lung cancer, cardiovascular diseases, reproductive disorders, and delayed wound healing all over the world. The goals of smoking cessation are both to reduce health risks and to improve quality of life. The development of novel and more effective medications for smoking cessation is crucial in the treatment of nicotine dependence. Currently, first-line smoking cessation therapies include nicotine replacement products and bupropion. The partial nicotinic receptor agonist, varenicline, has recently been approved by the US Food and Drug Administration (FDA for smoking cessation. Clonidine and nortriptyline have demonstrated some efficacy, but side effects may limit their use to second-line treatment products. Other therapeutic drugs that are under development include rimonabant, mecamylamine, monoamine oxidase inhibitors, and dopamine D3 receptor antagonists. Nicotine vaccines are among newer products seeking approval from the FDA. Antidrug vaccines are irreversible, provide protection over years and need booster injections far beyond the critical phase of acute withdrawal symptoms. Interacting with the drug in the blood rather than with a receptor in the brain, the vaccines are free of side effects due to central interaction. For drugs like nicotine, which interacts with different types of receptors in many organs, this is a further advantage. Three anti-nicotine vaccines are today in an advanced stage of clinical evaluation. Results

  19. Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson’s disease

    Science.gov (United States)

    Barreto, George E.; Iarkov, Alexander; Moran, Valentina Echeverria

    2015-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative disorder, which is characterized by neuroinflammation, dopaminergic neuronal cell death and motor dysfunction, and for which there are no proven effective treatments. The negative correlation between tobacco consumption and PD suggests that tobacco-derived compounds can be beneficial against PD. Nicotine, the more studied alkaloid derived from tobacco, is considered to be responsible for the beneficial behavioral and neurological effects of tobacco use in PD. However, several metabolites of nicotine, such as cotinine, also increase in the brain after nicotine administration. The effect of nicotine and some of its derivatives on dopaminergic neurons viability, neuroinflammation, and motor and memory functions, have been investigated using cellular and rodent models of PD. Current evidence shows that nicotine, and some of its derivatives diminish oxidative stress and neuroinflammation in the brain and improve synaptic plasticity and neuronal survival of dopaminergic neurons. In vivo these effects resulted in improvements in mood, motor skills and memory in subjects suffering from PD pathology. In this review, we discuss the potential benefits of nicotine and its derivatives for treating PD. PMID:25620929

  20. Effect of In Vivo Nicotine Exposure on Chlorpyrifos Pharmacokinetics and Pharmacodynamics in Rats

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sookwang; Poet, Torka S.; Smith, Jordan N.; Busby-Hjerpe, Andrea L.; Timchalk, Charles

    2010-03-30

    Routine use of tobacco products may modify physiological and metabolic functions, including drug metabolizing enzymes, which may impact the pharmacokinetics of environmental contaminants. Chlorpyrifos is an organophosphorus (OP) insecticide that is bioactivated to chlorpyrifos-oxon, and manifests its neurotoxicity by inhibiting acetylcholinesterase (AChE). The objective of this study was to evaluate the impact of repeated nicotine exposure on the pharmacokinetics of chlorpyrifos (CPF) and its major metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) in blood and urine and also to determine the impact on cholinesterase (ChE) activity in plasma and brain. Animals were exposed to 7-daily doses of either 1 mg nicotine/kg or saline (sc), and to either a single oral dose of 35 mg CPF/kg or a repeated dose of 5 mg CPF/kg/day for 7 days. Groups of rats were then sacrificed at multiple time-points after receiving the last dose of CPF. Repeated nicotine and CPF exposures resulted in enhanced metabolism of CPF to TCPy, as evidenced by increases in the measured TCPy concentration and AUC in blood. However, there was no significant difference in the amount of TCPy (free or total) excreted in the urine. The extent of brain acetylcholinesterase (AChE) inhibition was reduced due to nicotine co-exposure consistent with an increase in CYP450-mediated dearylation (detoxification) versus desulfuration. It was of interest to note that the impact of nicotine co-exposure was experimentally observed only after repeated CPF doses. Physiologically based pharmacokinetic model simulations of CPF-oxon concentrations in blood and brain were predicted to be lower in nicotine treated groups, which were simulated by increasing the dearylation Vmax based upon previously conducted in vitro metabolism studies. These results were consistent with the experimental data. The current study demonstrated that repeated nicotine exposure could alter CPF metabolism in vivo, further modulating brain AChE inhibition.

  1. The α4β2 nicotine acetylcholine receptor agonist ispronicline induces c-Fos expression in selective regions of the rat forebrain

    DEFF Research Database (Denmark)

    Jacobsen, Julie; Hansen, Henrik H; Kiss, Alexander;

    2012-01-01

    The dominant nicotine acetylcholine receptor (nAChR) subtype in the brain is the pentameric receptor containing both α4 and β2 subunits (α4β2). Due to the lack of selective agonists it has not been ruled out what neuronal circuits that are stimulated after systemic administration with nicotine. We...

  2. Hydrogen sulfide mediates nicotine biosynthesis in tobacco (Nicotiana tabacum) under high temperature conditions.

    Science.gov (United States)

    Chen, Xiaodong; Chen, Qian; Zhang, Xiaoming; Li, Ruijing; Jia, Yujie; Ef, Abd Allah; Jia, Aiqun; Hu, Liwei; Hu, Xiangyang

    2016-07-01

    Hydrogen sulfide (H2S) acts as a signal to induce many physiological processes in plants, but its role in controlling the biosynthesis of secondary metabolites is not well established. In this study, we found that high temperature (HT) treatment induced nicotine biosynthesis in tobacco (Nicotiana tabacum) and promoted the rapid accumulation of H2S. Furthermore, HT triggered the biosynthesis of jasmonic acid (JA), a plant hormone that promotes nicotine biosynthesis. Suppression of the H2S signal using chemical inhibitors or via RNAi suppression of l-cysteine desulphydrase (L-CD) in transgenic plants, compromised JA production and nicotine biosynthesis under HT treatments, and these inhibitory effects could be reversed by applying exogenous H2S. Based on these data, we propose that H2S is an important trigger of nicotine biosynthesis in tobacco under HT conditions, and that H2S acts upstream of JA signaling by modulating the transcription of genes associated with JA biosynthesis. PMID:27035256

  3. Electronic Nicotine Delivery Systems Key Facts Infographic

    Data.gov (United States)

    U.S. Department of Health & Human Services — Explore the Electronic Nicotine Delivery Systems Key Facts Infographic which outlines key facts related to electronic nicotine delivery systems (ENDS), including...

  4. Tumour-like thallium-201 accumulation in brain infarcts, an unexpected finding on single-photon emission tomography

    International Nuclear Information System (INIS)

    In the present study our purpose was to investigate whether or not foci of 201Tl accumulation occur in reperfused areas with sustained morphological integrity indicated by computed tomography (CT) scans not showing hypodensity in the acute or sub-acute period. In 16 stroke patients with possible cortical embolic infarction, dual 201Tl and technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) SPET was performed in both the acute and the subacute period. 99mTc-HMPAO SPET was performed to detect reperfusion. Follow-up CT scans from the same period were also available. In five cases 99mTc-HMPAO SPET ruled out reperfusion and 201Tl SPET was also negative. In four cases 99mTc-HMPAO studies indicated reperfusion early in the acute phase (24-72 h), and comparative CT, without showing hypodensity in the acute or subacute period, also favoured the possibility of sustained metabolic activity. In these cases 201Tl SPET was negative in both the acute and the subacute period. In seven cases CT already showed necrosis in 99mTc-HMPAO hypoperfused areas in the acute period, with negative results on corresponding 201Tl SPET. Later reperfusion occurred in the subacute period (8-14 days) as indicated by 99mTc-HMPAO SPET, at which time an unexpected focal accumulation of 201Tl was detected. (orig./MG)

  5. Enhanced immunogenicity of a bivalent nicotine vaccine

    OpenAIRE

    Keyler, DE; Roiko, SA; Earley, CA; Murtaugh, MP; Pentel, PR

    2008-01-01

    The efficacy of nicotine vaccines for smoking cessation is dependent upon their ability to elicit sufficiently high serum antibody concentrations. This study compared two nicotine immunogens representing different hapten presentations, 3′-aminomethyl nicotine conjugated to recombinant Pseudomonas exoprotein A (3′-AmNic-rEPA) and 6-carboxymethlureido nicotine conjugated to keyhole limpet hemocyanin (6-CMUNic-KLH), and assessed whether their concurrent administration would produce additive seru...

  6. Nicotine's Defensive Function in Nature

    Directory of Open Access Journals (Sweden)

    Steppuhn Anke

    2004-01-01

    Full Text Available 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 D4-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.

  7. 21 CFR 172.310 - Aluminum nicotinate.

    Science.gov (United States)

    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...

  8. 27 CFR 21.119 - Nicotine solution.

    Science.gov (United States)

    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 nicotine; 3.6 avoirdupois ounces of methylene blue, U.S.P.; water sufficient to make 100 gallons. (b)...

  9. Nicotine adsorption on single wall carbon nanotubes

    Energy Technology Data Exchange (ETDEWEB)

    Girao, Eduardo C. [Departamento de Fisica, Universidade Federal do Ceara, Caixa Postal 6030, Campus do Pici, 60455-900 Fortaleza, Ceara (Brazil); Fagan, Solange B.; Zanella, Ivana [Area de Ciencias Tecnologicas, Centro Universitario Franciscano - UNIFRA, 97010-032 Santa Maria, RS (Brazil); Filho, Antonio G. Souza, E-mail: agsf@fisica.ufc.br [Departamento de Fisica, Universidade Federal do Ceara, Caixa Postal 6030, Campus do Pici, 60455-900 Fortaleza, Ceara (Brazil)

    2010-12-15

    This work reports a theoretical study of nicotine molecules interacting with single wall carbon nanotubes (SWCNTs) through ab initio calculations within the framework of density functional theory (DFT). Different adsorption sites for nicotine on the surface of pristine and defective (8,0) SWCNTs were analyzed and the total energy curves, as a function of molecular position relative to the SWCNT surface, were evaluated. The nicotine adsorption process is found to be energetically favorable and the molecule-nanotube interaction is intermediated by the tri-coordinated nitrogen atom from the nicotine. It is also predicted the possibility of a chemical bonding between nicotine and SWCNT through the di-coordinated nitrogen.

  10. Chronic neonatal nicotine exposure increases mRNA expression of neurotrophic factors in the postnatal rat hippocampus.

    Science.gov (United States)

    Son, Jong-Hyun; Winzer-Serhan, Ursula H

    2009-06-30

    Nicotine, the psychoactive ingredient in tobacco, can be neuroprotective but the mechanism is unknown. In the adult hippocampus, chronic nicotine can increase expression of growth factors which could contribute to nicotine's neuroprotective effects. During development, nicotine could also increase expression of neurotrophic factors. Therefore, we determined whether chronic neonatal nicotine (CNN) exposure increased mRNA expression levels of brain-derived neurotrophic factor (BDNF), nerve-growth factor (NGF), neurotrophin-3 (NT-3), fibroblast growth factor-2 (FGF-2), and insulin-like growth factor-1 (IGF-1). Nicotine (6 mg/kg/day in milk formula) or milk formula (controls) were delivered in three daily doses via oral gastric intubation to rat pups from postnatal day (P)1 to P8, and then sacrificed. Brains were processed for in situ hybridization using specific (35)S-labeled cRNA probes. At P8, CNN had a significant stimulant treatment effect on the expression of BDNF, FGF-2, NT-3 and IGF-1 [pCNN increased the number of IGF-1-expressing cells in CA1 (18.0%), CA3 (20.9%) and DG (17.7%). Thus, nicotine exposure during early postnatal development differentially up-regulated expression of neurotrophic factor mRNAs in the hippocampus, which could increase neurotrophic tone and alter developmental processes. PMID:19410565

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

    Science.gov (United States)

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

    2016-09-01

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

  12. Mu Opioid Receptor Binding Correlates with Nicotine Dependence and Reward in Smokers.

    Directory of Open Access Journals (Sweden)

    Hiroto Kuwabara

    Full Text Available The rewarding effects of nicotine are associated with activation of nicotine receptors. However, there is increasing evidence that the endogenous opioid system is involved in nicotine's rewarding effects. We employed PET imaging with [11C]carfentanil to test the hypotheses that acute cigarette smoking increases release of endogenous opioids in the human brain and that smokers have an upregulation of mu opioid receptors (MORs when compared to nonsmokers. We found no significant changes in binding potential (BPND of [11C]carfentanil between the placebo and the active cigarette sessions, nor did we observe differences in MOR binding between smokers and nonsmokers. Interestingly, we showed that in smokers MOR availability in bilateral superior temporal cortices during the placebo condition was negatively correlated with scores on the Fagerström Test for Nicotine Dependence (FTND. Also in smokers, smoking-induced decreases in [11C]carfentanil binding in frontal cortical regions were associated with self-reports of cigarette liking and wanting. Although we did not show differences between smokers and nonsmokers, the negative correlation with FTND corroborates the role of MORs in superior temporal cortices in nicotine addiction and provides preliminary evidence of a role of endogenous opioid signaling in frontal cortex in nicotine reward.

  13. Effects of Nicotine on Emotional Reactivity in PTSD and Non-PTSD Smokers: Results of a Pilot fMRI Study

    OpenAIRE

    Brett Froeliger; Jean Crowell Beckham; Michelle Feldman Dennis; Rachel Victoria Kozink; Francis Joseph McClernon

    2012-01-01

    There is evidence that individuals with posttraumatic stress disorder (PTSD) may smoke in part to regulate negative affect. This pilot fMRI study examined the effects of nicotine on emotional information processing in smokers with and without PTSD. Across groups, nicotine increased brain activation in response to fearful/angry faces (compared to neutral faces) in ventral caudate. Patch x Group interactions were observed in brain regions involved in emotional and facial feature processing. The...

  14. Nitrosamines as nicotinic receptor ligands.

    Science.gov (United States)

    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. PMID:17459420

  15. Effects of Nicotine on Emotional Reactivity in PTSD and Non-PTSD Smokers: Results of a Pilot fMRI Study

    Directory of Open Access Journals (Sweden)

    Brett Froeliger

    2012-01-01

    Full Text Available There is evidence that individuals with posttraumatic stress disorder (PTSD may smoke in part to regulate negative affect. This pilot fMRI study examined the effects of nicotine on emotional information processing in smokers with and without PTSD. Across groups, nicotine increased brain activation in response to fearful/angry faces (compared to neutral faces in ventral caudate. Patch x Group interactions were observed in brain regions involved in emotional and facial feature processing. These preliminary findings suggest that nicotine differentially modulates negative information processing in PTSD and non-PTSD smokers.

  16. Nicotine regulates cocaine-amphetamine-Regulated Transcript (Cart) in the mesocorticolimbic system.

    Science.gov (United States)

    Kaya, Egemen; Gozen, Oguz; Ugur, Muzeyyen; Koylu, Ersin O; Kanit, Lutfiye; Balkan, Burcu

    2016-07-01

    Cocaine-and-Amphetamine Regulated Transcript (CART) mRNA and peptides are intensely expressed in the brain regions comprising mesocorticolimbic system. Studies suggest that CART peptides may have a role in the regulation of reward circuitry. The present study aimed to examine the effect of nicotine on CART expression in the mesocorticolimbic system. Three different doses of nicotine (0.2, 0.4, 0.6 mg/kg free base) were injected subcutaneously for 5 days, and on day 6, rats were decapitated following a challenge dose. CART mRNA and peptide levels in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), dorsal striatum (DST), amygdala (AMG), lateral hypothalamic area (LHA), and ventral tegmental area (VTA) were measured by quantitative real-time PCR (qPCR) and Western Blot analysis, respectively. In the mPFC, 0.4 and 0.6 mg/kg nicotine, decreased CART peptide levels whereas there was no effect on CART mRNA levels. In the VTA, a down-regulation of CART peptide expression was observed with 0.2 and 0.6 mg/kg nicotine. Conversely, 0.4 and 0.6 mg/kg nicotine increased CART mRNA levels in the AMG without affecting the CART peptide expression. Nicotine did not regulate CART mRNA or CART peptide expression in the NAc, DST, and LHA. We conclude that nicotine regulates CART expression in the mesocorticolimbic system and this regulation may play an important role in nicotine reward. Synapse 70:283-292, 2016. © 2016 Wiley Periodicals, Inc. PMID:26990424

  17. Tobacco industry manipulation of nicotine dosing.

    Science.gov (United States)

    Wayne, Geoffrey Ferris; Carpenter, Carrie M

    2009-01-01

    For more than a half century, tobacco manufacturers have conducted sophisticated internal research to evaluate nicotine delivery, and modified their products to ensure availability of nicotine to smokers and to optimize its effects. Tobacco has proven to be a particularly effective vehicle for nicotine, enabling manipulation of smoke chemistry and of mechanisms of delivery, and providing sensory cues that critically inform patterns of smoking behavior as well as reinforce the impact of nicotine. A range of physical and chemical product design changes provide precise control over the quantity, form, and perception of nicotine dose, and support compensatory behavior, which is driven by the smoker's addiction to nicotine. Cigarette manufacturers also enhance the physiological effects of nicotine through the introduction and use of compounds that interact with nicotine but do not directly alter its form or delivery. A review of internal documents indicates important historical differences, as well as significant differences between commercial brands, underscoring the effectiveness of methods adopted by manufacturers to control nicotine dosing and target the needs of specific populations of smokers through commercial product development. Although the focus of the current review is on the manipulation of nicotine dosing characteristics, the evidence indicates that product design facilitates tobacco addiction through diverse addiction-potentiating mechanisms. PMID:19184659

  18. Nicotine and elevated body temperature reduce the complexity of the genioglossus and diaphragm EMG signals in rats during early maturation

    Science.gov (United States)

    Akkurt, David; Akay, Yasemin M.; Akay, Metin

    2009-10-01

    In this paper, we examined the effect of nicotine exposure and increased body temperature on the complexity (dynamics) of the genioglossus muscle (EMGg) and the diaphragm muscle (EMGdia) to explore the effects of nicotine and hyperthermia. Nonlinear dynamical analysis of the EMGdia and EMGg signals was performed using the approximate entropy method on 15 (7 saline- and 8 nicotine-treated) juvenile rats (P25-P35) and 19 (11 saline- and 8 nicotine-treated) young adult rats (P36-P44). The mean complexity values were calculated over the ten consecutive breaths using the approximate entropy method during mild elevated body temperature (38 °C) and severe elevated body temperature (39-40 °C) in two groups. In the first (nicotine) group, rats were treated with single injections of nicotine enough to produce brain levels of nicotine similar to those achieved in human smokers (2.5 (mg kg-1)/day) until the recording day. In the second (control) group, rats were treated with injections of saline, beginning at postnatal 5 days until the recording day. Our results show that warming the rat by 2-3 °C and nicotine exposure significantly decreased the complexity of the EMGdia and EMGg for the juvenile age group. This reduction in the complexity of the EMGdia and EMGg for the nicotine group was much greater than the normal during elevated body temperatures. We speculate that the generalized depressive effects of nicotine exposure and elevated body temperature on the respiratory neural firing rate and the behavior of the central respiratory network could be responsible for the drastic decrease in the complexity of the EMGdia and EMGg signals, the outputs of the respiratory neural network during early maturation.

  19. Acute effects of high-dose intragastric nicotine on mucosal defense mechanisms

    DEFF Research Database (Denmark)

    Lindell, G; Bukhave, Klaus; Lilja, I; Madsen, J. Rask; Graffner, H

    1997-01-01

    Peptic ulcer disease is overrepresented among smokers; they also heal slowly and relapse frequently. Data are accumulating that smoking is detrimental to gastroduodenal mucosal cytoprotection. This study was designed to assess acute effects of high-dose intragastric nicotine, as it has been shown...

  20. Nicotine uses neuron-glia communication to enhance hippocampal synaptic transmission and long-term memory.

    Directory of Open Access Journals (Sweden)

    Mónica López-Hidalgo

    Full Text Available Nicotine enhances synaptic transmission and facilitates long-term memory. Now it is known that bi-directional glia-neuron interactions play important roles in the physiology of the brain. However, the involvement of glial cells in the effects of nicotine has not been considered until now. In particular, the gliotransmitter D-serine, an endogenous co-agonist of NMDA receptors, enables different types of synaptic plasticity and memory in the hippocampus. Here, we report that hippocampal long-term synaptic plasticity induced by nicotine was annulled by an enzyme that degrades endogenous D-serine, or by an NMDA receptor antagonist that acts at the D-serine binding site. Accordingly, both effects of nicotine: the enhancement of synaptic transmission and facilitation of long-term memory were eliminated by impairing glial cells with fluoroacetate, and were restored with exogenous D-serine. Together, these results show that glial D-serine is essential for the long-term effects of nicotine on synaptic plasticity and memory, and they highlight the roles of glial cells as key participants in brain functions.

  1. Estimating the health consequences of replacing cigarettes with nicotine inhalers

    OpenAIRE

    Sumner, W.

    2003-01-01

    Background: A fast acting, clean nicotine delivery system might substantially displace cigarettes. Public health consequences would depend on the subsequent prevalence of nicotine use, hazards of delivery systems, and intrinsic hazards of nicotine.

  2. Effect of in vivo nicotine exposure on chlorpyrifos pharmacokinetics and pharmacodynamics in rats

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Soo Kwang; Poet, Torka S.; Smith, Jordan N.; Busby-Hjerpe, Andrea L.; Timchalk, Charles

    2010-03-30

    Chlorpyrifos (CPF) is one of the most studied and widely used broad spectrum organophosphorus (OP) insecticides. The neurotoxicity of CPF results from inhibition of cholinesterase (ChE) by its metabolite, chlorpyrifos-oxon (CPF-oxon), which subsequently leads to cholinergic hyperstimulation. The routine consumption of alcoholic beverages and tobacco products will modify a number of metabolic and physiological processes which may impact the metabolism and pharmacokinetics of other xenobiotics including pesticides. The objective of this study was to evaluate the influence of repeated ethanol and nicotine co-exposure on in vivo CPF pharmacokinetics and pharmacodynamics. The major CPF metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) in blood and urine along with changes in plasma and brain AChE activities were measured in male Sprague-Dawley (S-D) rats. Animals were repeatedly treated with either saline or ethanol (1 g/kg/day, po) and nicotine (1 mg/kg/day, sc) in addition to CPF (1 or 5 mg/kg/day, po) for 7 days. Rats were sacrificed at times from 1 to 24 hr post-last dosing of CPF. There were apparent differences in blood TCPy pharmacokinetics following ethanol and nicotine pretreatments in both CPF dose groups, which showed higher TCPy peak concentrations and increased blood TCPy AUC in ethanol and nicotine groups over CPF-only (~1.8- and 3.8-fold at 1 and 5 mg CPF doses, respectively). Brain acetylcholinesterase (AChE) activities from both ethanol and nicotine-treated groups showed substantially less inhibition following repeated 5 mg CPF/kg dosing compared to CPF-only controls (96 ± 13 and 66 ± 7% of naïve at 4 hr post-last CPF dosing, respectively). Inhibition of brain AChE activities was minimal in both 1 mg CPF/kg/day dosing groups, but a similar trend indicating less inhibition following ethanol/nicotine pretreatment was apparent. No differences were observed in plasma ChE activities due to the combined alcohol and nicotine treatments. In vitro, CPF

  3. Safety of the Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging, Focusing in Part on Their Accumulation in the Brain and Especially the Dentate Nucleus.

    Science.gov (United States)

    Runge, Val M

    2016-05-01

    The established class of intravenous contrast media for magnetic resonance imaging is the gadolinium chelates, more generally referred to as the gadolinium-based contrast agents (GBCAs). These can be differentiated on the basis of stability in vivo, with safety and tolerability of the GBCAs dependent upon chemical and biologic inertness. This review discusses first the background in terms of development of these agents and safety discussions therein, and second their relative stability based both on in vitro studies and clinical observations before and including the advent of nephrogenic systemic fibrosis. This sets the stage for the subsequent focus of the review, the current knowledge regarding accumulation of gadolinium in the brain and specifically the dentate nucleus after intravenous administration of the GBCAs and differentiation among agents on this basis. The information available to date, from the initial conception of these agents in 1981 to the latest reports concerning safety, demonstrates a significant difference between the macrocyclic and linear chelates. The review concludes with a discussion of the predictable future, which includes, importantly, a reassessment of the use of the linear GBCAs or a subset thereof. PMID:26945278

  4. Synthesis and evaluation of new imaging agent for central nicotinic acetylcholine receptor α7 subtype

    International Nuclear Information System (INIS)

    Introduction: The nicotinic acetylcholine receptor (nAChR) α7 subtype (α7 nAChR) is one of the major nAChR subtypes in the brain. We synthesized C-11 labeled α7 nAChR ligands, (R)-2-[11C]methylamino-benzoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester ([11C](R)-MeQAA) and its isomer (S)-[11C]MeQAA, for in vivo investigation with positron emission tomography (PET). Then, the potential of (R)- and (S)-[11C]MeQAA for in vivo imaging of α7 nAChR in the brain was evaluated in mice and monkeys. Methods: The binding affinity for α7 nAChR was measured using rat brain. Biodistribution and in vivo receptor blocking studies were undertaken in mice. Dynamic PET scans were performed in conscious monkeys. Results: The affinity for α7 nAChR was 41 and 182 nM for (R)- and (S)-MeQAA, respectively. The initial uptake in the mouse brain was high ([11C](R)-MeQAA: 7.68 and [11C](S)-MeQAA: 6.65 %dose/g at 5 min). The clearance of [11C](R)-MeQAA was slow in the hippocampus (α7 nAChR-rich region) but was rapid in the cerebellum (α7 nAChR-poor region). On the other hand, the clearance was fast for [11C](S)-MeQAA in all regions. The brain uptake of [11C](R)-MeQAA was decreased by methyllycaconitine (α7 nAChR antagonist) treatment. In monkeys, α7 nAChRs were highly distributed in the thalamus and cortex but poorly distributed in the cerebellum. The high accumulation was observed in the cortex and thalamus for [11C](R)-MeQAA, while the uptake was rather homogeneous for [11C](S)-MeQAA. Conclusions: [11C](R)-MeQAA was successfully synthesized and showed high uptake to the brain. However, since the in vivo selectivity for α7 nAChR was not enough, further PET kinetic analysis or structure optimization is needed for specific visualization of brain α7 nAChRs in vivo.

  5. Nicotine administration enhances conditioned inhibition in rats

    OpenAIRE

    MacLeod, Jill E.; Potter, Alexandra S.; Simoni, Michael K.; Bucci, David J.

    2006-01-01

    The effect of nicotine on conditioned inhibition was examined using a serial feature negative discrimination task. Nicotine (0.35mg/kg) or vehicle was administered before each of 16 training sessions. On some trials in each session, a tone was presented and followed by food reward. On other trials, the tone was preceded by a visual stimulus and not reinforced. Nicotine-treated rats exhibited greater discrimination between the two trial types as evidenced by less frequent responding during non...

  6. Adult Behavior in Male Mice Exposed to E-Cigarette Nicotine Vapors during Late Prenatal and Early Postnatal Life.

    Directory of Open Access Journals (Sweden)

    Dani Smith

    Full Text Available Timed-pregnant C57BL/6J mice were exposed to 2.4% nicotine in propylene glycol (PG or 0% nicotine /PG once a day from gestational day 15 until delivery. After delivery, offspring and mothers were exposed to E-cigarette vapors for an additional 14 days from postnatal day 2 through 16. Following their last exposure serum cotinine levels were measured in female juvenile mice. Male mice underwent behavioral testing at 14 weeks of age to assess sensorimotor, affective, and cognitive functional domains.Adult male mice exposed to 2.4% nicotine/PG E-cigarette vapors had significantly more head dips in the zero maze test and higher levels of rearing activity in the open field test compared to 0% nicotine/PG exposed mice and untreated controls. In the water maze test after reversal training, the 2.4% nicotine/PG mice spent more than 25% of time in the new location whereas the other groups did not.Adult male mice exhibited increased levels of activity in the zero maze and open field tests when exposed to E-cigarette vapor containing nicotine during late prenatal and early postnatal life. These findings indicate that nicotine exposure from E-cigarettes may cause persistent behavioral changes when exposure occurs during a period of rapid brain growth.

  7. Differential effects of TRPV1 receptor ligands against nicotine-induced depression-like behaviors

    OpenAIRE

    2011-01-01

    Background The contributions of brain cannabinoid (CB) receptors, typically CB1 (CB type 1) receptors, to the behavioral effects of nicotine (NC) have been reported to involve brain transient receptor potential vanilloid 1 (TRPV1) receptors, and the activation of candidate endogenous TRPV1 ligands is expected to be therapeutically effective. In the present study, the effects of TRPV1 ligands with or without affinity for CB1 receptors were examined on NC-induced depression-like behavioral alte...

  8. Rescue of amyloid-Beta-induced inhibition of nicotinic acetylcholine receptors by a peptide homologous to the nicotine binding domain of the alpha 7 subtype.

    Directory of Open Access Journals (Sweden)

    Arthur A Nery

    Full Text Available Alzheimer's disease (AD is characterized by brain accumulation of the neurotoxic amyloid-β peptide (Aβ and by loss of cholinergic neurons and nicotinic acetylcholine receptors (nAChRs. Recent evidence indicates that memory loss and cognitive decline in AD correlate better with the amount of soluble Aβ than with the extent of amyloid plaque deposits in affected brains. Inhibition of nAChRs by soluble Aβ40 is suggested to contribute to early cholinergic dysfunction in AD. Using phage display screening, we have previously identified a heptapeptide, termed IQ, homologous to most nAChR subtypes, binding with nanomolar affinity to soluble Aβ40 and blocking Aβ-induced inhibition of carbamylcholine-induced currents in PC12 cells expressing α7 nAChRs. Using alanine scanning mutagenesis and whole-cell current recording, we have now defined the amino acids in IQ essential for reversal of Aβ40 inhibition of carbamylcholine-induced responses in PC12 cells, mediated by α7 subtypes and other endogenously expressed nAChRs. We further investigated the effects of soluble Aβ, IQ and analogues of IQ on α3β4 nAChRs recombinantly expressed in HEK293 cells. Results show that nanomolar concentrations of soluble Aβ40 potently inhibit the function of α3β4 nAChRs, and that subsequent addition of IQ or its analogues does not reverse this effect. However, co-application of IQ makes the inhibition of α3β4 nAChRs by Aβ40 reversible. These findings indicate that Aβ40 inhibits different subtypes of nAChRs by interacting with specific receptor domains homologous to the IQ peptide, suggesting that IQ may be a lead for novel drugs to block the inhibition of cholinergic function in AD.

  9. Nicotine in Combination With a High-Fat Diet Causes Intramyocellular Mitochondrial Abnormalities in Male Mice

    OpenAIRE

    Sinha-Hikim, Indrani; Friedman, Theodore C; Shin, Chang-Sung; Lee, Desean; Ivey, Rasheed; Sinha-Hikim, Amiya P.

    2014-01-01

    Smoking is a major risk factor for diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. The health risk associated with smoking can be exaggerated by obesity. We hypothesize that nicotine when combined with a high-fat diet (HFD) can also cause ectopic lipid accumulation in skeletal muscle, similar to recently observed hepatic steatosis. Adult C57BL6 male mice were fed a normal chow diet or HFD and received twice-daily ip injections of nicotine (0.75 mg/kg body weight) or sa...

  10. Prostate stem cell antigen interacts with nicotinic acetylcholine receptors and is affected in Alzheimer's disease

    DEFF Research Database (Denmark)

    Jensen, Majbrit Myrup; Mikkelsen, Jens D.; Arvaniti, Maria; Pinborg, Lars Hageman; Thomsen, Morten Skøtt

    2015-01-01

    Alzheimer's disease (AD) is a neurodegenerative disorder involving impaired cholinergic neurotransmission and dysregulation of nicotinic acetylcholine receptors (nAChRs). Ly-6/neurotoxin (Lynx) proteins have been shown to modulate cognition and neural plasticity by binding to nAChR subtypes and...... are present in the human brain. We further showed that PSCA forms stable complexes with the α4 nAChR subunit and decreases nicotine-induced extracellular-signal regulated kinase phosphorylation in PC12 cells. In addition, we analyzed protein levels of PSCA and Lypd6 in postmortem tissue of medial...

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

    Science.gov (United States)

    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. PMID:26996314

  12. Nicotine During Pregnancy: Changes induced in neurotransmission, which could heighten proclivity to addict and induce maladaptive control of attention

    DEFF Research Database (Denmark)

    Kohlmeier, Kristi Anne

    2015-01-01

    Prenatal exposure to nicotine, occurring either via maternal smoking or via use of transdermal nicotine patches to facilitate cigarette abstinence by pregnant women, is associated with ∼ 13% of pregnancies worldwide. Nicotine exposure during gestation has been correlated with several negative...... physiological and psychosocial outcomes, including heightened risk for aberrant behaviors involving alterations in processing of attention as well as an enhanced liability for development of drug dependency. Nicotine is a terotogen, altering neuronal development of various neurotransmitter systems, and it is...... likely these alterations participate in postnatal deficits in attention control and facilitate development of drug addiction. This review discusses the alterations in neuronal development within the brain's major neurotransmitter systems, with special emphasis placed on alterations within the...

  13. Do the metabolites of 6-[F-18]fluoro-L-dopa and of [F-18]fluoro-meta-L-tyrosine contribute to the F-18 accumulation in the human brain?

    International Nuclear Information System (INIS)

    The purpose of this study was to determine if the metabolites of 6-[F-18]fluoro-L-dopa (F-dopa) and of [F-18]fluoro-meta-L-tyrosine (FmLtyr) contribute to the accumulation of fluorine-18 in the brain through unspecific retention. PET studies were conducted on a healthy human subject who was treated with both of the radiopharmaceuticals and their labelled metabolites. Results indicated that in contrast to F-dopa, the metabolite of FmLtyr does not 'contaminate' the brain with extraneous fluorine-18

  14. Bispyridinium Compounds Inhibit Both Muscle and Neuronal Nicotinic Acetylcholine Receptors in Human Cell Lines.

    Directory of Open Access Journals (Sweden)

    Avi Ring

    Full Text Available Standard treatment of poisoning by organophosphorus anticholinesterases uses atropine to reduce the muscarinic effects of acetylcholine accumulation and oximes to reactivate acetylcholinesterase (the effectiveness of which depends on the specific anticholinesterase, but does not directly address the nicotinic effects of poisoning. Bispyridinium molecules which act as noncompetitive antagonists at nicotinic acetylcholine receptors have been identified as promising compounds and one has been shown to improve survival following organophosphorus poisoning in guinea-pigs. Here, we have investigated the structural requirements for antagonism and compared inhibitory potency of these compounds at muscle and neuronal nicotinic receptors and acetylcholinesterase. A series of compounds was synthesised, in which the length of the polymethylene linker between the two pyridinium moieties was increased sequentially from one to ten carbon atoms. Their effects on nicotinic receptor-mediated calcium responses were tested in muscle-derived (CN21 and neuronal (SH-SY5Y cells. Their ability to inhibit acetylcholinesterase activity was tested using human erythrocyte ghosts. In both cell lines, the nicotinic response was inhibited in a dose-dependent manner and the inhibitory potency of the compounds increased with greater linker length between the two pyridinium moieties, as did their inhibitory potency for human acetylcholinesterase activity in vitro. These results demonstrate that bispyridinium compounds inhibit both neuronal and muscle nicotinic receptors and that their potency depends on the length of the hydrocarbon chain linking the two pyridinium moieties. Knowledge of structure-activity relationships will aid the optimisation of molecular structures for therapeutic use against the nicotinic effects of organophosphorus poisoning.

  15. Acute behavioral effects of nicotine in male and female HINT1 knockout mice.

    Science.gov (United States)

    Jackson, K J; Wang, J B; Barbier, E; Chen, X; Damaj, M I

    2012-11-01

    Human genetic association and brain expression studies, and mouse behavioral and molecular studies implicate a role for the histidine triad nucleotide-binding protein 1 (HINT1) in schizophrenia, bipolar disorder, depression and anxiety. The high comorbidity between smoking and psychiatric disorders, schizophrenia in particular, is well established. Associations with schizophrenia and HINT1 are also sex specific, with effects more predominant in males; however, it is unknown if sex differences associated with the gene extend to other phenotypes. Thus, in this study, using a battery of behavioral tests, we elucidated the role of HINT1 in acute nicotine-mediated behaviors using male and female HINT1 wild-type (+/+) and knockout (-/-) mice. The results show that male HINT1 -/- mice were less sensitive to acute nicotine-induced antinociception in the tail-flick, but not hot-plate test. At low nicotine doses, male and female HINT1 -/- mice were less sensitive to nicotine-induced hypomotility, although the effect was more pronounced in females. Baseline differences in locomotor activity observed in male HINT1 +/+ and -/- mice were absent in females. Nicotine did not produce an anxiolytic effect in male HINT1 -/- mice, but rather an anxiogenic response. Diazepam also failed to induce an anxiolytic response in these mice, suggesting a general anxiety phenotype not specific to nicotine. Differences in anxiety-like behavior were not observed in female mice. These results further support a role for HINT1 in nicotine-mediated behaviors and suggest that alterations in the gene may have differential effects on phenotype in males and females. PMID:22827509

  16. Acute effects of nicotine amplify accumbal neural responses during nicotine-taking behavior and nicotine-paired environmental cues.

    Directory of Open Access Journals (Sweden)

    Karine Guillem

    Full Text Available Nicotine self-administration (SA is maintained by several variables, including the reinforcing properties of nicotine-paired cues and the nicotine-induced amplification of those cue properties. The nucleus accumbens (NAc is implicated in mediating the influence of these variables, though the underlying neurophysiological mechanisms are not yet understood. In the present study, Long-Evans rats were trained to self-administer nicotine. During SA sessions each press of a lever was followed by an intravenous infusion of nicotine (30 µg/kg paired with a combined light-tone cue. Extracellular recordings of single-neuron activity showed that 20% of neurons exhibited a phasic change in firing during the nicotine-directed operant, the light-tone cue, or both. The phasic change in firing for 98% of neurons was an increase. Sixty-two percent of NAc neurons additionally or alternatively showed a sustained decrease in average firing during the SA session relative to a presession baseline period. These session decreases in firing were significantly less prevalent in a group of neurons that were activated during either the operant or the cue than in a group of neurons that were nonresponsive during those events (referred to as task-activated and task-nonactivated neurons, respectively. Moreover, the session decrease in firing was dose-dependent for only the task-nonactivated neurons. The data of the present investigation provide supportive correlational evidence for two hypotheses: (1 excitatory neurophysiological mechanisms mediate the NAc role in cue-maintenance of nicotine SA, and (2 a differential nicotine-induced inhibition of task-activated and task-nonactivated neurons mediates the NAc role in nicotine-induced amplification of cue effects on nicotine SA.

  17. Cardiac adverse effects of nicotine replacement therapy.

    Science.gov (United States)

    2015-12-01

    Smoking markedly increases the risk of cardiovascular disease. Nicotine replacement therapy is available to assist in smoking cessation. To assess the cardiac adverse effects of nicotine replacement therapy, we conducted a review of the literature using the standard Prescrire methodology. A meta-analysis of 21 randomised, placebo-controlled trials published in early 2014 included a total of 11 647 patients, including 828 patients at high risk of cardiovascular events and 187 patients with acute coronary disorders. It showed that nicotine replacement therapy was associated with an increased risk of cardiac disorders, particularly palpitations, which are a known adverse effect of smoking. Among patients at high cardiovascular risk, 1.2% experienced a serious cardiovascular event, with no statistically significant difference versus placebo. Bupropion and varenicline both have serious adverse effects and have been less extensively evaluated in patients at high cardiovascular risk. In practice, when a drug is needed to assist in smoking cessation, nicotine appears to be a reasonable choice. Nicotine replacement therapy exposes patients to a risk of palpitations but rarely to serious cardiac disorders, even in individuals with a cardiovascular history. In addition, these adverse effects are better documented than those of bupropion and varenidine in such patients. Nonetheless, the cardiac effects of nicotine call for prudent use of nicotine replacement therapy: the minimum effective dose should be sought, and the goal should be total nicotine withdrawal. PMID:26788573

  18. Measurement of nicotine in household dust

    International Nuclear Information System (INIS)

    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

  19. Nicotine modulation of fear memories and anxiety: Implications for learning and anxiety disorders.

    Science.gov (United States)

    Kutlu, Munir Gunes; Gould, Thomas J

    2015-10-15

    Anxiety disorders are a group of crippling mental diseases affecting millions of Americans with a 30% lifetime prevalence and costs associated with healthcare of $42.3 billion. While anxiety disorders show high levels of co-morbidity with smoking (45.3% vs. 22.5% in healthy individuals), they are also more common among the smoking population (22% vs. 11.1% in the non-smoking population). Moreover, there is clear evidence that smoking modulates symptom severity in patients with anxiety disorders. In order to better understand this relationship, several animal paradigms are used to model several key symptoms of anxiety disorders; these include fear conditioning and measures of anxiety. Studies clearly demonstrate that nicotine mediates acquisition and extinction of fear as well as anxiety through the modulation of specific subtypes of nicotinic acetylcholine receptors (nAChRs) in brain regions involved in emotion processing such as the hippocampus. However, the direction of nicotine's effects on these behaviors is determined by several factors that include the length of administration, hippocampus-dependency of the fear learning task, and source of anxiety (novelty-driven vs. social anxiety). Overall, the studies reviewed here suggest that nicotine alters behaviors related to fear and anxiety and that nicotine contributes to the development, maintenance, and reoccurrence of anxiety disorders. PMID:26231942

  20. Nicotine Contamination in Particulate Matter Sampling

    Directory of Open Access Journals (Sweden)

    Eric Garshick

    2009-02-01

    Full Text Available We have addressed potential contamination of PM2.5 filter samples by nicotine from cigarette smoke. We collected two nicotine samples – one nicotine sampling filter was placed in-line after the collection of PM2.5 and the other stood alone. The overall correlation between the two nicotine filter levels was 0.99. The nicotine collected on the “stand-alone” filter was slightly greater than that on the “in-line” filter (mean difference = 1.10 μg/m3, but the difference was statistically significant only when PM2.5 was low (≤ 50 μg/m3. It is therefore important to account for personal and secondhand smoke exposure while assessing occupational and environmental PM.

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

    Science.gov (United States)

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

    2016-01-01

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

  2. Littered cigarette butts as a source of nicotine in urban waters

    Science.gov (United States)

    Roder Green, Amy L.; Putschew, Anke; Nehls, Thomas

    2014-11-01

    The effect of nicotine from littered cigarette butts on the quality of urban water resources has yet to be investigated. This two-part study addresses the spatial variation, seasonal dynamics and average residence time of littered cigarette butts in public space, as well as the release of nicotine from cigarette butts to run-off in urban areas during its residence time. Thereby, we tested two typical situations: release to standing water in a puddle and release during alternating rainfall and drying. The study took place in Berlin, Germany, a city which completely relies on its own water resources to meet its drinking water demand. Nine typical sites located in a central district, each divided into 20 plots were studied during five sampling periods between May 2012 and February 2013. The nicotine release from standardized cigarette butts prepared with a smoking machine was examined in batch and rainfall experiments. Littered cigarette butts are unevenly distributed among both sites and plots. The average butt concentration was 2.7 m-2 (SD = 0.6 m-2, N = 862); the maximum plot concentration was 48.8 butts m-2. This heterogeneity is caused by preferential littering (gastronomy, entrances, bus stops), redistribution processes such as litter removal (gastronomy, shop owners), and the increased accumulation in plots protected from mechanized street sweeping (tree pits, bicycle stands). No significant seasonal variation of cigarette butt accumulation was observed. On average, cigarette butt accumulation is characterized by a 6 days cadence due to the rhythm and effectiveness of street sweeping (mean weekly butt accumulation rate = 0.18 m-2 d-1; SD = 0.15 m-1). Once the butt is exposed to standing water, elution of nicotine occurs rapidly. Standardized butts released 7.3 mg g-1 nicotine in a batch experiment (equivalent to 2.5 mg L-1), 50% of which occurred within the first 27 min. In the rainfall experiment, the cumulative nicotine release from fifteen consecutive

  3. Compound list: nicotinic acid [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available nicotinic acid NIC 00081 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in_vitro/nicotinic_aci...d.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vitro/nicotinic_aci.../in_vivo/Liver/Single/nicotinic_acid.Rat.in_vivo.Liver.Single.zip ftp://ftp.biosc...iencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Repeat/nicotinic_acid.Rat.in_vivo.Liver.Repeat.zip ...

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

    OpenAIRE

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

    2015-01-01

    Electronic cigarettes (ECIGs) use an electric heater to aerosolize a liquid that usually contains propylene glycol, vegetable glycerin, flavorants, and the dependence-producing drug nicotine. ECIG-induced nicotine dependence has become an important concern, as some ECIGs deliver very little nicotine while some may exceed the nicotine delivery profile of a tobacco cigarette. This variability is relevant to tobacco cigarette smokers who try to switch to ECIGs. Products with very low nicotine de...

  5. Airborne Nicotine Concentrations in the Workplaces of Tobacco Farmers

    OpenAIRE

    Yoo, Seok-Ju; Park, Sung-Jun; Kim, Byoung-Seok; Lee, Kwan; 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 far...

  6. Synthesis and in vivo evaluation of (E)-N-[11C]Methyl-4- (3-pyridinyl)-3-butene-1-amine ([11C]metanicotine) as a nicotinic receptor radioligand

    International Nuclear Information System (INIS)

    (E)-N-[11C]Methyl-4-(3-pyridinyl)-3-butene-1-amine ([11C]metanicotine), a high affinity (Ki=16 nM) CNS-selective nicotinic agonist, was prepared by the [11C]alkylation of the desmethyl precursor with [11C]methyl trifluoromethanesulfonate. In vivo distribution studies in mice demonstrated good blood brain permeability but essentially uniform regional brain distribution and no evidence of specific binding to nicotinic cholinergic receptors. Identical results were obtained in an imaging study performed in a monkey brain. Therefore, despite literature reports supporting the use of metanicotine as a cognition enhancing nicotinic agonist, (E)-N-[11C]methyl-4-(3-pyridinyl)-3-butene-1-amine does not appear to be a suitable candidate for in vivo imaging studies of nicotinic acetylcholine receptors in the mammalian brain

  7. The genetics of nicotine dependence.

    Science.gov (United States)

    Li, Ming D

    2006-04-01

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

  8. Chronic co-administration of nicotine and methamphetamine causes differential expression of immediate early genes in the dorsal striatum and nucleus accumbens

    OpenAIRE

    Saint-Preux, Fabienne; Bores, Lorena Rodríguez; Tulloch, Ingrid; Ladenheim, Bruce; Kim, Ronald; Thanos, Panayotis K.; Nora D Volkow; Cadet, Jean Lud

    2013-01-01

    Nicotine and methamphetamine (METH) cause addiction by triggering neuroplastic changes in brain reward pathways though they each engage distinct molecular targets (nicotine receptors and dopamine transporters respectively). Addiction to both drugs is very prevalent, with the vast majority of METH users being also smokers of cigarettes. This co-morbid occurrence thus raised questions about potential synergistic rewarding effects of the drugs. However, few studies have investigated the chronic ...

  9. Nicotinic α4β2 receptor imaging agents

    International Nuclear Information System (INIS)

    The α4β2 nicotinic acetylcholine receptor (nAChR) has been implicated in various neurodegenerative diseases. Optimal positron emission tomography (PET) imaging agents are therefore highly desired for this receptor. We report here the development and initial evaluation of 2-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (nifene). In vitro binding affinity of nifene in rat brain homogenate using 3H-cytisine exhibited a K i=0.50 nM for the α4β2 sites. The radiosynthesis of 2-18F-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (18F-nifene) was accomplished in 2.5 h with an overall radiochemical yield of 40-50%, decay corrected. The specific activity was estimated to be approx. 37-185 GBq/μmol. In vitro autoradiography in rat brain slices indicated selective binding of 18F-nifene to anteroventral thalamic (AVT) nucleus, thalamus, subiculum, striata, cortex and other regions consistent with α4β2 receptor distribution. Rat cerebellum showed some binding, whereas regions in the hippocampus had the lowest binding. The highest ratio of >13 between AVT and cerebellum was measured for 18F-nifene in rat brain slices. The specific binding was reduced (>95%) by 300 μM nicotine in these brain regions. Positron emission tomography imaging study of 18F-nifene (130 MBq) in anesthetized rhesus monkey was carried out using an ECAT EXACT HR+ scanner. PET study showed selective maximal uptake in the regions of the anterior medial thalamus, ventro-lateral thalamus, lateral geniculate, cingulate gyrus, temporal cortex including the subiculum. The cerebellum in the monkeys showed lower binding than the other regions. Thalamus-to-cerebellum ratio peaked at 30-35 min postinjection to a value of 2.2 and subsequently reduced. The faster binding profile of 18F-nifene indicates promise as a PET imaging agent and thus needs further evaluation

  10. COMT polymorphism modulates the resting-state EEG alpha oscillatory response to acute nicotine in male non-smokers.

    Science.gov (United States)

    Bowers, H; Smith, D; de la Salle, S; Choueiry, J; Impey, D; Philippe, T; Dort, H; Millar, A; Daigle, M; Albert, P R; Beaudoin, A; Knott, V

    2015-07-01

    Performance improvements in cognitive tasks requiring executive functions are evident with nicotinic acetylcholine receptor (nAChR) agonists, and activation of the underlying neural circuitry supporting these cognitive effects is thought to involve dopamine neurotransmission. As individual difference in response to nicotine may be related to a functional polymorphism in the gene encoding catechol-O-methyltransferase (COMT), an enzyme that strongly influences cortical dopamine metabolism, this study examined the modulatory effects of the COMT Val158Met polymorphism on the neural response to acute nicotine as measured with resting-state electroencephalographic (EEG) oscillations. In a sample of 62 healthy non-smoking adult males, a single dose (6 mg) of nicotine gum administered in a randomized, double-blind, placebo-controlled design was shown to affect α oscillatory activity, increasing power of upper α oscillations in frontocentral regions of Met/Met homozygotes and in parietal/occipital regions of Val/Met heterozygotes. Peak α frequency was also found to be faster with nicotine (vs. placebo) treatment in Val/Met heterozygotes, who exhibited a slower α frequency compared to Val/Val homozygotes. The data tentatively suggest that interindividual differences in brain α oscillations and their response to nicotinic agonist treatment are influenced by genetic mechanisms involving COMT. PMID:26096691

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

    OpenAIRE

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

    2010-01-01

    We assessed the reinforcing effects of nicotine and non-nicotine components of cigarette smoke, by presenting a concurrent choice paradigm in which participants had access to intravenous (IV) nicotine infusions vs. saline (placebo) infusions and puffs from denicotinized (“denic”) cigarettes vs. air (sham puffs). We also measured the effects on self-administration of prior satiation with each component. Sixteen smokers participated in 7 sessions, consisting of: 1) a baseline smoking assessment...

  12. Discriminative and Reinforcing Stimulus Effects of Nicotine, Cocaine, and Cocaine + Nicotine Combinations in Rhesus Monkeys

    OpenAIRE

    Mello, Nancy K.; Newman, Jennifer L.

    2011-01-01

    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 two-fold: 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 discriminati...

  13. Variants in nicotinic acetylcholine receptors α5 and α3 increase risks to nicotine dependence†

    OpenAIRE

    Chen, Xiangning; Chen, Jingchun; Williamson, Vernell S; An, Seon-Sook; Hettema, John M.; Aggen, Steven H.; Neale, Michael C.; Kendler, Kenneth S.

    2009-01-01

    Nicotinic acetylcholine receptors bind to nicotine and initiate the physiological and pharmacological responses to tobacco smoking. In this report, we studied the association of α5 and α3 subunits with nicotine dependence and with the symptoms of alcohol and cannabis abuse and dependence in two independent epidemiological samples (n = 815 and 1,121, respectively). In this study, seven single nucleotide polymorphisms were genotyped in the CHRNA5 and CHRNA3 genes. In both samples, we found that...

  14. Gamma-lactams--a novel scaffold for highly potent and selective alpha 7 nicotinic acetylcholine receptor agonists.

    Science.gov (United States)

    Enz, Albert; Feuerbach, Dominik; Frederiksen, Mathias U; Gentsch, Conrad; Hurth, Konstanze; Müller, Werner; Nozulak, Joachim; Roy, Bernard L

    2009-03-01

    A novel class of alpha7 nicotinic acetylcholine receptor (nAChR) agonists has been discovered through high-throughput screening. The cis gamma-lactam scaffold has been optimized to reveal highly potent and selective alpha7 nAChR agonists with in vitro activity and selectivity and with good brain penetration in mice. PMID:19208472

  15. Nicotinic activation of laterodorsal tegmental neurons

    DEFF Research Database (Denmark)

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

    2009-01-01

    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...... 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...

  16. Evaluation of PET Radioligands for the neuronal nicotinic acetylcholine receptor

    International Nuclear Information System (INIS)

    Full text: A-186253.1, a compound made by Abbott laboratories, was labelled with carbon-11 and evaluated as a PET ligand for the neuronal nicotinic acetylcholine receptor (nAChR). The compound was labelled with C-11 by methylation with 11C-MeI of the desmethyl precursor A-183828.1. The affinity of A-186253.1 for the α4β2 and the α7 subtype of the nAChR was determined in displacement studies. PET-studies were performed in rats and pigs Inhibitory constants (Ki) versus cytsine were 461 ± 99 pM for A-186253.1 and versus α-Bungarotoxin >100 μM. which means a very high selectivity for the α4β2-receptor (>227,000). Highest uptake of [11C]-A-186253.1 was observed in the thalamus where an increase in radiotracer uptake was seen until 45 min p.i.. Thereafter, the radiotracer concentration remained constant until the end of the scan indicating slow washout of [11C]-A-186253.1. Application of cold A-186253.1 (0.5 mg/kg) 40 min p.i. resulted in a decrease in radiotracer concentration in the thalamus and the cortex indicating displacement of [11C]-A-186253.1. Blockade studies with cytisine (0.5 mg/kg), a selective ligand for the α4β2 nicotinic receptor, showed just a slight reduction of the radioligand uptake in the thalamus and in the cortex whereas the blockade with cold A-186253.1 (1 mg/kg) resulted in a 50 % reduction. These results suggest, that 50 % of the [11C]-A-186253.1 in the brain corresponds to specifically bound radioligand, but not to the α4β2 subtype of the nicotinic receptor. (author)

  17. Need for validation of fagerstrom test for nicotine dependence in Indian context: Implications for nicotine replacement therapy

    Directory of Open Access Journals (Sweden)

    Manoj Kumar Sharma

    2016-01-01

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

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

    Science.gov (United States)

    Sharma, Manoj Kumar; Sharma, Priyamvada

    2016-01-01

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

  19. Addiction to the nicotine gum in never smokers

    OpenAIRE

    Etter Jean-François

    2007-01-01

    Abstract Background Addiction to nicotine gum has never been described in never smokers or in never users of tobacco. Methods Internet questionnaire in 2004–2006 in a self-selected sample of 434 daily users of nicotine gum. To assess dependence on nicotine gum, we used modified versions of the Nicotine Dependence Syndrome Scale (NDSS), the Fagerström Test for Nicotine Dependence and the Cigarette Dependence Scale. Results Five never smokers used the nicotine gum daily. They had been using the...

  20. Nicotine ameliorates NMDA receptor antagonist-induced deficits in contextual fear conditioning through high-affinity nicotinic acetylcholine receptors in the hippocampus.

    Science.gov (United States)

    André, Jessica M; Leach, Prescott T; Gould, Thomas J

    2011-03-01

    NMDA glutamate receptors (NMDARs) and nicotinic acetylcholine receptors (nAChRs) are both involved in learning and synaptic plasticity. Increasing evidence suggests processes mediated by these receptors may interact to modulate learning; however, little is known about the neural substrates involved in these interactive processes. The present studies investigated the effects of nicotine on MK-801 hydrogen maleate (MK-801) and DL-2-Amino-5-phosphonovaleric acid (APV)-induced disruption of contextual fear conditioning in male C57BL/6J mice, using direct drug infusion and selective nAChR antagonists to define the brain regions and the nAChR subtypes involved. Mice treated with MK-801 showed a deficit in contextual fear conditioning that was ameliorated by nicotine. Direct drug infusion demonstrated that the NMDAR antagonists disrupted hippocampal function and that nicotine acted in the dorsal hippocampus to ameliorate the deficit in learning. The high-affinity nAChR antagonist Dihydro-β-erythroidine hydrobromide (DhβE) blocked the effects of nicotine on MK-801-induced deficits while the α7 nAChR antagonist methyllycaconitine citrate salt hydrate (MLA) did not. These results suggest that NMDARs and nAChRs may mediate similar hippocampal processes involved in contextual fear conditioning. Furthermore, these results may have implications for developing effective therapeutics for the cognitive deficits associated with schizophrenia because a large subset of patients with schizophrenia exhibit cognitive deficits that may be related to NMDAR dysfunction and smoke at much higher rates than the healthy population, which may be an attempt to ameliorate cognitive deficits. PMID:21167848

  1. Deviant Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP)-mediated Ca2+ Signaling upon Lysosome Proliferation*

    OpenAIRE

    Dickinson, G. D.; Churchill, G. C.; Brailoiu, E; Patel, S.

    2010-01-01

    Accumulating evidence suggests that the endolysosomal system is a novel intracellular Ca2+ pool mobilized by the second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). Although lysosomes in neurons are known to proliferate in numerous neurodegenerative diseases and during the normal course of aging, little is known concerning the effect of lysosomal proliferation on Ca2+ homeostasis. Here, we induce proliferation of lysosomes in primary cultures of rat hippocampal neurons an...

  2. Novel Anti-Nicotine Vaccine Using a Trimeric Coiled-Coil Hapten Carrier.

    Directory of Open Access Journals (Sweden)

    Keith D Miller

    Full Text Available Tobacco addiction represents one of the largest public health problems in the world and is the leading cause of cancer and heart disease, resulting in millions of deaths a year. Vaccines for smoking cessation have shown considerable promise in preclinical models, although functional antibody responses induced in humans are only modestly effective in preventing nicotine entry into the brain. The challenge in generating serum antibodies with a large nicotine binding capacity is made difficult by the fact that this drug is non-immunogenic and must be conjugated as a hapten to a protein carrier. To circumvent the limitations of traditional carriers like keyhole limpet hemocyanin (KLH, we have synthesized a short trimeric coiled-coil peptide (TCC that creates a series of B and T cell epitopes with uniform stoichiometry and high density. Here we compared the relative activities of a TCC-nic vaccine and two control KLH-nic vaccines using Alum as an adjuvant or GLA-SE, which contains a synthetic TLR4 agonist formulated in a stable oil-in-water emulsion. The results showed that the TCC's high hapten density correlated with a better immune response in mice as measured by anti-nicotine Ab titer, affinity, and specificity, and was responsible for a reduction in anti-carrier immunogenicity. The Ab responses achieved with this synthetic vaccine resulted in a nicotine binding capacity in serum that could prevent >90% of a nicotine dose equivalent to three smoked cigarettes (0.05 mg/kg from reaching the brain.

  3. Bupropion inhibits the cellular effects of nicotine in the ventral tegmental area

    OpenAIRE

    Mansvelder, Huibert D.; Fagen, Zara M.; Chang, Ben; Mitchum, Robert; Daniel S Mcgehee

    2007-01-01

    Each year, tobacco use causes over 4 million deaths worldwide and billions of dollars are spent on treatment for tobacco-related illness. Bupropion, an atypical antidepressant, improves the rates of successful smoking cessation, however, the mechanisms by which bupropion reduces cigarette smoking and depression are unknown. Here we show that clinical concentrations of bupropion inhibit nicotine’s stimulatory effects on brain reward areas. Many drugs of abuse, including nicotine, stimulate dop...

  4. Nucleosome Repositioning: A Novel Mechanism for Nicotine- and Cocaine-Induced Epigenetic Changes

    OpenAIRE

    Brown, Amber N.; Vied, Cynthia; Dennis, Jonathan H.; Bhide, Pradeep G

    2015-01-01

    Drugs of abuse modify behavior by altering gene expression in the brain. Gene expression can be regulated by changes in DNA methylation as well as by histone modifications, which alter chromatin structure, DNA compaction and DNA accessibility. In order to better understand the molecular mechanisms directing drug-induced changes in chromatin structure, we examined DNA-nucleosome interactions within promoter regions of 858 genes in human neuroblastoma cells (SH-SY5Y) exposed to nicotine or coca...

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

    Science.gov (United States)

    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...

  6. Tying up Nicotine: New Selective Competitive Antagonist of the Neuronal Nicotinic Acetylcholine Receptors

    DEFF Research Database (Denmark)

    Petersen, Ida Nymann; Crestey, François; Jensen, Anders A; Indurthi, Dinesh C; Pedersen, Henrik; Andreasen, Jesper T; Balle, Thomas; Kristensen, Jesper L

    2015-01-01

    Conformational restriction of the pyrrolidine nitrogen in nicotine by the introduction of an ethylene bridge provided a potent and selective antagonist of the α4β2-subtype of the nicotinic acetylcholine receptors. Resolution by chiral SFC, pharmacological characterization of the two enantiomers...

  7. A common biological basis of obesity and nicotine addiction.

    Science.gov (United States)

    Thorgeirsson, T E; Gudbjartsson, D F; Sulem, P; Besenbacher, S; Styrkarsdottir, U; Thorleifsson, G; Walters, G B; Furberg, H; Sullivan, P F; Marchini, J; McCarthy, M I; Steinthorsdottir, V; Thorsteinsdottir, U; Stefansson, K

    2013-01-01

    Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 × 10(-5)) and CPD (P=9.3 × 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity. PMID:24084939

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

    International Nuclear Information System (INIS)

    Highlights: ► Cigarette smoke may induce liver fibrosis via nicotine receptors. ► Nicotine induces proliferation of hepatic stellate cells (HSCs). ► Nicotine activates hepatic fibrogenic pathways. ► Nicotine receptor antagonists attenuate HSC proliferation. ► 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-α2 and the pro-fibrogenic cytokine transforming growth factor beta 1 (TGF-β1) 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 (α1, β1, delta and epsilon) and neuronal type (α3, α6, α7, β2 and β4) nAChR subunits at the mRNA level. Among these subunits, α3, α7, β1 and ε were predominantly expressed as confirmed by Western blotting. Nicotine induced hHSC proliferation was attenuated by mecamylamine (p < 0.05). Additionally, collagen1-α2 and TGF-β1 mRNA expression were significantly upregulated by nicotine and inhibited by mecamylamine. α1 and α3-nAChR mRNA expression was significantly upregulated in NASH fibrosis compared to normal livers. Conclusion: Nicotine at levels in smokers’ blood is pro-fibrogenic, through

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

    Energy Technology Data Exchange (ETDEWEB)

    Soeda, Junpei; Morgan, Maelle; McKee, Chad; Mouralidarane, Angelina; Lin, ChingI [University College London, Centre for Hepatology, Royal Free Hospital, London NW3 2PF (United Kingdom); Roskams, Tania [Department of Morphology and Molecular Pathology, University of Leuven (Belgium); Oben, Jude A., E-mail: j.oben@ucl.ac.uk [University College London, Centre for Hepatology, Royal Free Hospital, London NW3 2PF (United Kingdom); Department of Gastroenterology and Hepatology, Guy' s and St Thomas' Hospital, London SE1 7EH (United Kingdom)

    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

  10. Yield and Nicotine Content of Flue-Cured Tobacco as Affected by Soil Nitrogen Mineralization

    Institute of Scientific and Technical Information of China (English)

    JU Xiao-Tang; CHAO Feng-Chun; LI Chun-Jian; JIANG Rong-Feng; P.CHRISTIE; ZHANG Fu-Suo

    2008-01-01

    Nitrogen (N) supply is the most important factor affecting yield and quality of flue-cured tobacco (FCT).A field experiment and an in situ incubation method were used to study the effects of soil N mineralization in the later stages of growth on yield and nicotine content of FCT in Fenggang and Jiusha,Guizhou Province.The yield and market value of FCT at Fenggang were much lower than those at Jinsha.However,the nicotine content of middle and upper leaves was much higher at Fenggang than at Jiusha when the same rate of fertilizer N was applied,which might be due to a higher N supply capacity at the Fenggang site.At later stages of growth (7-16 weeks after transplanting),the soil net N mineralization at Fenggang (56 kg N ha-1) was almost double that at Jiusha (30 kg N ha-1).While soil NHa-N and NO3-N were almost exhausted by the plants or leached 5 weeks after transplanting,the N taken up at the later growth stages at Fenggang were mainly derived from soil N mineralization,which contributed to a high nicotine content in the upper leaves.The order of soil N contribution to N buildup in different leaves was:upper leaves > middle leaves > lower leaves.Thus,soil N mineralization at late growth stages was an important factor affecting N accumulation and therefore the nicotine content in the upper leaves.

  11. Nicotine and the Developing Human: A Neglected Element in the Electronic Cigarette Debate.

    Science.gov (United States)

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

    2015-08-01

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

  12. Resting-state functional connectivity between the dorsal anterior cingulate cortex and thalamus is associated with risky decision-making in nicotine addicts.

    Science.gov (United States)

    Wei, Zhengde; Yang, Nannan; Liu, Ying; Yang, Lizhuang; Wang, Ying; Han, Long; Zha, Rujing; Huang, Ruiqi; Zhang, Peng; Zhou, Yifeng; Zhang, Xiaochu

    2016-01-01

    Nicotine addiction is associated with risky behaviors and abnormalities in local brain areas related to risky decision-making such as the dorsal anterior cingulate cortex (dACC), anterior insula (AI), and thalamus. Although these brain abnormalities are anatomically separated, they may in fact belong to one neural network. However, it is unclear whether circuit-level abnormalities lead to risky decision-making in smokers. In the current study, we used task-based functional magnetic resonance imaging (fMRI) and examined resting-state functional connectivity (RSFC) to study how connectivity between the dACC, insula, and thalamus influence risky decision-making in nicotine addicts. We found that an increase in risky decision-making was associated with stronger nicotine dependence and stronger RSFC of the dACC-rAI (right AI), the dACC-thalamus, the dACC-lAI (left AI), and the rAI-lAI, but that risky decision-making was not associated with risk level-related activation. Furthermore, the severity of nicotine dependence positively correlated with RSFC of the dACC-thalamus but was not associated with risk level-related activation. Importantly, the dACC-thalamus coupling fully mediated the effect of nicotine-dependent severity on risky decision-making. These results suggest that circuit-level connectivity may be a critical neural link between risky decision-making and severity of nicotine dependence in smokers. PMID:26879047

  13. Design, formulation and evaluation of nicotine chewing gum

    Directory of Open Access Journals (Sweden)

    Abolfazl Aslani

    2012-01-01

    Conclusion: Taste enhancement of nicotine gums was achieved where formulations comprised aspartame as the sweetener and cherry and eucalyptus as the flavoring agents. Nicotine gums of pleasant taste may, therefore, be used as NRT to assist smokers quit smoking.

  14. Adolescent mice are less sensitive to the effects of acute nicotine on context pre-exposure than adults.

    Science.gov (United States)

    Kutlu, Munir Gunes; Braak, David C; Tumolo, Jessica M; Gould, Thomas J

    2016-07-01

    Adolescence is a critical developmental period associated with both increased vulnerability to substance abuse and maturation of certain brain regions important for learning and memory such as the hippocampus. In this study, we employed a hippocampus-dependent learning context pre-exposure facilitation effect (CPFE) paradigm in order to test the effects of acute nicotine on contextual processing during adolescence (post-natal day (PND) 38) and adulthood (PND 53). In Experiment 1, adolescent or adult C57BL6/J mice received either saline or one of three nicotine doses (0.09, 0.18, and 0.36mg/kg) prior to contextual pre-exposure and testing. Our results demonstrated that both adolescent and adult mice showed CPFE in the saline groups. However, adolescent mice only showed acute nicotine enhancement of CPFE with the highest nicotine dose whereas adult mice showed the enhancing effects of acute nicotine with all three doses. In Experiment 2, to determine if the lack of nicotine's effects on CPFE shown by adolescent mice is specific to the age when they are tested, mice were either given contextual pre-exposure during adolescence or adulthood and received immediate shock and testing during adulthood after a 15day delay. We found that both adolescent and adult mice showed CPFE in the saline groups when tested during adulthood. However, like Experiment 1, mice that received contextual pre-exposure during adolescence did not show acute nicotine enhancement except at the highest dose (0.36mg/kg) whereas both low (0.09mg/kg) and high (0.36mg/kg) doses enhanced CPFE in adult mice. Finally, we showed that the enhanced freezing response found with 0.36mg/kg nicotine in the 15-day experiment may be a result of decreased locomotor activity as mice that received this dose of nicotine traveled shorter distances in an open field paradigm. Overall, our results indicate that while adolescent mice showed normal contextual processing when tested both during adolescence and adulthood, they

  15. Difference in {sup 201}TlCl accumulation mechanism in brain tumors. A comparison of their Na{sup +}-K{sup +} ATPase activities

    Energy Technology Data Exchange (ETDEWEB)

    Sugo, Nobuo; Kuroki, Takao; Nemoto, Masaaki; Mito, Toshiaki; Seiki, Yoshikatsu; Shibata, Iekado [Toho Univ., Tokyo (Japan). Omori Hospital

    2000-07-01

    The accumulation levels of {sup 201}TlCl and Na{sup +} -K{sup +} ATPase activity in tumor tissue were compared among glioblastoma, benign glioma and meningioma to study the difference in the mechanism of {sup 201}TlCl accumulation. The subjects were 19 cases comprised of 6 glioblastoma, 2 oligodendroglioma, 1 fibrillary astrocytoma, 1 pilocytic astrocytoma and 9 meningioma. Preoperative {sup 201}TlCl SPECT was performed in all the cases, and Thallium Index (TL index) was calculated by a ratio of {sup 201}TlCl in the tumor area and the contralateral area. In addition, cell membrane was extracted from the tumor tissue collected intraoperatively to determine Na{sup +} -K{sup +} ATPase activity. No statistically significant difference in TL index was noted between the glioblastoma group (6.97{+-}2.67) and the meningioma group (5.87{+-}1.99). This fact showed that there was no difference in the accumulation level of {sup 201}TlCl between the two groups. On the other hand, the glioblastoma group indicated a higher value of Na{sup +} -K{sup +} ATPase activity (49.13{+-}43.76 {mu}mole/hour/mg protein) than the meningioma group (7.73{+-}13.84 {mu}mol/hour/mg protein) (p<0.05, t test). These results suggested the involvement of Na{sup +} -K{sup +} ATPase activity in {sup 201}TlCl accumulation in glioblastoma and the influences of other accumulation mechanism than Na{sup +} -K{sup +} ATPase activity such as the volume of intratumoral vascular bed in meningioma. (author)

  16. Accumulation and aberrant composition of cholesteryl esters in Scrapie-infected N2a cells and C57BL/6 mouse brains

    Directory of Open Access Journals (Sweden)

    Di Bari Michele A

    2011-08-01

    Full Text Available Abstract Objective Cholesterol changes have been described in prion-cell models and in experimental rodent scrapie; yet, the pattern of this association is still controversial. Methods To shed light on the matter, we analysed and compared cholesterol variations in ScN2a cells and in brains of Scrapie-infected C57Bl/6 mice, using two different methods: a fluorimetric-enzymatic cholesterol assay, and high performance liquid chromatography-mass spectroscopy (HPLC-MS. Results Compared to uninfected controls, similar cholesterol metabolism anomalies were observed in infected cells and brains by both methods; however, only HPLC-MS revealed statistically significant cholesterol variations, particularly in the cholesteryl esters (CE fraction. HPLC-MS analyses also revealed different fatty acid composition of the CE fraction in cells and brains. In N2a cells, their profile reflected that of serum, while in normal brains cholesteryl-linoleate only was found at detectable levels. Following prion infection, most CE species were increased in the CE pool of ScN2a cells, whereas a conspicuous amount of cholesteryl-arachidonate only was found to contribute to the cerebral increase of CE. Of interest, oral pravastatin administration to Scrapie-infected mice, was associated with a significant reduction of cerebral free cholesterol (FC along with a concomitant further increase of the CE pool, which included increased amounts of both cholesteryl-linoleate and cholesteryl-arachidonate. Conclusion Although mechanistic studies are needed to establish the pathophysiological relevance of changes in cerebral CE concentrations, to the best of our knowledge this is the first report to provide evidence of increased cholesterol esterification in brains of prion-infected mice, untreated and treated with pravastatin.

  17. Addiction to the nicotine gum in never smokers

    Directory of Open Access Journals (Sweden)

    Etter Jean-François

    2007-07-01

    Full Text Available Abstract Background Addiction to nicotine gum has never been described in never smokers or in never users of tobacco. Methods Internet questionnaire in 2004–2006 in a self-selected sample of 434 daily users of nicotine gum. To assess dependence on nicotine gum, we used modified versions of the Nicotine Dependence Syndrome Scale (NDSS, the Fagerström Test for Nicotine Dependence and the Cigarette Dependence Scale. Results Five never smokers used the nicotine gum daily. They had been using the nicotine gum for longer than the 429 ever smokers (median = 6 years vs 0.8 years, p = 0.004, and they had higher NDSS-gum Tolerance scores (median = 0.73 vs = -1.0, p = 0.03, a difference of 1.5 standard deviation units. Two never smokers had never used smokeless tobacco, both answered "extremely true" to: "I use nicotine gums because I am addicted to them", both "fully agreed" with: "after a few hours without chewing a nicotine gum, I feel an irresistible urge to chew one" and: "I am a prisoner of nicotine gum". Conclusion This is to our knowledge the first report of addiction to nicotine gum in never users of tobacco. However, this phenomenon is rare, and although the long-term effect of nicotine gum is unknown, this product is significantly less harmful than tobacco.

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

    Science.gov (United States)

    Abbas, Muzaffar; Rahman, Shafiqur

    2016-07-15

    Evidence indicates that microglial activation contributes to the pathophysiology and maintenance of neuroinflammatory pain involving central nervous system alpha-7 nicotinic acetylcholine receptors. The objective of the present study was to determine the effects of 3a,4,5,9b-Tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS), an alpha-7 nicotinic acetylcholine receptor positive allosteric modulator (PAM), on tactile allodynia and thermal hyperalgesia following lipopolysaccharide (LPS)-induced microglial activation in hippocampus, a neuroinflammatory pain model in mice. In addition, we examined the effects of TQS on microglial activation marker, an ionized calcium-binding adapter molecule 1 (Iba-1), in the hippocampus may be associated with neuroinflammatory pain. Pretreatment of TQS (4mg/kg) significantly reduced LPS (1mg/kg)-induced tactile allodynia and thermal hyperalgesia. Moreover, pretreatment of methyllycaconitine (3mg/kg) significantly reversed TQS-induced antiallodynic and antihyperalgesic responses indicating the involvement of alpha-7 nicotinic acetylcholine receptor. Pretreatment of TQS significantly decreased LPS-induced increased in hippocampal Iba-1 expression. Overall, these results suggest that TQS reduces LPS-induced neuroinflammatory pain like symptoms via modulating microglial activation likely in the hippocampus and/or other brain region by targeting alpha-7 nicotinic acetylcholine receptor. Therefore, alpha-7 nicotinic acetylcholine receptor PAM such as TQS could be a potential drug candidate for the treatment of neuroinflammatory pain. PMID:27154173

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

    Science.gov (United States)

    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...

  20. Postsynaptic scaffolds for nicotinic receptors on neurons

    Institute of Scientific and Technical Information of China (English)

    Robert A NEFF III; David GOMEZ-VARELA; Catarina C FERNANDES; Darwin K BERG

    2009-01-01

    Complex postsynaptic scaffolds determine the structure and signaling capabilities of glutamatergic synapses. Recent studies indicate that some of the same scaffold components contribute to the formation and function of nicotinic synapses on neurons. PDZ-containing proteins comprising the PSD-95 family co-localize with nicotinic acetylcholine receptors (nAChRs) and mediate downstream signaling in the neurons. The PDZ-proteins also promote functional nicotinic innerva- tion of the neurons, as does the scaffold protein APC and transmembrane proteins such as neuroligin and the EphB2 recep- tor. In addition, specific chaperones have been shown to facilitate nAChR assembly and transport to the cell surface. This review summarizes recent results in these areas and raises questions for the future about the mechanism and synaptic role of nAChR trafficking.

  1. Ammonia inhibits the C-type natriuretic peptide-dependent cyclic GMP synthesis and calcium accumulation in a rat brain endothelial cell line.

    Science.gov (United States)

    Konopacka, Agnieszka; Zielińska, Magdalena; Albrecht, Jan

    2008-05-01

    Recently we reported a decrease of C-type natriuretic peptide (CNP)-dependent, natriuretic peptide receptor 2 (NPR2)-mediated cyclic GMP (cGMP) synthesis in a non-neuronal compartment of cerebral cortical slices of hyperammonemic rats [Zielińska, M., Fresko, I., Konopacka, A., Felipo, V., Albrecht, J., 2007. Hyperammonemia inhibits the natriuretic peptide receptor 2 (NPR2)-mediated cyclic GMP synthesis in the astrocytic compartment of rat cerebral cortex slices. Neurotoxicology 28, 1260-1263]. Here we accounted for the possible involvement of cerebral capillary endothelial cells in this response by measuring the effect of ammonia on the CNP-mediated cGMP formation and intracellular calcium ([Ca2+]i) accumulation in a rat cerebral endothelial cell line (RBE-4). We first established that stimulation of cGMP synthesis in RBE-4 cells was coupled to protein kinase G (PKG)-mediated Ca2+ influx from the medium which was inhibited by an L-type channel blocker nimodipine. Ammonia treatment (1h, 5mM NH4Cl) evoked a substantial decrease of CNP-stimulated cGMP synthesis which was related to a decreased binding of CNP to NPR2 receptors, and depressed the CNP-dependent [Ca2+]i accumulation in these cells. Ammonia also abolished the CNP-dependent Ca2+ accumulation in the absence of Na+. In cells incubated with ammonia in the absence of Ca2+ a slight CNP-dependent increase of [Ca2+]i was observed, most likely representing Ca2+ release from intracellular stores. Depression of CNP-dependent cGMP-mediated [Ca2+]i accumulation may contribute to cerebral vascular endothelial dysfunction associated with hyperammonemia or hepatic encephalopathy. PMID:18222015

  2. Brain region-specific perfluoroalkylated sulfonate (PFSA) and carboxylic acid (PFCA) accumulation and neurochemical biomarker responses in east Greenland polar bears (Ursus maritimus)

    DEFF Research Database (Denmark)

    Pedersen, Kathrine Eggers; Basu, Niladri; Letcher, Robert J.;

    2015-01-01

    MAO activity in occipital lobe (e.g. ∑PFCA; rp=0.83, p=0.041, n=6) and across brain regions (e.g. ∑PFCA; rp=0.47, p=0.001, ∑PFSA; rp=0.44, p>0.001; n=50). GABA-A receptor density was positively correlated with two PFASs across brain regions (PFOS; rp=0.33, p=0.02 and PFDoDA; rp=0.34, p=0.014; n=52...... regions, whereas GS activity was positively correlated with PFASs primarily in occipital lobe. Results from the present study support the hypothesis that PFAS concentrations in polar bears from East Greenland have exceeded the threshold limits for neurochemical alterations. It is not known whether the...

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

    International Nuclear Information System (INIS)

    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 3H-nicotine and unlabeled nicotine. Specific binding was calculated as the difference between 3H-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 3H-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

  4. Therapeutic Potential of α7 Nicotinic Acetylcholine Receptors.

    Science.gov (United States)

    Bertrand, Daniel; Lee, Chih-Hung L; Flood, Dorothy; Marger, Fabrice; Donnelly-Roberts, Diana

    2015-10-01

    Progress in the fields of neuroscience and molecular biology has identified the forebrain cholinergic system as being important in many higher order brain functions. Further analysis of the genes encoding the nicotinic acetylcholine receptors (nAChRs) has highlighted, in particular, the role of α7 nAChRs in these higher order brain functions as evidenced by their peculiar physiologic and pharmacological properties. As this receptor has gained the attention of scientists from academia and industry, our knowledge of its roles in various brain and bodily functions has increased immensely. We have also seen the development of small molecules that have further refined our understanding of the roles of α7 nAChRs, and these molecules have begun to be tested in clinical trials for several indications. Although a large body of data has confirmed a role of α7 nAChRs in cognition, the translation of small molecules affecting α7 nAChRs into therapeutics has to date only progressed to the stage of testing in clinical trials. Notably, however, most recent human genetic and biochemical studies are further underscoring the crucial role of α7 nAChRs and associated genes in multiple organ systems and disease states. The aim of this review is to discuss our current knowledge of α7 nAChRs and their relevance as a target in specific functional systems and disease states. PMID:26419447

  5. Complex suicide with homemade nicotine patches.

    Science.gov (United States)

    Lardi, C; Vogt, S; Pollak, S; Thierauf, A

    2014-03-01

    Suicide by self-poisoning is rather common around the world. This paper presents an exceptional complex suicide in which nicotine was applied in the form of self-made patches soaked with an extraction from fine-cut tobacco. In addition, the 51-year-old suicide victim took a lethal dose of diphenhydramine. Toxicological analysis also revealed the presence of tetrazepam in subtherapeutic concentrations. The scene of death suggested an autoerotic accident at first, as the body was tied with tapes, cables and handcuffs. As a result of the entire investigations, the fatality had to be classified as a suicidal intoxication by nicotine and diphenhydramine. PMID:24439154

  6. A REVIEW: TRANSDERMAL DRUG DELIVERY OF NICOTINE

    OpenAIRE

    Saurabh Ravi; Sharma P. K; Bansal M

    2011-01-01

    Cigarette smoking has been the leading cause of premature death and illness in many industrialized country in the world, while the U.S. alone registers more than 4,00,000 deaths each year. The nicotine patch serves to deliver a constant dose of nicotine across the skin that helps to relieve the symptoms which are associated with tobacco withdrawal. Further, the use of carbon nanotube membranes and micro needle based transdermal drug delivery has lead to the great advancements. Some of the mai...

  7. A REVIEW: TRANSDERMAL DRUG DELIVERY OF NICOTINE

    Directory of Open Access Journals (Sweden)

    Saurabh Ravi

    2011-06-01

    Full Text Available Cigarette smoking has been the leading cause of premature death and illness in many industrialized country in the world, while the U.S. alone registers more than 4,00,000 deaths each year. The nicotine patch serves to deliver a constant dose of nicotine across the skin that helps to relieve the symptoms which are associated with tobacco withdrawal. Further, the use of carbon nanotube membranes and micro needle based transdermal drug delivery has lead to the great advancements. Some of the main advantages of transdermal drug delivery are bypassing of hepatic first pass metabolism, maintenance of steady plasma level of the drug and enhancement of therapeutic efficiency.

  8. Effect of chronic nicotine pre-treatment on phencyclidine (PCP) disposition in the rat.

    Science.gov (United States)

    Vadlamani, N L; Pontani, R B; Misra, A L

    1983-09-01

    Disposition of [3H] phencyclidine (5 mg kg-1 i.p.) in brain, liver and plasma of rats treated chronically with 0.9% saline or nicotine (1 mg kg-1 s.c. twice a day for 11 days) was studied using a method possessing high sensitivity and specificity for PCP. No significant differences were observed in the values of PCP in plasma and tissues and in brain or liver to plasma PCP concentration ratios in the 2 groups 0.5, 1, 2 hr after [3H] PCP injection. With the exception of the value of PCP metabolites in plasma at 0.5 hr, the PCP metabolites concentrations were also not significantly different in the 2 groups. Data suggested that chronic nicotine pretreatment of rats did not affect the disposition of PCP and the potentiation of PCP-induced locomotor stimulant effects by nicotine possibly involves the additive pharmacodynamic interaction of 2 compounds at the level of the central nervous system. PMID:6651404

  9. [Nicotine and animal models: what does the environmental enrichment paradigm tell us?].

    Science.gov (United States)

    Mesa-Gresa, Patricia; Pérez-Martínez, Asunción; Redolat-Iborra, Rosa

    2012-01-01

    The Environmental Enrichment (EE) paradigm is a housing condition which aims is to provide physical, cognitive and sensorial stimulation to rodents. Animals are housed in larger cages containing inanimate objects such as tunnels, toys and running wheels. The main aim of the current work is to tackle the arguments which suggest that EE may diminish vulnerability to developing addiction to nicotine and other drugs of abuse and to review recent experimental studies performed in relation to this subject. We discuss the major changes induced by EE at physical, neurobiological and behavioral levels and review the results of recent studies which indicate that EE promotes both neurochemical (potentiation of the increase in dopamine release induced by nicotine in the brain cortex) and behavioral changes (increased ability to discriminate the presence of reward and decreased impulsivity), thus supporting the hypothesis put forward. In light of these results, EE can be proposed as a model for the study of vulnerability to addiction to different drugs of abuse, including cocaine and nicotine, though further studies are needed in order to establish the neurobiological implications of the effects of exposure to enriched environments and their possible relationship with changes in brain reward systems. PMID:22648311

  10. Anxiogenic-like effects of chronic nicotine exposure in zebrafish.

    Science.gov (United States)

    Stewart, Adam Michael; Grossman, Leah; Collier, Adam D; Echevarria, David J; Kalueff, Allan V

    2015-12-01

    Nicotine is one of the most widely used and abused legal drugs. Although its pharmacological profile has been extensively investigated in humans and rodents, nicotine CNS action remains poorly understood. The importance of finding evolutionarily conserved signaling pathways, and the need to apply high-throughput in vivo screens for CNS drug discovery, necessitate novel efficient experimental models for nicotine research. Zebrafish (Danio rerio) are rapidly emerging as an excellent organism for studying drug abuse, neuropharmacology and toxicology and have recently been applied to testing nicotine. Anxiolytic, rewarding and memory-modulating effects of acute nicotine treatment in zebrafish are consistently reported in the literature. However, while nicotine abuse is more relevant to long-term exposure models, little is known about chronic effects of nicotine on zebrafish behavior. In the present study, chronic 4-day exposure to 1-2mg/L nicotine mildly increased adult zebrafish shoaling but did not alter baseline cortisol levels. We also found that chronic exposure to nicotine evokes robust anxiogenic behavioral responses in zebrafish tested in the novel tank test paradigm. Generally paralleling clinical and rodent data on anxiogenic effects of chronic nicotine, our study supports the developing utility of zebrafish for nicotine research. PMID:25643654

  11. Nicotinic {alpha}4{beta}2 receptor imaging agents

    Energy Technology Data Exchange (ETDEWEB)

    Pichika, Rama [Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-3960 (United States); Easwaramoorthy, Balasubramaniam [Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-3960 (United States); Collins, Daphne [Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-3960 (United States); Christian, Bradley T. [Department of Nuclear Medicine, Kettering Medical Center, Dayton, OH 45429 (United States); Shi, Bingzhi [Department of Nuclear Medicine, Kettering Medical Center, Dayton, OH 45429 (United States); Narayanan, Tanjore K. [Department of Nuclear Medicine, Kettering Medical Center, Dayton, OH 45429 (United States); Potkin, Steven G. [Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-3960 (United States); Mukherjee, Jogeshwar [Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-3960 (United States)]. E-mail: j.mukherjee@uci.edu

    2006-04-15

    The {alpha}4{beta}2 nicotinic acetylcholine receptor (nAChR) has been implicated in various neurodegenerative diseases. Optimal positron emission tomography (PET) imaging agents are therefore highly desired for this receptor. We report here the development and initial evaluation of 2-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (nifene). In vitro binding affinity of nifene in rat brain homogenate using {sup 3}H-cytisine exhibited a K {sub i}=0.50 nM for the {alpha}4{beta}2 sites. The radiosynthesis of 2-{sup 18}F-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine ({sup 18}F-nifene) was accomplished in 2.5 h with an overall radiochemical yield of 40-50%, decay corrected. The specific activity was estimated to be approx. 37-185 GBq/{mu}mol. In vitro autoradiography in rat brain slices indicated selective binding of {sup 18}F-nifene to anteroventral thalamic (AVT) nucleus, thalamus, subiculum, striata, cortex and other regions consistent with {alpha}4{beta}2 receptor distribution. Rat cerebellum showed some binding, whereas regions in the hippocampus had the lowest binding. The highest ratio of >13 between AVT and cerebellum was measured for {sup 18}F-nifene in rat brain slices. The specific binding was reduced (>95%) by 300 {mu}M nicotine in these brain regions. Positron emission tomography imaging study of {sup 18}F-nifene (130 MBq) in anesthetized rhesus monkey was carried out using an ECAT EXACT HR+ scanner. PET study showed selective maximal uptake in the regions of the anterior medial thalamus, ventro-lateral thalamus, lateral geniculate, cingulate gyrus, temporal cortex including the subiculum. The cerebellum in the monkeys showed lower binding than the other regions. Thalamus-to-cerebellum ratio peaked at 30-35 min postinjection to a value of 2.2 and subsequently reduced. The faster binding profile of {sup 18}F-nifene indicates promise as a PET imaging agent and thus needs further evaluation.

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

    Science.gov (United States)

    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.

  13. Electrical Stimulation of the Insular Region Attenuates Nicotine-Taking and Nicotine-Seeking Behaviors

    OpenAIRE

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

    2012-01-01

    Pharmacological inactivation of the granular insular cortex is able to block nicotine-taking and -seeking behaviors in rats. In this study, we explored the potential of modulating activity in the insular region using electrical stimulation. Animals were trained to self-administer nicotine (0.03 mg/kg per infusion) under a fixed ratio-5 (FR-5) schedule of reinforcement followed by a progressive ratio (PR) schedule. Evaluation of the effect of stimulation in the insular region was performed on ...

  14. Nicotinic and iso nicotinic acids: interactions with gamma radiation and acid-base equilibrium

    International Nuclear Information System (INIS)

    The values of pKa1 and pKa2 for nicotinic and iso nicotinic acids in aqueous medium were determined. The effects of gamma radiation about these acids by infrared and ultraviolet spectrophotometry and thermal gravimetric analysis were also studied. It was verified that the radiolysis of acids occurred by the two process of first order, determining the degradation constant and the degradation factors for each one of the solutions. (C.G.C.)

  15. Low dose nicotine self-administration is reduced in adult male rats naïve to high doses of nicotine: Implications for nicotine product standards

    OpenAIRE

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

    2014-01-01

    Product standards that greatly reduce the content of nicotine within cigarettes may result in improved public health. The present study used an animal model to investigate whether individuals who start smoking following implementation of regulation may be affected differently from current smokers who form the basis of most clinical studies. One group of adult male rats (n=14/group) acquired nicotine self-administration at a high nicotine dose (60 μg/kg/infusion) before experiencing a reductio...

  16. Histamine receptors coupled to [3H]cAMP accumulation in brain: pharmacological characterization in a vesicular preparation of guinea pig cortex

    International Nuclear Information System (INIS)

    The histamine-stimulated accumulation of [3H]cAMP (formed by prelabeling with [3H]adenine) was characterized pharmacologically in a vesicular preparation of guinea pig cortex. The H2 antagonist cimetidine maximally blocked 80% of the response, whereas only 45% of the response could be inhibited by H1 antagonists. A combination of H1 and H2 antagonists completely abolished the response. These and other findings show that both H1 and H2 receptors mediate the response, but 25% of the response may require simultaneous activation of both receptors. A role for adenosine as a mediator of the histamine response was investigated. Adenosine deaminase (EC 3.5.4.4., 2.5 units/ml) decreased basal [3H]cAMP levels, abolished the cimetidine-resistant component of the histamine response, and reduced maximal H1 antagonism of the histamine response to 30%. Treatment with a combination of adenosine deaminase and the calcium chelator EGTA (2 mM) appeared to eliminate the H1 component completely. Under these latter conditions only H2 receptors appeared to mediate the histamine response. Thus, both H1 and H2 receptors stimulate [3H]cAMP accumulation in the vesicular preparation, but the H1 response seems to require either concomitant adenosine or H2 receptor stimulation and may be calcium dependent. These findings differ from those found in broken cell membrane preparations, where only H2 receptors appear to be coupled to adenylate cyclase activation

  17. Phosphorylation of Akt by SC79 Prevents Iron Accumulation and Ameliorates Early Brain Injury in a Model of Experimental Subarachnoid Hemorrhage

    Directory of Open Access Journals (Sweden)

    Shuangying Hao

    2016-03-01

    Full Text Available Previous studies have demonstrated that activation of Akt may alleviate early brain injury (EBI following subarachnoid hemorrhage (SAH. This study is undertaken to determine whether iron metabolism is involved in the beneficial effect of Akt activation after SAH. Therefore, we used a novel molecule, SC79, to activate Akt in an experimental Sprague–Dawley rat model of SAH. Rats were randomly divided into four groups as follows: sham, SAH, SAH + vehicle, SAH + SC79. The results confirmed that SC79 effectively enhanced the defense against oxidative stress and alleviated EBI in the temporal lobe after SAH. Interestingly, we found that phosphorylation of Akt by SC79 reduced cell surface transferrin receptor-mediated iron uptake and promoted ferroportin-mediated iron transport after SAH. As a result, SC79 administration diminished the iron content in the brain tissue. Moreover, the impaired Fe-S cluster biogenesis was recovered and loss of the activities of the Fe-S cluster-containing enzymes were regained, indicating that injured mitochondrial functions are restored to healthy levels. These findings suggest that disrupted iron homeostasis could contribute to EBI and Akt activation may regulate iron metabolism to relieve iron toxicity, further protecting neurons from EBI after SAH.

  18. The influence of chronic nicotine treatment on proteins expressed in the mouse hippocampus and cortex.

    Science.gov (United States)

    Matsuura, Kenji; Otani, Mieko; Takano, Masaoki; Kadoyama, Keiichi; Matsuyama, Shogo

    2016-06-01

    Chronic treatment with nicotine, the primary psychoactive substance in tobacco smoke, affects central nervous system functions, such as synaptic plasticity. Here, to clarify the effects of chronic nicotine treatment on the higher brain functions, proteomic analysis of the hippocampus and cortex of mice treated for 6 months with nicotine was performed using two-dimensional gel electrophoresis (2-DE) followed by mass spectrometry. There was significant change in the expression of 16 proteins and one phosphoprotein in the hippocampus (increased tubulin β-5, atp5b, MDH1, cytochrome b-c1 complex subunit 1, Hsc70, dynamin, profilin-2, 4-aminobutyrate aminotransferase, mitochondrial isoform 1 precursor, calpain small subunit 1, and vacuolar adenosine triphosphatase subunit B and decreased γ-actin, α-tubulin isotype M-α-2, putative β-actin, tubulin β-2A, NDUFA10, and G6PD) and 24 proteins and two phosphoproteins in the cortex (increased spectrin α chain, non-erythrocytic 1 isoform 1, tubulin β-5, γ-actin, creatine kinase B-type, LDH-B, secernin-1, UCH-L1, 14-3-3 γ, type II peroxiredoxin 1, PEBP-1, and unnamed protein product and decreased tubulin α-1C, α-internexin, γ-enolase, PDHE1-B, DPYL2, vacuolar adenosine triphosphatase subunit A, vacuolar adenosine triphosphatase subunit B, TCTP, NADH dehydrogenase Fe-S protein 1, protein disulfide-isomerase A3, hnRNP H2, γ-actin, atp5b, and unnamed protein product). Additionally, Western blotting validated the changes in dynamin, Hsc70, MDH1, NDUFA10, α-internexin, tubulin β-5 chain, and secernin-1. Thus, these findings indicate that chronic nicotine treatment changes the expression of proteins and phosphoproteins in the hippocampus and cortex. We propose that effect of smoking on higher brain functions could be mediated by alterations in expression levels of these proteins. PMID:26988295

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

    Science.gov (United States)

    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. PMID:27068856

  20. Cannabinoid CB2 Receptor Mediates Nicotine-Induced Anti-Inflammation in N9 Microglial Cells Exposed to β Amyloid via Protein Kinase C

    Directory of Open Access Journals (Sweden)

    Ji Jia

    2016-01-01

    Full Text Available Background. Reducing β amyloid- (Aβ- induced microglial activation is considered to be effective in treating Alzheimer’s disease (AD. Nicotine attenuates Aβ-induced microglial activation; the mechanism, however, is still elusive. Microglia could be activated into classic activated state (M1 state or alternative activated state (M2 state; the former is cytotoxic and the latter is neurotrophic. In this investigation, we hypothesized that nicotine attenuates Aβ-induced microglial activation by shifting microglial M1 to M2 state, and cannabinoid CB2 receptor and protein kinase C mediate the process. Methods. We used Aβ1–42 to activate N9 microglial cells and observed nicotine-induced effects on microglial M1 and M2 biomarkers by using western blot, immunocytochemistry, and enzyme-linked immunosorbent assay (ELISA. Results. We found that nicotine reduced the levels of M1 state markers, including inducible nitric oxide synthase (iNOS expression and tumor necrosis factor α (TNF-α and interleukin- (IL- 6 releases; meanwhile, it increased the levels of M2 state markers, including arginase-1 (Arg-1 expression and brain-derived neurotrophic factor (BDNF release, in the Aβ-stimulated microglia. Coadministration of cannabinoid CB2 receptor antagonist or protein kinase C (PKC inhibitor partially abolished the nicotine-induced effects. Conclusion. These findings indicated that cannabinoid CB2 receptor mediates nicotine-induced anti-inflammation in microglia exposed to Aβ via PKC.

  1. Cigarette Smoking and Brain Regulation of Energy Homeostasis

    OpenAIRE

    HuiChen; SoniaSaad; ShaunSandow

    2012-01-01

    Cigarette smoking is an addictive behavior, and is the primary cause of cardiovascular and pulmonary disease, and cancer (among other diseases). Cigarette smoke contains thousands of components that may affect caloric intake and energy expenditure, although nicotine is the major addictive substance present, and has the best described actions. Nicotine exposure from cigarette smoke can change brain feeding regulation to reduce appetite via both energy homeostatic and reward mechanisms, causing...

  2. Common biology of craving across legal and illegal drugs - a quantitative meta-analysis of cue-reactivity brain response.

    Science.gov (United States)

    Kühn, Simone; Gallinat, Jürgen

    2011-04-01

    The present quantitative meta-analysis set out to test whether cue-reactivity responses in humans differ across drugs of abuse and whether these responses constitute the biological basis of drug craving as a core psychopathology of addiction. By means of activation likelihood estimation, we investigated the concurrence of brain regions activated by cue-induced craving paradigms across studies on nicotine, alcohol and cocaine addicts. Furthermore, we analysed the concurrence of brain regions positively correlated with self-reported craving in nicotine and alcohol studies. We found direct overlap between nicotine, alcohol and cocaine cue reactivity in the ventral striatum. In addition, regions of close proximity were observed in the anterior cingulate cortex (ACC; nicotine and cocaine) and amygdala (alcohol, nicotine and cocaine). Brain regions of concurrence in drug cue-reactivity paradigms that overlapped with brain regions of concurrence in self-reported craving correlations were found in the ACC, ventral striatum and right pallidum (for alcohol). This first quantitative meta-analysis on drug cue reactivity identifies brain regions underlying nicotine, alcohol and cocaine dependency, i.e. the ventral striatum. The ACC, right pallidum and ventral striatum were related to drug cue reactivity as well as self-reported craving, suggesting that this set of brain regions constitutes the core circuit of drug craving in nicotine and alcohol addiction. PMID:21261758

  3. 1H chemical shift imaging of the brain in guanidino methyltransferase deficiency, a creatine deficiency syndrome; guanidinoacetate accumulation in the gray matter

    International Nuclear Information System (INIS)

    MR spectroscopy results in a mild case of guanidinoacetate methyltransferase (GAMT) deficiency are presented. The approach differs from previous MRS studies in the acquisition of a chemical shift imaging spectral map showing gray and white matter with the corresponding spectra in one overview. MR spectroscopy revealed guanidinoacetate (GAA) in the absence of creatine. New is that GAA signals are more prominent in gray matter than in white. In the prevailing view, that enzyme deficiency is localized in liver and pancreas and that all GAA is transported into the brain from the blood and the cerebrospinal fluid, this would be compatible with a more limited uptake and/or better clearance of GAA from the white matter compared to the grey matter. (orig.)

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

    Science.gov (United States)

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

    2016-04-01

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

  5. Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits.

    Science.gov (United States)

    Vieira-Brock, Paula L; McFadden, Lisa M; Nielsen, Shannon M; Ellis, Jonathan D; Walters, Elliot T; Stout, Kristen A; McIntosh, J Michael; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

    2015-12-01

    Repeated methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of Parkinson's disease. Many METH abusers smoke cigarettes and thus self-administer nicotine; yet few studies have investigated the effects of nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that nicotine can be neuroprotective, perhaps owing to effects involving α4β2 and α6β2 nicotinic acetylcholine receptors (nAChRs). This study revealed that oral nicotine exposure beginning in adolescence [postnatal day (PND) 40] through adulthood [PND 96] attenuated METH-induced striatal dopaminergic deficits when METH was administered at PND 89. This protection did not appear to be due to nicotine-induced alterations in METH pharmacokinetics. Short-term (i.e., 21-day) high-dose nicotine exposure also protected when administered from PND 40 to PND 61 (with METH at PND 54), but this protective effect did not persist. Short-term (i.e., 21-day) high-dose nicotine exposure did not protect when administered postadolescence (i.e., beginning at PND 61, with METH at PND 75). However, protection was engendered if the duration of nicotine exposure was extended to 39 days (with METH at PND 93). Autoradiographic analysis revealed that nicotine increased striatal α4β2 expression, as assessed using [(125)I]epibatidine. Both METH and nicotine decreased striatal α6β2 expression, as assessed using [(125)I]α-conotoxin MII. These findings indicate that nicotine protects against METH-induced striatal dopaminergic deficits, perhaps by affecting α4β2 and/or α6β2 expression, and that both age of onset and duration of nicotine exposure affect this protection. PMID:26391161

  6. NMDA Receptors and Oxidative Stress Induced by the Major Metabolites Accumulating in HMG Lyase Deficiency Mediate Hypophosphorylation of Cytoskeletal Proteins in Brain From Adolescent Rats: Potential Mechanisms Contributing to the Neuropathology of This Disease.

    Science.gov (United States)

    Fernandes, Carolina Gonçalves; Pierozan, Paula; Soares, Gilberto Machado; Ferreira, Fernanda; Zanatta, Ângela; Amaral, Alexandre Umpierrez; Borges, Clarissa Günther; Wajner, Moacir; Pessoa-Pureur, Regina

    2015-10-01

    Neurological symptoms and cerebral abnormalities are commonly observed in patients with 3-hydroxy-3-methylglutaryl-CoA lyase (HMG lyase) deficiency, which is biochemically characterized by predominant tissue accumulation of 3-hydroxy-3-methylglutaric (HMG), 3-methylglutaric (MGA), and 3-methylglutaconic (MGT) acids. Since the pathogenesis of this disease is poorly known, the present study evaluated the effects of these compounds on the cytoskeleton phosphorylating system in rat brain. HMG, MGA, and MGT caused hypophosphorylation of glial fibrillary acidic protein (GFAP) and of the neurofilament subunits NFL, NFM, and NFH. HMG-induced hypophosphorylation was mediated by inhibiting the cAMP-dependent protein kinase (PKA) on Ser55 residue of NFL and c-Jun kinase (JNK) by acting on KSP repeats of NFM and NFH subunits. We also evidenced that the subunit NR2B of NMDA receptor and Ca(2+) was involved in HMG-elicited hypophosphorylation of cytoskeletal proteins. Furthermore, the antioxidants L-NAME and TROLOX fully prevented both the hypophosphorylation and the inhibition of PKA and JNK caused by HMG, suggesting that oxidative damage may underlie these effects. These findings indicate that the main metabolites accumulating in HMG lyase deficiency provoke hypophosphorylation of cytoskeleton neural proteins with the involvement of NMDA receptors, Ca(2+), and reactive species. It is presumed that these alterations may contribute to the neuropathology of this disease. PMID:26174040

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

    Science.gov (United States)

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

    2016-01-01

    The sensory experience of smoking is a key component of nicotine addiction known to result, in part, from stimulation of nicotinic acetylcholine receptors (nAChRs) at peripheral sensory nerve endings. Such stimulation of nAChRs is followed by activation of neurons at multiple sites in the mesocorticolimbic reward pathways. However, the neurochemical profiles of CNS cells that mediate the peripheral sensory impact of nicotine remain unknown. In the present study in mice, we first used c-Fos immunohistochemistry to identify CNS cells stimulated by nicotine (NIC, 40 μg/kg, IP) and by a peripherally-acting analog of nicotine, nicotine pyrrolidine methiodide (NIC-PM, 30 μg/kg, IP). Sequential double-labelling was then performed to determine whether noradrenergic and dopaminergic neurons of the nicotine reward-addiction circuitry were primary targets of NIC and NIC-PM. Double-labelling of NIC and/or NIC-PM activated c-Fos immunoreactive cells with tyrosine hydroxylase (TH) showed no apparent c-Fos expression by the dopaminergic cells of the ventral tegmental area (VTA). With the exception of sparse numbers of TH immunoreactive D11 cells, dopamine-containing neurons in other areas of the reward-addiction circuitry, namely periaqueductal gray, and dorsal raphe, were also devoid of c-Fos immunoreactivity. Noradrenergic neurons of locus coeruleus (LC), known to innervate VTA, were activated by both NIC and NIC-PM. These results demonstrate that noradrenergic neurons of LC are among the first structures that are stimulated by single acute IP injection of NIC and NIC-PM. Dopaminergic neurons of VTA and other CNS sites, did not respond to acute IP administration of NIC or NIC-PM by induction of c-Fos.

  8. Effect of variation in BDNF Val(66)Met polymorphism, smoking, and nicotine dependence on symptom severity of depressive and anxiety disorders

    NARCIS (Netherlands)

    Jamal, Mumtaz; Van der Does, Willem; Penninx, Brenda W. J. H.

    2015-01-01

    Background: Smoking, especially nicotine dependence is associated with more severe symptoms of depression and anxiety disorders. However, the mechanisms underlying this association are unclear. We investigated the effect of brain-derived neurotrophic factor (BDNF) VaI(66)Met polymorphism on the seve

  9. Effects of simultaneous exposure to stress and nicotine on nicotine-induced locomotor activation in adolescent and adult rats

    Energy Technology Data Exchange (ETDEWEB)

    Zago, A. [Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Leão, R.M.; Carneiro-de-Oliveira, P.E. [Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Programa Interinstitucional de Pós-Graduação em Ciências Fisiológicas, Universidade Federal de São Carlos/Universidade Estadual de São Paulo, Araraquara, SP (Brazil); Marin, M.T.; Cruz, F.C. [Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Planeta, C.S. [Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Programa Interinstitucional de Pós-Graduação em Ciências Fisiológicas, Universidade Federal de São Carlos/Universidade Estadual de São Paulo, Araraquara, SP (Brazil)

    2011-11-18

    Preclinical studies have shown that repeated stress experiences can result in an increase in the locomotor response to the subsequent administration of drugs of abuse, a phenomenon that has been termed behavioral cross-sensitization. Behavioral sensitization reflects neuroadaptive processes associated with drug addiction and drug-induced psychosis. Although crosssensitization between stress- and drug-induced locomotor activity has been clearly demonstrated in adult rats, few studies have evaluated this phenomenon in adolescent rats. In the present study, we determined if the simultaneous exposure to stress and nicotine was capable of inducing behavioral sensitization to nicotine in adolescent and adult rats. To this end, adolescent (postnatal day (P) 28-37) and adult (P60-67) rats received nicotine (0.4 mg/kg, sc) or saline (0.9% NaCl, sc) and were immediately subjected to restraint stress for 2 h once a day for 7 days. The control group for stress was undisturbed following nicotine or saline injections. Three days after the last exposure to stress and nicotine, rats were challenged with a single dose of nicotine (0.4 mg/kg, sc) or saline and nicotine-induced locomotion was then recorded for 30 min. In adolescent rats, nicotine caused behavioral sensitization only in animals that were simultaneously exposed to stress, while in adult rats nicotine promoted sensitization independently of stress exposure. These findings demonstrate that adolescent rats are more vulnerable to the effects of stress on behavioral sensitization to nicotine than adult rats.

  10. Effects of simultaneous exposure to stress and nicotine on nicotine-induced locomotor activation in adolescent and adult rats

    International Nuclear Information System (INIS)

    Preclinical studies have shown that repeated stress experiences can result in an increase in the locomotor response to the subsequent administration of drugs of abuse, a phenomenon that has been termed behavioral cross-sensitization. Behavioral sensitization reflects neuroadaptive processes associated with drug addiction and drug-induced psychosis. Although crosssensitization between stress- and drug-induced locomotor activity has been clearly demonstrated in adult rats, few studies have evaluated this phenomenon in adolescent rats. In the present study, we determined if the simultaneous exposure to stress and nicotine was capable of inducing behavioral sensitization to nicotine in adolescent and adult rats. To this end, adolescent (postnatal day (P) 28-37) and adult (P60-67) rats received nicotine (0.4 mg/kg, sc) or saline (0.9% NaCl, sc) and were immediately subjected to restraint stress for 2 h once a day for 7 days. The control group for stress was undisturbed following nicotine or saline injections. Three days after the last exposure to stress and nicotine, rats were challenged with a single dose of nicotine (0.4 mg/kg, sc) or saline and nicotine-induced locomotion was then recorded for 30 min. In adolescent rats, nicotine caused behavioral sensitization only in animals that were simultaneously exposed to stress, while in adult rats nicotine promoted sensitization independently of stress exposure. These findings demonstrate that adolescent rats are more vulnerable to the effects of stress on behavioral sensitization to nicotine than adult rats

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

    Directory of Open Access Journals (Sweden)

    Kia J Jackson

    Full Text Available 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.

  12. Antifungal activity of nicotine and its cadmium complex

    International Nuclear Information System (INIS)

    Nicotine and its metal complex; Cd(II)-nicotine were isolated from leaves of Nicotiana tabacum using various metal ions by the reported techniques and studied for their antifungal activities against fourteen different species of fungi. For comparative study, pure sample of nicotine and metal salt used for complexation; cadmium(II) iodide was also subjected to antifungal tests with the same species of fungus under similar conditions. Results indicated that nicotine is quite effective against the rare pathogenic and Non pathogenic fungi but comparatively less effective against Pathogenic fungi. Nicotine was found to be completely ineffective against the selected species of Occasional pathogenic fungi. Cadmium(II) iodide effectively inhibited Pathogenic and Non pathogenic fungi whereas relatively ineffective against the Occasional pathogenic and Rare pathogenic fungi. On the other hand, Cadmium(II) nicotine complex inhibited all the selected species of fungi except Fusarium solani. (author)

  13. Genotoxicity study on nicotine and nicotine-derived nitrosamine by accelerator mass spectrometry

    International Nuclear Information System (INIS)

    The authors have studied DNA adduction with 14C-labelled nicotine and nicotine-derived nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), by accelerator mass spectrometry (AMS) in mouse liver at doses equivalent to low-level exposure of humans. The dose ranges of nicotine and NNK administered were from 0.4 μg to 4.0 x 102 μg·kg-1, and from 0.1 μg to 2.0 x 104 μg·kg-1, respectively. In the exposure of mice to either nicotine or NNK, the number of DNA adducts increased linearly with increasing dose. The detection limit of DNA adducts was 1 adduct per 1011 nucleotide molecules. This limit is 1-4 orders of magnitude lower than that of other techniques used for quantification of DNA adducts. The results of the animal experiments enabled us to speculate that nicotine is a potential carcinogen. According to the procedure for 14C-labelled-NNK synthesis, the authors discuss the ultimate chemical speciation of NNK bound to DNA. From the animal tests the authors derived a directly perceivable relation between tobacco consumption and DNA adduction as the carcinogenic risk assessment

  14. Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate

    Science.gov (United States)

    Xu, Yuanfu; Li, Hongmei; Bajrami, Besnik; Kwak, Hyunjeong; Cao, Shannan; Liu, Peng; Zhou, Jiaxi; Zhou, Yuan; Zhu, Haiyan; Ye, Keqiang; Luo, Hongbo R.

    2013-01-01

    Diphosphoinositol pentakisphosphate (InsP7), a higher inositol phosphate containing energetic pyrophosphate bonds, is beginning to emerge as a key cellular signaling molecule. However, the various physiological and pathological processes that involve InsP7 are not completely understood. Here we report that cigarette smoke (CS) extract and nicotine reduce InsP7 levels in aging neutrophils. This subsequently leads to suppression of Akt deactivation, a causal mediator of neutrophil spontaneous death, and delayed neutrophil death. The effect of CS extract and nicotine on neutrophil death can be suppressed by either directly inhibiting the PtdIns(3,4,5)P3/Akt pathway, or increasing InsP7 levels via overexpression of InsP6K1, an inositol hexakisphosphate (InsP6) kinase responsible for InsP7 production in neutrophils. Delayed neutrophil death contributes to the pathogenesis of CS-induced chronic obstructive pulmonary disease. Therefore, disruption of InsP6K1 augments CS-induced neutrophil accumulation and lung damage. Taken together, these results suggest that CS and nicotine delay neutrophil spontaneous death by suppressing InsP7 production and consequently blocking Akt deactivation in aging neutrophils. Modifying neutrophil death via this pathway provides a strategy and therapeutic target for the treatment of tobacco-induced chronic obstructive pulmonary disease. PMID:23610437

  15. Performance of motor associated behavioural tests following chronic nicotine administration

    OpenAIRE

    Ijomone, Omamuyovwi M.; Olaibi, Olayemi K; Biose, Ifechukwude J.; Mba, Christian; Umoren, Kenneth E.; Nwoha, Polycarp U

    2014-01-01

    Background Nicotine has shown potential therapeutic value for neurodegenerative diseases though there are concerns that it may induce behavioural deficits. Purpose The present study sought to determine the effect of chronic nicotine administration on overall motor functions and coordination. Methods Forty adult female and male Wistar rats were randomly grouped into 4 groups. Treated groups were administered nicotine via subcutaneous injections at doses of 0.25, 2 and 4 mg/kg body weight for 2...

  16. Narcolepsy with Cataplexy Masked by the Use of Nicotine

    OpenAIRE

    Ebben, Matthew R.; Krieger, Ana C.

    2012-01-01

    This report describes a case of narcolepsy with cataplexy masked by the chronic use of cigarettes and nicotine patches. It has been described that narcoleptic smokers report relief of symptoms by smoking tobacco cigarettes.1 In addition, a case describing partial treatment of sleepiness using a nicotine patch in an adolescent with narcolepsy was recently reported in this journal.2 Our case adds to the growing literature that nicotine may be used to manage symptoms associated with narcolepsy.

  17. Nicotine-like effects of the neonicotinoid insecticides acetamiprid and imidacloprid on cerebellar neurons from neonatal rats.

    Directory of Open Access Journals (Sweden)

    Junko Kimura-Kuroda

    Full Text Available BACKGROUND: Acetamiprid (ACE and imidacloprid (IMI belong to a new, widely used class of pesticide, the neonicotinoids. With similar chemical structures to nicotine, neonicotinoids also share agonist activity at nicotinic acetylcholine receptors (nAChRs. Although their toxicities against insects are well established, their precise effects on mammalian nAChRs remain to be elucidated. Because of the importance of nAChRs for mammalian brain function, especially brain development, detailed investigation of the neonicotinoids is needed to protect the health of human children. We aimed to determine the effects of neonicotinoids on the nAChRs of developing mammalian neurons and compare their effects with nicotine, a neurotoxin of brain development. METHODOLOGY/PRINCIPAL FINDINGS: Primary cultures of cerebellar neurons from neonatal rats allow for examinations of the developmental neurotoxicity of chemicals because the various stages of neurodevelopment-including proliferation, migration, differentiation, and morphological and functional maturation-can be observed in vitro. Using these cultures, an excitatory Ca(2+-influx assay was employed as an indicator of neural physiological activity. Significant excitatory Ca(2+ influxes were evoked by ACE, IMI, and nicotine at concentrations greater than 1 µM in small neurons in cerebellar cultures that expressed the mRNA of the α3, α4, and α7 nAChR subunits. The firing patterns, proportion of excited neurons, and peak excitatory Ca(2+ influxes induced by ACE and IMI showed differences from those induced by nicotine. However, ACE and IMI had greater effects on mammalian neurons than those previously reported in binding assay studies. Furthermore, the effects of the neonicotinoids were significantly inhibited by the nAChR antagonists mecamylamine, α-bungarotoxin, and dihydro-β-erythroidine. CONCLUSIONS/SIGNIFICANCE: This study is the first to show that ACE, IMI, and nicotine exert similar excitatory effects

  18. Effect of nicotine on rectal mucus and mucosal eicosanoids.

    OpenAIRE

    Zijlstra, F.J.; Srivastava, E D; Rhodes, M.; van Dijk, A P; Fogg, F; Samson, H J; Copeman, M; Russell, M. A.; Feyerabend, C; Williams, G T

    1994-01-01

    Because ulcerative colitis is largely a disease of non-smokers and nicotine may have a beneficial effect on the disease, the effect of nicotine on rectal mucosa in rabbits was examined. Nicotine was given subcutaneously by an Alzet mini-pump in doses of 0.5, 1.25, and 2 mg/kg/day for 14 days to three groups of eight animals and compared with eight controls. Mean (SD) serum nicotine concentrations (ng/ml) were 3.5 (1.1), 8.8 (2.3), and 16.2 (5.2) respectively in the treated groups. The thickne...

  19. INDIVIDUAL DIFFERENCES IN ORAL NICOTINE INTAKE IN RATS

    OpenAIRE

    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 hours/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 ar...

  20. Estradiol promotes the rewarding effects of nicotine in female rats.

    Science.gov (United States)

    Flores, Rodolfo J; Pipkin, Joseph A; Uribe, Kevin P; Perez, Adriana; O'Dell, Laura E

    2016-07-01

    It is presently unclear whether ovarian hormones, such as estradiol (E2), promote the rewarding effects of nicotine in females. Thus, we compared extended access to nicotine intravenous self-administration (IVSA) in intact male, intact female, and OVX female rats (Study 1) as well as OVX females that received vehicle or E2 supplementation (Study 2). The E2 supplementation procedure involved a 4-day injection regimen involving 2 days of vehicle and 2 days of E2 administration. Two doses of E2 (25 or 250μg) were assessed in separate groups of OVX females in order to examine the dose-dependent effects of this hormone on the rewarding effects of nicotine. The rats were given 23-hour access to nicotine IVSA using an escalating dose regimen (0.015, 0.03, and 0.06mg/kg/0.1mL). Each dose was self-administered for 4 days with 3 intervening days of nicotine abstinence. The results revealed that intact females displayed higher levels of nicotine intake as compared to males. Also, intact females displayed higher levels of nicotine intake versus OVX females. Lastly, our results revealed that OVX rats that received E2 supplementation displayed a dose-dependent increase in nicotine intake as compared to OVX rats that received vehicle. Together, our results suggest that the rewarding effects of nicotine are enhanced in female rats via the presence of the ovarian hormone, E2. PMID:27059334

  1. Stable isotope studies of nicotine kinetics and bioavailability

    International Nuclear Information System (INIS)

    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

  2. Revisiting the Effect of Nicotine on Interval Timing

    Science.gov (United States)

    Daniels, Carter W.; Watterson, Elizabeth; Garcia, Raul; Mazur, Gabriel J.; Brackney, Ryan J.; Sanabria, Federico

    2015-01-01

    This paper reviews the evidence for nicotine-induced acceleration of the internal clock when timing in the seconds-to-minutes timescale, and proposes an alternative explanation to this evidence: that nicotine reduces the threshold for responses that result in more reinforcement. These two hypotheses were tested in male Wistar rats using a novel timing task. In this task, rats were trained to seek food at one location after 8 s since trial onset and at a different location after 16 s. Some rats received the same reward at both times (group SAME); some received a larger reward at 16 s (group DIFF). Steady baseline performance was followed by 3 days of subcutaneous nicotine administration (0.3 mg/kg), baseline recovery, and an antagonist challenge (mecamylamine, 1.0 mg/kg). Nicotine induced a larger, immediate reduction in latencies to switch (LTS) in group DIFF than in group SAME. This effect was sustained throughout nicotine administration. Mecamylamine administration and discontinuation of nicotine rapidly recovered baseline performance. These results support a response-threshold account of nicotinic disruption of timing performance, possibly mediated by nicotinic acetylcholine receptors. A detailed analysis of the distribution of LTSs suggests that anomalous effects of nicotine on LTS dispersion may be due to loss of temporal control of behavior. PMID:25637907

  3. Effects of maternal nicotine on breastfeeding infants.

    Science.gov (United States)

    Primo, Cândida Caniçali; Ruela, Priscilla Bôa F; Brotto, Léia Damasceno de A; Garcia, Telma Ribeiro; Lima, Eliane de Fátima

    2013-09-01

    OBJECTIVE To assess scientific evidence about the effects of maternal nicotine on infant by an integrative review. DATA SOURCES Studies published in Portuguese, English and Spanish, from 1990 to 2009, with abstracts available in the Latin American Health Sciences Literature (Lilacs) and Medical Literature Analysis and Retrieval System On-Line (Medline) databases. The descriptors were: "breastfeeding", "lactation" and "smoking". DATA SYNTHESIS The main identified effects of nicotine on infants were: changes in sleep and wakefulness patterns; reduction of iodine supply; hystopathological damage on liver and lung; intracellular oxidative damage; reduction of pancreatic ß cells; and decreased glucose tolerance. CONCLUSIONS It is recommended to inform mothers about harmful chemicals contained in cigarettes that can be secreted into breast milk. They should be strongly encouraged to stop smoking during lactation. PMID:24142324

  4. Alcohol, nicotine, caffeine, and mental disorders

    OpenAIRE

    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 cl...

  5. The Demand for Nicotine Replacement Therapies

    OpenAIRE

    John A. Tauras; Chaloupka, Frank J.

    2001-01-01

    This paper is the first econometric study to examine the determinants of nicotine replacement therapy (NRT) demand. Pooled cross-sectional time-series scanner-based data for 50 major metropolitan markets in the United States covering the period between the second quarter 1996 and the third quarter 1999 are used in the analysis. Fixed-effects modeling is employed to assess the impact of NRT prices, cigarette prices, and other determinants on NRT demand. The estimates indicate that decreases in...

  6. Disentangling the nature of the nicotine stimulus✩

    OpenAIRE

    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...

  7. The Duration of Nicotine Withdrawal-Associated Deficits in Contextual Fear Conditioning Parallels Changes in Hippocampal High Affinity Nicotinic Acetylcholine Receptor Upregulation

    OpenAIRE

    Gould, Thomas J.; Portugal, George S.; André, Jessica M.; Tadman, Matthew P.; Marks, Michael J.; Kenney, Justin W.; YILDIRIM, Emre; Adoff, Michael

    2012-01-01

    A predominant symptom of nicotine withdrawal is cognitive deficits, yet understanding of the neural basis for these deficits is limited. Withdrawal from chronic nicotine disrupts contextual learning in mice and this deficit is mediated by direct effects of nicotine in the hippocampus. Chronic nicotine treatment upregulates nicotinic acetylcholine receptors (nAChR); however, it is unknown whether upregulation is related to the observed withdawal-induced cognitive deficits. If a relationship be...

  8. Nicotinic receptor blockade decreases fos immunoreactivity within orexin/hypocretin-expressing neurons of nicotine-exposed rats.

    Science.gov (United States)

    Simmons, Steven J; Gentile, Taylor A; Mo, Lili; Tran, Fionya H; Ma, Sisi; Muschamp, John W

    2016-11-01

    Tobacco smoking is the leading cause of preventable death in the United States. Nicotine is the principal psychoactive ingredient in tobacco that causes addiction. The structures governing nicotine addiction, including those underlying withdrawal, are still being explored. Nicotine withdrawal is characterized by negative affective and cognitive symptoms that enhance relapse susceptibility, and suppressed dopaminergic transmission from ventral tegmental area (VTA) to target structures underlies behavioral symptoms of nicotine withdrawal. Agonist and partial agonist therapies help 1 in 4 treatment-seeking smokers at one-year post-cessation, and new targets are needed to more effectively aid smokers attempting to quit. Hypothalamic orexin/hypocretin neurons send excitatory projections to dopamine (DA)-producing neurons of VTA and modulate mesoaccumbal DA release. The effects of nicotinic receptor blockade, which is commonly used to precipitate withdrawal, on orexin neurons remain poorly investigated and present an attractive target for intervention. The present study sought to investigate the effects of nicotinic receptor blockade on hypothalamic orexin neurons using mecamylamine to precipitate withdrawal in rats. Separate groups of rats were treated with either chronic nicotine or saline for 7-days at which point effects of mecamylamine or saline on somatic signs and anxiety-like behavior were assessed. Finally, tissue from rats was harvested for immunofluorescent analysis of Fos within orexin neurons. Results demonstrate that nicotinic receptor blockade leads to reduced orexin cell activity, as indicated by lowered Fos-immunoreactivity, and suggest that this underlying cellular activity may be associated with symptoms of nicotine withdrawal as effects were most prominently observed in rats given chronic nicotine. We conclude from this study that orexin transmission becomes suppressed in rats upon nicotinic receptor blockade, and that behavioral symptoms associated

  9. Synthesis, Nicotinic Acetylcholine Receptor Binding, and Antinociceptive Properties of 3′-(Substituted Phenyl)epibatidine Analogues. Nicotinic Partial Agonists⊥

    OpenAIRE

    Carroll, F. Ivy; Ma, Wei; Deng, Liu; Navarro, Hernán A.; Damaj, M. Imad; Martin, Billy R.

    2010-01-01

    In 1992, John Daly et al. reported the isolation and structure determination of epibatidine. Epibatidine’s unique structure and its potent nicotinic agonist activity have had a tremendous impact on nicotine receptor research. This research has led to a better understanding of the nicotinic acetylcholine receptor (nAChR) pharmacophore and to epibatidine analogues with potential as pharmacotherapies for treating various CNS disorders. In this study, we report the synthesis, receptor binding ([3...

  10. Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo-Interpeduncular Pathway in Nicotine Reinforcement in Mice.

    Science.gov (United States)

    Harrington, Lauriane; Viñals, Xavier; Herrera-Solís, Andrea; Flores, Africa; Morel, Carole; Tolu, Stefania; Faure, Philippe; Maldonado, Rafael; Maskos, Uwe; Robledo, Patricia

    2016-06-01

    Nicotine exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR), composed of alpha and/or beta subunits, giving rise to a diverse population of receptors with a distinct pharmacology. β4-containing (β4*) nAChRs are located almost exclusively in the habenulo-interpeduncular pathway. We examined the role of β4* nAChRs in the medial habenula (MHb) and the interpeduncular nucleus (IPN) in nicotine reinforcement using behavioral, electrophysiological, and molecular techniques in transgenic mice. Nicotine intravenous self-administration (IVSA) was lower in constitutive β4 knockout (KO) mice at all doses tested (7.5, 15, 30, and 60 μg/kg/infusion) compared with wild-type (WT) mice. In vivo microdialysis showed that β4KO mice have higher extracellular dopamine (DA) levels in the nucleus accumbens than in WT mice, and exhibit a differential sensitivity to nicotine-induced DA outflow. Furthermore, electrophysiological recordings in the ventral tegmental area (VTA) demonstrated that DA neurons of β4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of β4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that β4* nAChRs in the IPN have a role in maintaining nicotine IVSA. PMID:26585290

  11. Environmental fate and effects of nicotine released during cigarette production.

    Science.gov (United States)

    Seckar, Joel A; Stavanja, Mari S; Harp, Paul R; Yi, Yongsheng; Garner, Charles D; Doi, Jon

    2008-07-01

    A variety of test methods were used to study the gradation, bioaccumulation, and toxicity of nicotine. Studies included determination of the octanol-water partition coefficient, conversion to CO2 in soil and activated sludge, and evaluation of the effects on microbiological and algal inhibition as well as plant germination and root elongation. The partitioning of nicotine between octanol and water indicated that nicotine will not bioaccumulate regardless of the pH of the medium. The aqueous and soil-based biodegradation studies indicated that nicotine is readily biodegradable in both types of media. The microbiological inhibition and aquatic and terrestrial toxicity tests indicated that nicotine has low toxicity. The U.S. Environmental Protection Agency Persistence, Bioaccumulation, and Toxicity Profiler model, based on the structure of nicotine and the predictive rates of hydroxyl radical and ozone reactions, estimated an atmospheric half-life of less than 5.0 h. Using this value in the Canadian Environmental Modeling Center level III model, the half-life of nicotine was estimated as 3.0 d in water and 0.5 d in soil. This model also estimated nicotine discharge into the environment; nicotine would be expected to be found predominantly in water (93%), followed by soil (4%), air (3%), and sediment (0.4%). Using the estimated nicotine concentrations in water, soil, and sediment and the proper median effective concentrations derived from the algal growth, biomass inhibition, and buttercrunch lettuce (Lactuca sativa) seed germination and root elongation studies, hazard quotients of between 10(-7) and 10(-8) were calculated, providing further support for the conclusion that the potential for nicotine toxicity to aquatic and terrestrial species in the environment is extremely low. PMID:18399728

  12. SLEEP QUALITY AMONG TYPE 2 DIABETICS WITH NICOTINE DEPENDENCE

    Directory of Open Access Journals (Sweden)

    Sivaraman

    2014-05-01

    Full Text Available INTRODUCTION: Sleep disorders are reported due to varied reasons and are on the rise. Diabetes is established as the one of the reasons for alterations in the quality of sleep. Studies have established that nicotine acts on the neurotransmitter system and influence the quality of sleep. Nicotine use by the diabetic patients is an added factor and will interfere with their quality of sleep. The objectives of the study were to assess the quality of sleep among uncontrolled and uncomplicated type 2 diabetics with and without nicotine dependence and to find out the effect of nicotine in the day time functioning of the study population. MATERIALS AND METHODS: This study was carried out in a tertiary care teaching hospital among 50 individuals without Nicotine dependence and 50 individuals with Nicotine dependence of uncontrolled and uncomplicated known type 2 Diabetes mellitus. A pretested questionnaire, Fagerstrom test form for Nicotine dependence for smokers, the Pittsburg Sleep Quality Index and Epworth Sleepiness Scale were used to collect data from the study subjects in order to assess the quality of sleep among the study group. RESULTS: The sleep quality among the smokers was different in terms of time of going to bed, time to sleep, hours of sleep, time taken to fall asleep, waking up in the middle of sleep, breathing problem, pain in the leg, and afternoon nap and cough or snore during sleep [p0.05]. In this study, 92% of the smokers belonged to the low to moderate dependence category as per the Fagerstrom test. DISCUSSION: The sleep quality of low and moderate nicotine dependent type 2 diabetics differed significantly from the non-nicotine users. Most of the study population belonged to low to moderate nicotine dependence [92%]. Health education and enforcement on prevention of smoking in public places is found to have an effect on the Nicotine use in Tamil Nadu.

  13. Neurocomputational models of brain disorders

    NARCIS (Netherlands)

    Cutsuridis, Vassilis; Heida, Tjitske; Duch, Wlodek; Doya, Kenji

    2011-01-01

    Recent decades have witnessed dramatic accumulation of knowledge about the genetic, molecular, pharmacological, neurophysiological, anatomical, imaging and psychological characteristics of brain disorders. Despite these advances, however, experimental brain science has offered very little insight in

  14. Prenatal nicotine is associated with reduced AMPA and NMDA receptor-mediated rises in calcium within the laterodorsal tegmentum: a pontine nucleus involved in addiction processes

    DEFF Research Database (Denmark)

    Mc Nair, Laura Kristine Frendrup; Kohlmeier, Kristi Anne

    2015-01-01

    enhanced proclivity postnatally to addict to drugs of abuse, which suggests that the drug exposure during gestation changed the developing brain in such a way that biased it towards addiction. Glutamate signalling has been shown to be altered by prenatal nicotine exposure (PNE) and glutamate is the major...... excitatory neurotransmitter within the laterodorsal tegmental nucleus (LDT), which is a brainstem region importantly involved in responding to motivational stimuli and critical in development of drug addiction-associated behaviours, however, it is unknown whether PNE alters glutamate signalling within this...... that neurobiological changes are induced if gestation is accompanied by nicotine exposure. We conclude that in light of the role played by the LDT in motivated behaviour, the cellular changes in the LDT induced by exposures to nicotine prenatally, when combined with alterations in other reward...

  15. Brain-actuated interaction

    OpenAIRE

    Millán, José del R.; Renkens, F.; Mourino, J.; Gerstner, W.

    2004-01-01

    Over the last years evidence has accumulated that shows the possibility to analyze human brain activity on-line and translate brain states into actions such as selecting a letter from a virtual keyboard or moving a robotics device. These initial results have been obtained with either invasive approaches (requiring surgical implantation of electrodes) or synchronous protocols (where brain signals are time-locked to external cues). In this paper we describe a portable noninvasive brain-computer...

  16. Sex differences in nicotine self-administration in rats during progressive unit dose reduction: implications for nicotine regulation policy.

    Science.gov (United States)

    Grebenstein, Patricia; Burroughs, Danielle; Zhang, Yan; LeSage, Mark G

    2013-12-01

    Reducing the nicotine content in tobacco products is being considered by the FDA as a policy to reduce the addictiveness of tobacco products. Understanding individual differences in response to nicotine reduction will be critical to developing safe and effective policy. Animal and human research demonstrating sex differences in the reinforcing effects of nicotine suggests that males and females may respond differently to nicotine-reduction policies. However, no studies have directly examined sex differences in the effects of nicotine unit-dose reduction on nicotine self-administration (NSA) in animals. The purpose of the present study was to examine this issue in a rodent self-administration model. Male and female rats were trained to self-administer nicotine (0.06mg/kg) under an FR 3 schedule during daily 23h sessions. Rats were then exposed to saline extinction and reacquisition of NSA, followed by weekly reductions in the unit dose (0.03 to 0.00025mg/kg) until extinction levels of responding were achieved. Males and females were compared with respect to baseline levels of intake, resistance to extinction, degree of compensatory increases in responding during dose reduction, and the threshold reinforcing unit dose of nicotine. Exponential demand-curve analysis was also conducted to compare the sensitivity of males and females to increases in the unit price (FR/unit dose) of nicotine (i.e., elasticity of demand or reinforcing efficacy). Females exhibited significantly higher baseline intake and less compensation than males. However, there were no sex differences in the reinforcement threshold or elasticity of demand. Dose-response relationships were very well described by the exponential demand function (r(2) values>0.96 for individual subjects). These findings suggest that females may exhibit less compensatory smoking in response to nicotine reduction policies, even though their nicotine reinforcement threshold and elasticity of demand may not differ from males

  17. Nicotine dependence, physical activity, and sedentary behavior among adult smokers

    Directory of Open Access Journals (Sweden)

    Paul D Loprinzi

    2015-01-01

    Full Text Available Background: Research has previously demonstrated an inverse association between smoking status and physical activity; however, few studies have examined the association between nicotine dependence and physical activity or sedentary behavior. Aim: This study examined the association between nicotine dependence and accelerometer-determined physical activity and sedentary behavior. Materials and Methods: Data from the 2003-2006 National Health and Nutrition Examination Survey (NHANES were used. A total of 851 adult (≥20 years smokers wore an accelerometer for ≥4 days and completed the Fagerstrom Test for Nicotine Dependence scale. Regression models were used to examine the association between nicotine dependence and physical activity/sedentary behavior. Results: After adjusting for age, gender, race-ethnicity, poverty level, hypertension, emphysema, bronchitis, body mass index (BMI, cotinine, and accelerometer wear time, smokers 50 + years of age with greater nicotine dependence engaged in more sedentary behavior (β = 11.4, P = 0.02 and less light-intensity physical activity (β = −9.6, P = 0.03 and moderate-to-vigorous physical activity (MVPA; β = −0.14, P = 0.003 than their less nicotine dependent counterparts. Conclusion: Older adults who are more nicotine dependent engage in less physical activity (both MVPA and light-intensity and more sedentary behavior than their less nicotine dependent counterparts.

  18. Effects of Nicotine Fading and Relapse Prevention on Smoking Cessation.

    Science.gov (United States)

    Brown, Richard A.; And Others

    1984-01-01

    Conducted a pilot study which combined nicotine-fading and relapse prevention with smokers (N=30) and compared this program to conditions where subjects (N=46) received nicotine-fading or relapse prevention only. Results showed no difference among groups in abstinence or rate at any follow-up point. (LLL)

  19. Effect of chronic (-)-nicotine treatment on rat cerebral benzodiazepine receptors

    International Nuclear Information System (INIS)

    The purpose of this study was to clarify the effect of (-)-nicotine on cerebral benzodiazepine receptors (BzR) with radiotracer methods. The effect of (-)-nicotine on BzR was examined in in vitro studies using chronic (-)-nicotine-treated rats using 3H-diazepam. The in vitro radioreceptor assay showed a 14% increase in the maximum number of binding sites of BzR in chronic (-)-nicotine-treated rats in comparison with the control rats. Moreover, a convenient in vivo uptake index of 125I-iomazenil was calculated and a higher uptake of the radioactivity was observed in the chronic (-)-nicotine-treated group than in the control group. Although further studies of the mechanism of (-)-nicotine on such BzR changes are required, an increase in the amount of BzR in the cerebral cortex was found in rats that underwent chronic (-)-nicotine treatment, and this result contributed to the understanding of the effects of (-)-nicotine and smoking on neural functions

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

    Directory of Open Access Journals (Sweden)

    Seyed Saadat Seyedeh Nazanin

    2014-03-01

    Full Text Available 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 40 μg/kg, Group C: injected with melatonin 10 μg, Group D: injected with nicotine 40 μg/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

  1. Epidemiology, radiology, and genetics of nicotine dependence in COPD

    Directory of Open Access Journals (Sweden)

    Hokanson John E

    2011-01-01

    Full Text Available Abstract Background Cigarette smoking is the principal environmental risk factor for developing COPD, and nicotine dependence strongly influences smoking behavior. This study was performed to elucidate the relationship between nicotine dependence, genetic susceptibility to nicotine dependence, and volumetric CT findings in smokers. Methods Current smokers with COPD (GOLD stage ≥ 2 or normal spirometry were analyzed from the COPDGene Study, a prospective observational study. Nicotine dependence was determined by the Fagerstrom test for nicotine dependence (FTND. Volumetric CT acquisitions measuring the percent of emphysema on inspiratory CT (% of lung Results Among 842 currently smoking subjects (335 COPD cases and 507 controls, 329 subjects (39.1% showed high nicotine dependence. Subjects with high nicotine dependence had greater cumulative and current amounts of smoking. However, emphysema severity was negatively correlated with the FTND score in controls (ρ = -0.19, p Conclusions Nicotine dependence was a negative predictor for emphysema on CT in COPD and control smokers. Increased inflammation in more highly addicted current smokers could influence the CT lung density distribution, which may influence genetic association studies of emphysema phenotypes. Trial registration ClinicalTrials (NCT: NCT00608764

  2. Sensory reinforcement-enhancing effects of nicotine via smoking.

    Science.gov (United States)

    Perkins, Kenneth A; Karelitz, Joshua L

    2014-12-01

    As has been found in nicotine research on animals, research on humans has shown that acute nicotine enhances reinforcement from rewards unrelated to nicotine intake, but this effect may be specific to rewards from stimuli that are "sensory" in nature. We assessed acute effects of nicotine via smoking on responding for music or video rewards (sensory), for monetary reward (nonsensory), or for no reward (control), to gauge the generalizability of nicotine's reinforcement-enhancing effects. Using a fully within-subjects design, dependent smokers (N = 20) participated in 3 similar experimental sessions, each following overnight abstinence (verified by carbon monoxide fashion prior to responding on a simple operant computer task for each reward separately using a progressive ratio schedule. The reinforcing effects of music and video rewards, but not money, were significantly greater due to the nicotine versus denic cigarette (i.e., nicotine per se), whereas there were no differences between denic cigarette smoking and no smoking (i.e., smoking behavior per se), except for no reward. These effects were not influenced by withdrawal relief from either cigarette. Results that generalize from an auditory to a visual reward confirm that acute nicotine intake per se enhances the reinforcing value of sensory rewards, but its effects on the value of other (perhaps nonsensory) types of rewards may be more modest. PMID:25180451

  3. Effects of Maternal Nicotine Exposure on Expression of Collagen Type IV and its Roles on Pulmonary Bronchogenesis and Alveolarization in Newborn Mice

    Directory of Open Access Journals (Sweden)

    Mehdi Jalali

    2010-09-01

    Full Text Available Nicotine is one the chemical substance with high level of toxically. It crosses the placenta and accumulates in the developing organs of fetus. Our previous investigations indicated that collagen type IV plays a key role in basement membrane of various embryonic organs. In this study we evaluated the effect of maternal nicotine exposure pre and postnatal period on collagen IV expression during bronchogenesis and alveolarization in the lungs of newborn mice. Female Balb/C mice were mated and Sperm positive in vaginal smear was designated as embryonic day zero. Pregnant mice were divided into 2 experimental and 2 control groups. Experimental group 1, received 3 mg/kg nicotine intrapritoneally from day 5 of gestation to last day of pregnancy. Experimental group 2 received the same amount of nicotine during the same gestational days as well as 2 first week after birth (lactation. The control groups received the same volume of normal saline during the same periods. At the end of exposure times, all of newborns were anesthetized and their lungs were removed for immunohistochemical method.Our finding indicated that collagen reaction in the bronchial basement membrane and extra cellular matrix of lung parenchyma in experimental groups increased significantly compared to control groups. Our results also showed alveolar remodeling and abnormal bronchogenesis were observed in experimental group especially group 2. These data indicate that maternal nicotine exposure may induce abnormal collagen IV expression and cause defects in bronchopulmonary development.

  4. Nicotinic mechanisms influencing synaptic plasticity in the hippocampus

    Institute of Scientific and Technical Information of China (English)

    Andon Nicholas PLACZEK; Tao A ZHANG; John Anthony DANI

    2009-01-01

    Nicotinic acetylcholine receptors (nAChRs) are expressed throughout the hippocampus, and nicotinic signaling plays an important role in neuronal function. In the context of learning and memory related behaviors associated with hippocampal function, a potentially significant feature of nAChR activity is the impact it has on synaptic plasticity. Synaptic plasticity in hippocampal neurons has long been considered a contributing cellular mechanism of learning and memory. These same kinds of cellular mechanisms are a factor in the development of nicotine addiction. Nicotinic signaling has been demonstrated by in vitro studies to affect synaptic plasticity in hippocampal neurons via multiple steps, and the signaling has also been shown to evoke synaptic plasticity in vivo. This review focuses on the nAChRs subtypes that contribute to hippocampal synaptic plasticity at the cellular and circuit level. It also considers nicotinic influences over long-term changes in the hippocampus that may contribute to addiction.

  5. Expression and function of nicotinic acetylcholine receptors in stem cells

    Directory of Open Access Journals (Sweden)

    Carlos M. Carballosa

    2016-07-01

    Full Text Available Nicotinic acetylcholine receptors are prototypical ligand gated ion channels typically found in muscular and neuronal tissues. Functional nicotinic acetylcholine receptors, however, have also recently been identified on other cell types, including stem cells. Activation of these receptors by the binding of agonists like choline, acetylcholine, or nicotine has been implicated in many cellular changes. In regards to stem cell function, nicotinic acetylcholine receptor activation leads to changes in stem cell proliferation, migration and differentiation potential. In this review we summarize the expression and function of known nicotinic acetylcholine receptors in different classes of stem cells including: pluripotent stem cells, mesenchymal stem cells, periodontal ligament derived stem cells, and neural progenitor cells and discuss the potential downstream effects of receptor activation on stem cell function.

  6. Antifungal activity of nicotine and its cobalt complex

    International Nuclear Information System (INIS)

    Nicotine and its metal complex; Co(II)-nicotine were isolated from leaves of Nicotiana tabacum using various metal ions by the reported techniques and studied for their antifungal activity against fourteen different species of fungi. For comparative study, pure sample of nicotine and metal salt used for complexation; cobalt(II) chloride was also subjected to antifungal tests with the same species of fungus under similar conditions. Results indicated that nicotine had antifungal activity against all species of fungi studied except Candida albicans, Microsporum canis, Epidermophyton floccosum, Candida tropicalis, and Alternaria infectoria. Cobalt(II) nicotine was found to be effective against all selected species of fungi but ineffective against Candida solani, Penicillium notalum, Microsporum canis, Fusarium solani and Fusarium moniliforme. (author)

  7. Chronic injections of saline produce subsensitivity to nicotine.

    Science.gov (United States)

    Flemmer, D D; Dilsaver, S C

    1989-10-01

    The routine handling of rats and the injection of saline is a stressor. The authors report that chronic twice daily injections of normal saline (1 ml/kg IP) for 14 days produced subsensitivity to the hypothermic effects of nicotine (1 ml/kg IP). The weekly injection of nicotine (1 mg/kg IP) does not produce this effect. The investigators propose that their findings reflect the effect of chronic stress on a nicotinic mechanism. Lithium, desipramine, fluoxetine, and amitriptyline also alter the thermic response to systemically injected nicotine. A nicotinic mechanism(s) may be involved in the neurobiology of chronic stress, actions of antidepressants, and conceivably the pathophysiology of depression. PMID:2622980

  8. Knowledge and Perceptions about Nicotine, Nicotine Replacement Therapies and Electronic Cigarettes among Healthcare Professionals in Greece

    Directory of Open Access Journals (Sweden)

    Anastasia Moysidou

    2016-05-01

    Full Text Available 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

  9. Bupropion Dose-Dependently Reverses Nicotine Withdrawal Deficits in Contextual Fear Conditioning

    OpenAIRE

    Portugal, George S.; Gould, Thomas J.

    2007-01-01

    Bupropion, a norepinephrine and dopamine reuptake inhibitor and nicotinic acetylcholine receptor antagonist, facilitates smoking cessation and reduces some symptoms of nicotine withdrawal. However, the effects of bupropion on nicotine withdrawal-associated deficits in learning remain unclear. The present study investigated whether bupropion has effects on contextual and cued fear conditioning following withdrawal from chronic nicotine or when administered alone. Bupropion was administered alo...

  10. New trends in the treatment of nicotine addiction.

    Science.gov (United States)

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

    2014-01-01

    The aim of this study was to discuss the therapeutic substances used to treat nicotine addiction, not registered in Poland. This paper presents the results of the latest clinical trials and the possibility of their use in the treatment of nicotine addiction. The first two discussed drugs clonidine and nortriptyline are recommended by clinical practice guidelines AHRQ (Agency for Healthcare Research and Quality) as the substance of the second line in the fight against addiction. Nortriptyline belongs to tricyclic antidepressants. Its mechanism of action is the inhibition of the reuptake of norepinephrine. It is suggested as the antagonist of activity of nicotinic receptors. The results confirm its efficacy in the treatment of nicotine addiction, but many side effects limit its use. Clonidine acts presumably by inhibition of sympathetic hyperactivity characteristic of symptoms associated with nicotine rehab. The remaining compounds under discussion, such as: venlafaxine, fluoxetine, moclobemide and rimonabant, are not registered in any country with an indication to use in the treatment of nicotine addiction, however, due to the mechanism in which they act, the possibility of their use in the treatment of this disease is considered. The possibility of using anxiolytics such as: buspirone, diazepam, meprobamate and beta-blockers: metoprolol and oxprenolol is also considered in order to treat the anxiety appearing as one of the symptoms of abstinence. An interesting proposal to combat nicotine addiction are vaccines--NicVAX, CYT002-NicQb and TA-NIC. Currently, they are in clinical phase I and II of their development. Their operation would be based on the induction of specific antibodies that bind nicotine in the plasma, thus prevent it reaching the nicotinic receptors. Preliminary results confirm the possible positive effects in the prevention and treatment of nicotine addiction. PMID:25272878

  11. Incorporation of Nicotine into Silicone Coatings for Marine Applications

    Science.gov (United States)

    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

  12. ACSL6 is associated with the number of cigarettes smoked and its expression is altered by chronic nicotine exposure.

    Directory of Open Access Journals (Sweden)

    Jingchun Chen

    Full Text Available Individuals with schizophrenia tend to be heavy smokers and are at high risk for tobacco dependence. However, the nature of the comorbidity is not entirely clear. We previously reported evidence for association of schizophrenia with SNPs and SNP haplotypes in a region of chromosome 5q containing the SPEC2, PDZ-GEF2 and ACSL6 genes. In this current study, analysis of the control subjects of the Molecular Genetics of Schizophrenia (MGS sample showed similar pattern of association with number of cigarettes smoked per day (numCIG for the same region. To further test if this locus is associated with tobacco smoking as measured by numCIG and FTND, we conducted replication and meta-analysis in 12 independent samples (n>16,000 for two markers in ACSL6 reported in our previous schizophrenia study. In the meta-analysis of the replication samples, we found that rs667437 and rs477084 were significantly associated with numCIG (p = 0.00038 and 0.00136 respectively but not with FTND scores. We then used in vitro and in vivo techniques to test if nicotine exposure influences the expression of ACSL6 in brain. Primary cortical culture studies showed that chronic (5-day exposure to nicotine stimulated ACSL6 mRNA expression. Fourteen days of nicotine administration via osmotic mini pump also increased ACSL6 protein levels in the prefrontal cortex and hippocampus of mice. These increases were suppressed by injection of the nicotinic receptor antagonist mecamylamine, suggesting that elevated expression of ACSL6 requires nicotinic receptor activation. These findings suggest that variations in the ACSL6 gene may contribute to the quantity of cigarettes smoked. The independent associations of this locus with schizophrenia and with numCIG in non-schizophrenic subjects suggest that this locus may be a common liability to both conditions.

  13. TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects.

    Science.gov (United States)

    Gatto, Gregory J; Bohme, G Andrees; Caldwell, William S; Letchworth, Sharon R; Traina, Vincent M; Obinu, M Carmen; Laville, Michel; Reibaud, Michel; Pradier, Laurent; Dunbar, Geoffrey; Bencherif, Merouane

    2004-01-01

    The development of selective ligands targeting neuronal nicotinic acetylcholine receptors to alleviate symptoms associated with neurodegenerative diseases presents the advantage of affecting multiple deficits that are the hallmarks of these pathologies. TC-1734 is an orally active novel neuronal nicotinic agonist with high selectivity for neuronal nicotinic receptors. Microdialysis studies indicate that TC-1734 enhances the release of acetylcholine from the cortex. TC-1734, by either acute or repeated administration, exhibits memory enhancing properties in rats and mice and is neuroprotective following excitotoxic insult in fetal rat brain in cultures and against alterations of synaptic transmission induced by deprivation of glucose and oxygen in hippocampal slices. At submaximal doses, TC-1734 produced additive cognitive effects when used in combination with tacrine or donepezil. Unlike (-)-nicotine, behavioral sensitization does not develop following repeated administration of TC-1734. Its pharmacokinetic (PK) profile (half-life of 2 h) contrasts with the long lasting improvement in working memory (18 h) demonstrating that cognitive improvement extends beyond the lifetime of the compound. The very low acute toxicity of TC-1734 and its receptor activity profile provides additional mechanistic basis for its suggested potential as a clinical candidate. TC-1734 was very well tolerated in acute and chronic oral toxicity studies in mice, rats and dogs. Phase I clinical trials demonstrated TC-1734's favorable pharmacokinetic and safety profile by acute oral administration at doses ranging from 2 to 320 mg. The bioavailability, pharmacological, pharmacokinetic, and safety profile of TC-1734 provides an example of a safe, potent and efficacious neuronal nicotinic modulator that holds promise for the management of the hallmark symptomatologies observed in dementia. PMID:15179444

  14. 5-(123)I-A-85380 binding to the α4β2-nicotinic receptor in mild cognitive impairment.

    Science.gov (United States)

    Terrière, Emma; Dempsey, Mary F; Herrmann, Lucie L; Tierney, Kevin M; Lonie, Jane A; O'Carroll, Ronan E; Pimlott, Sally; Wyper, David J; Herholz, Karl; Ebmeier, Klaus P

    2010-11-01

    Treatments currently licensed for Alzheimer's dementia target cholinergic brain systems. In vivo nicotinic receptor binding may provide an early marker of illness and treatment suitability. In this pilot, we examined nine patients with amnestic mild cognitive impairment (MCI) and 10 age and education matched healthy volunteers with high resolution SPECT and the nicotinic receptor ligand 5-(123)I-A-85380. Uptake data were analysed using voxel-based techniques for group comparisons and regression analyses with cognitive impairment as covariates. MCI patients had discrete reductions in uptake in medial temporal cortex. Correlations with cognitive impairment were found in left temporo-parietal areas (Addenbrooke's Cognitive Examination) and bilateral temporo-limbic areas (Rey Auditory Verbal Learning Test), and right parahippocampal gyrus (Rey Complex Figure Test) within the patient group. In vivo nicotinic receptor binding appears to be sensitive to brain changes in MCI. Larger scale explorations of patients undergoing treatment will be necessary to evaluate its use in predicting or monitoring treatment response. PMID:19036475

  15. Radioligand imaging of α4β2* nicotinic acetylcholine receptors in Alzheimer’s disease and Parkinson’s disease

    International Nuclear Information System (INIS)

    The α4β2* nicotinic acetylcholine receptors (α4β2*-nAChR) are highly abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as memory, learning and attention as well as mood and motor function. Post mortem studies suggest that abnormalities of α4β2*-nAChRs are closely linked to histopathological hallmarks of Alzheimer’s disease (AD), such as amyloid aggregates/oligomers and tangle pathology and of Parkinson’s disease (PD) such as Lewy body pathology and the nigrostriatal dopaminergic deficit. In this review we summarize and discuss nicotinic receptor imaging findings of 2-[18F]FA-85380 PET, [11C]nicotine PET and 5-[123I]IA-85380 SPECT studies investigating α4β2*-nAChR binding in vivo and their relationship to mental dysfunction in the brain of patients with AD and patients out of the spectrum of Lewy body disorders such as PD and Lewy body dementia (DLB). Furthermore, recent developments of novel α4β2*-nAChR-specific PET radioligands, such as (-)[18F]Flubatine or [18F]AZAN are summarized. We conclude that α4β2*-nAChR-specific PET might become a biomarker for early diagnostics and drug developments in patients with AD, DLB and PD, even at early or prodromal stages.

  16. Effects of simultaneous exposure to stress and nicotine on nicotine-induced locomotor activation in adolescent and adult rats

    Directory of Open Access Journals (Sweden)

    A. Zago

    2012-01-01

    Full Text Available Preclinical studies have shown that repeated stress experiences can result in an increase in the locomotor response to the subsequent administration of drugs of abuse, a phenomenon that has been termed behavioral cross-sensitization. Behavioral sensitization reflects neuroadaptive processes associated with drug addiction and drug-induced psychosis. Although cross-sensitization between stress- and drug-induced locomotor activity has been clearly demonstrated in adult rats, few studies have evaluated this phenomenon in adolescent rats. In the present study, we determined if the simultaneous exposure to stress and nicotine was capable of inducing behavioral sensitization to nicotine in adolescent and adult rats. To this end, adolescent (postnatal day (P 28-37 and adult (P60-67 rats received nicotine (0.4 mg/kg, sc or saline (0.9% NaCl, sc and were immediately subjected to restraint stress for 2 h once a day for 7 days. The control group for stress was undisturbed following nicotine or saline injections. Three days after the last exposure to stress and nicotine, rats were challenged with a single dose of nicotine (0.4 mg/kg, sc or saline and nicotine-induced locomotion was then recorded for 30 min. In adolescent rats, nicotine caused behavioral sensitization only in animals that were simultaneously exposed to stress, while in adult rats nicotine promoted sensitization independently of stress exposure. These findings demonstrate that adolescent rats are more vulnerable to the effects of stress on behavioral sensitization to nicotine than adult rats.

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

    Science.gov (United States)

    Kostygina, Ganna; England, Lucinda; Ling, Pamela

    2016-07-01

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

  18. Bioavailability and absorption kinetics of nicotine following application of a transdermal system.

    OpenAIRE

    Gupta, S.K.; Benowitz, N L; Jacob, P.; Rolf, C N; Gorsline, J

    1993-01-01

    1. The absolute bioavailability and absorption kinetics of nicotine were investigated in 13 healthy adult male smokers following single and multiple applications of a nicotine transdermal system (NTS), designed to release nicotine at an approximate rate of 1.5 mg h-1 over 24 h. The absorption of nicotine from the single NTS application was calculated with reference to a simultaneous intravenous infusion (i.v.) of deuterium-labelled nicotine. 2. The mean input time (MIT) and mean absorption ti...

  19. Isolation and Screening of a native Citrobacter sp. with high nicotine-tolerant and its application as a biocatalyst for biodegradation of nicotine

    Directory of Open Access Journals (Sweden)

    Morahem Ashengroph

    2015-12-01

    Full Text Available Introduction: Nicotine is a toxic plant alkaloid and it has been designated as hazardous by the United States Environmental Protection Agency (USEPA since 1994. The present work was directed to screen nicotine resistant bacteria, that is used as biocatalyst in the biodegradation of nicotine from contaminated sites. Materials and methods: Collected soil samples from 12 tobacco farms were selected as target sites for sampling. Enrichment nicotine-degrading bacteria were performed in minimal salt media containing nicotine as the sole carbon and nitrogen sources. Agar dilution plate method was performed for determining intrinsic tolerance of bacterial isolates to nicotine. Phenotypic characterization and phylogenetic analysis were used to identify the selected bacterial isolate able to degrade nicotine. To determine the optimal conditions for the bio-removal of nicotine, the effects of initial nicotine concentration, incubation time and the addition of carbon and nitrogen sources in the selected strain were tested. The quantification of residual nicotine in the culture media was measured by high performance liquid chromatography (HPLC. Results: Among 20 bacterial isolates for degradation of nicotine, the strain TPS2 showed a high level of resistance and degradation efficiency. Results of phenotypic identification and phylogenetic analysis showed the native strain TPS2 belongs to the Citrobacter sp. strain TPS2 (GeneBank accession no. KM110046. According to the results of de-nicotination experiment, the native strain TPS2 is able to remove 100% of nicotine with an initial concentration 2.5 g/l in the presence of 2.5 g/l fructose. Discussion and conclusion: The results showed that the screened Citrobacter sp. was suitable candidate for degradation of nicotine from wastewater and sites that contaminated with nicotine. It is seemed by using of the microbial biocatalyst the ecosystem contamination of toxic nicotine can be decreased. The present work is

  20. A key role for the N/OFQ-NOP receptor system in modulating nicotine taking in a model of nicotine and alcohol co-administration.

    Science.gov (United States)

    Cippitelli, Andrea; Schoch, Jennifer; Debevec, Ginamarie; Brunori, Gloria; Zaveri, Nurulain T; Toll, Lawrence

    2016-01-01

    Alcohol and nicotine are often co-abused. Although the N/OFQ-NOP receptor system is considered a potential target for development of drug abuse pharmacotherapies, especially for alcoholism, little is known about the role of this system in nicotine dependence. Furthermore, the effect of prior history of nicotine dependence on subsequent nicotine and alcohol taking is understudied. Using an operant co-administration paradigm, in which rats concurrently self-administer nicotine and alcohol, we found that nicotine dependent rats increased nicotine self-administration over time as compared to non-dependent animals, while patterns of alcohol lever pressing did not change between groups. Pretreatment with the potent NOP receptor agonist AT-202 (0.3-3 mg/kg) increased nicotine lever pressing of both dependent and non-dependent groups, whereas the selective antagonist SB612111 (1-10 mg/kg) elicited a clear reduction of nicotine responses, in both dependent and non-dependent rats. In parallel, AT-202 only produced minor changes on alcohol responses and SB612111 reduced alcohol taking at a dose that also reduced locomotor behavior. Results indicate that a history of nicotine dependence affects subsequent nicotine- but not alcohol-maintained responding, and that NOP receptor antagonism, rather than agonism, blocks nicotine self-administration, which strongly suggests a critical role for the endogenous N/OFQ in the modulation of nicotine reinforcement processes. PMID:27199205

  1. Innate Immunity and Inflammation Post-Stroke: An α7-Nicotinic Agonist Perspective

    Directory of Open Access Journals (Sweden)

    Silke Neumann

    2015-12-01

    Full Text Available Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer’s disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using α7-nicotinic acetylcholine receptor (α7-nAChR ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of α7-nAChR modulators on innate immune cells.

  2. Brain derived neurotrophic factor

    DEFF Research Database (Denmark)

    Mitchelmore, Cathy; Gede, Lene

    2014-01-01

    Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin with important functions in neuronal development and neuroplasticity. Accumulating evidence suggests that alterations in BDNF expression levels underlie a variety of psychiatric and neurological disorders. Indeed, BDNF therapies are...

  3. Bupropion-induced inhibition of α7 nicotinic acetylcholine receptors expressed in heterologous cells and neurons from dorsal raphe nucleus and hippocampus.

    Science.gov (United States)

    Vázquez-Gómez, Elizabeth; Arias, Hugo R; Feuerbach, Dominik; Miranda-Morales, Marcela; Mihailescu, Stefan; Targowska-Duda, Katarzyna M; Jozwiak, Krzysztof; García-Colunga, Jesús

    2014-10-01

    The pharmacological activity of bupropion was compared between α7 nicotinic acetylcholine receptors expressed in heterologous cells and hippocampal and dorsal raphe nucleus neurons. The inhibitory activity of bupropion was studied on GH3-α7 cells by Ca2+ influx, as well as on neurons from the dorsal raphe nucleus and interneurons from the stratum radiatum of the hippocampal CA1 region by using a whole-cell voltage-clamp technique. In addition, the interaction of bupropion with the α7 nicotinic acetylcholine receptor was determined by [3H]imipramine competition binding assays and molecular docking. The fast component of acetylcholine- and choline-induced currents from both brain regions was inhibited by methyllycaconitine, indicating the participation of α7-containing nicotinic acetylcholine receptors. Choline-induced currents in hippocampal interneurons were partially inhibited by 10 µM bupropion, a concentration that could be reached in the brain during clinical administration. Additionally, both agonist-induced currents were reversibly inhibited by bupropion at concentrations that coincide with its inhibitory potency (IC50=54 µM) and binding affinity (Ki=63 µM) for α7 nicotinic acetylcholine receptors from heterologous cells. The [3H]imipramine competition binding and molecular docking results support a luminal location for the bupropion binding site(s). This study may help to understand the mechanisms of actions of bupropion at neuronal and molecular levels related with its therapeutic actions on depression and for smoking cessation. PMID:25016090

  4. Impact of Tobacco Smoke and Nicotine Exposure on Lung Development.

    Science.gov (United States)

    Gibbs, Kevin; Collaco, Joseph M; McGrath-Morrow, Sharon A

    2016-02-01

    Tobacco smoke and nicotine exposure during prenatal and postnatal life can impair lung development, alter the immune response to viral infections, and increase the prevalence of wheezing during childhood. The following review examines recent discoveries in the fields of lung development and tobacco and nicotine exposure, emphasizing studies published within the last 5 years. In utero tobacco and nicotine exposure remains common, occurring in approximately 10% of pregnancies within the United States. Exposed neonates are at increased risk for diminished lung function, altered central and peripheral respiratory chemoreception, and increased asthma symptoms throughout childhood. Recently, genomic and epigenetic risk factors, such as alterations in DNA methylation, have been identified that may influence the risk for long-term disease. This review examines the impact of prenatal tobacco and nicotine exposure on lung development with a particular focus on nicotinic acetylcholine receptors. In addition, this review examines the role of prenatal and postnatal tobacco smoke and nicotine exposure and its association with augmenting infection risk, skewing the immune response toward a T-helper type 2 bias and increasing risk for developing an allergic phenotype and asthmalike symptoms during childhood. Finally, this review outlines the respiratory morbidities associated with childhood secondhand smoke and nicotine exposure and examines genetic and epigenetic modifiers that may influence respiratory health in infants and children exposed to in utero or postnatal tobacco smoke. PMID:26502117

  5. Blockade of smoking satisfaction using the peripheral nicotinic antagonist trimethaphan.

    Science.gov (United States)

    Rose, J E; Westman, E C; Behm, F M; Johnson, M P; Goldberg, J S

    1999-01-01

    The present study was conducted to investigate the role of peripheral nicotinic receptors in mediating the rewarding effects of cigarette smoking. Twelve cigarette smokers rated cigarettes after intravenous infusion of the short-acting peripheral nicotinic receptor antagonist trimethaphan and after placebo (saline) infusions. Subjects were blinded to the infusion and cigarette conditions. Cigarette conditions included subjects' usual brand of cigarette, denicotinized tobacco cigarettes, and nicotine-injected cigarettes that had a tar delivery equal to that of the denicotinized cigarettes but with an enhanced nicotine delivery equal to that of subjects' usual brands. The latter cigarettes were rated as extremely harsh due to the high nicotine/tar ratio. Trimethaphan significantly attenuated the airway sensations associated with nicotine, and eliminated the difference in smoking satisfaction between the usual brand of cigarette and the other two cigarettes. These findings suggest that nicotinic receptors on peripheral nerve endings in the respiratory tract modulate smoking satisfaction and may be important in the maintenance of cigarette addiction. PMID:9972860

  6. Multigenerational epigenetic effects of nicotine on lung function

    Directory of Open Access Journals (Sweden)

    Leslie Frances M

    2013-02-01

    Full Text Available Abstract A recent preclinical study has shown that not only maternal smoking but also grandmaternal smoking is associated with elevated pediatric asthma risk. Using a well-established rat model of in utero nicotine exposure, Rehan et al. have now demonstrated multigenerational effects of nicotine that could explain this 'grandmother effect'. F1 offspring of nicotine-treated pregnant rats exhibited asthma-like changes to lung function and associated epigenetic changes to DNA and histones in both lungs and gonads. These alterations were blocked by co-administration of the peroxisome proliferator-activated receptor-γ agonist, rosiglitazone, implicating downregulation of this receptor in the nicotine effects. F2 offspring of F1 mated animals exhibited similar changes in lung function to that of their parents, even though they had never been exposed to nicotine. Thus epigenetic mechanisms appear to underlie the multigenerational transmission of a nicotine-induced asthma-like phenotype. These findings emphasize the need for more effective smoking cessation strategies during pregnancy, and cast further doubt on the safety of using nicotine replacement therapy to reduce tobacco use in pregnant women. Please see related article: http://www.biomedcentral.com/1741-7015/10/129

  7. Schizophrenia and the alpha7 nicotinic acetylcholine receptor.

    Science.gov (United States)

    Martin, Laura F; Freedman, Robert

    2007-01-01

    In addition to the devastating symptoms of psychosis, many people with schizophrenia also suffer from cognitive impairment. These cognitive symptoms lead to marked dysfunction and can impact employability, treatment adherence, and social skills. Deficits in P50 auditory gating are associated with attentional impairment and may contribute to cognitive symptoms and perceptual disturbances. This nicotinic cholinergic-mediated inhibitory process represents a potential new target for therapeutic intervention in schizophrenia. This chapter will review evidence implicating the nicotinic cholinergic, and specifically, the alpha7 nicotinic receptor system in the pathology of schizophrenia. Impaired auditory sensory gating has been linked to the alpha7 nicotinic receptor gene on the chromosome 15q14 locus. A majority of persons with schizophrenia are heavy smokers. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. The alpha7 nicotinic agonist 3-(2,4 dimethoxy)benzylidene-anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and a new study in persons with schizophrenia has found that DMXBA enhances both P50 auditory gating and cognition. alpha7 Nicotinic acetylcholine receptor agonists appear to be viable candidates for the treatment of cognitive disturbances in schizophrenia. PMID:17349863

  8. Parazoanthoxanthin A blocks Torpedo nicotinic acetylcholine receptors.

    Science.gov (United States)

    Rozman, Klara Bulc; Araoz, Romulo; Sepcić, Kristina; Molgo, Jordi; Suput, Dusan

    2010-09-01

    Nicotinic acetylcholine receptors are implicated in different nervous system-related disorders, and their modulation could improve existing therapy of these diseases. Parazoanthoxanthin A (ParaA) is a fluorescent pigment of the group of zoanthoxanthins. Since it is a potent acetylcholinesterase inhibitor, it may also bind to nicotinic acetylcholine receptors (nAChRs). For this reason its effect on Torpedo nAChR (alpha1(2)betagammadelta) transplanted to Xenopus laevis oocytes was evaluated, using the voltage-clamp technique. ParaA dose-dependently reduced the acetylcholine-induced currents. This effect was fully reversible only at lower concentrations. ParaA also reduced the Hill coefficient and the time to peak current, indicating a channel blocking mode of action. On the other hand, the combined effect of ParaA and d-tubocurarine (d-TC) on acetylcholine-induced currents exhibited only partial additivity, assuming a competitive mode of action of ParaA on nAChR. These results indicate a dual mode of action of ParaA on the Torpedo AChR. PMID:20230806

  9. Orally administered nicotine induces urothelial hyperplasia in rats and mice

    International Nuclear Information System (INIS)

    Highlights: • Rats and mice orally administered with nicotine tartrate for total of 4 weeks. • No treatment-related death or whole body toxicity observed in any of the groups. • Urothelium showed simple hyperplasia in treated rats and mice. • No significant change in BrdU labeling index or SEM classification of urothelium. - Abstract: Tobacco smoking is a major risk factor for multiple human cancers including urinary bladder carcinoma. Tobacco smoke is a complex mixture containing chemicals that are known carcinogens in humans and/or animals. Aromatic amines a major class of DNA-reactive carcinogens in cigarette smoke, are not present at sufficiently high levels to fully explain the incidence of bladder cancer in cigarette smokers. Other agents in tobacco smoke could be excreted in urine and enhance the carcinogenic process by increasing urothelial cell proliferation. Nicotine is one such major component, as it has been shown to induce cell proliferation in multiple cell types in vitro. However, in vivo evidence specifically for the urothelium is lacking. We previously showed that cigarette smoke induces increased urothelial cell proliferation in mice. In the present study, urothelial proliferative and cytotoxic effects were examined after nicotine treatment in mice and rats. Nicotine hydrogen tartrate was administered in drinking water to rats (52 ppm nicotine) and mice (514 ppm nicotine) for 4 weeks and urothelial changes were evaluated. Histopathologically, 7/10 rats and 4/10 mice showed simple hyperplasia following nicotine treatment compared to none in the controls. Rats had an increased mean BrdU labeling index compared to controls, although it was not statistically significantly elevated in either species. Scanning electron microscopic visualization of the urothelium did not reveal significant cytotoxicity. These findings suggest that oral nicotine administration induced urothelial hyperplasia (increased cell proliferation), possibly due to a

  10. The effects of extrinsic context on nicotine discrimination.

    Science.gov (United States)

    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. PMID:11990718

  11. Brain derived neurotrophic factor

    DEFF Research Database (Denmark)

    Mitchelmore, Cathy; Gede, Lene

    2014-01-01

    Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin with important functions in neuronal development and neuroplasticity. Accumulating evidence suggests that alterations in BDNF expression levels underlie a variety of psychiatric and neurological disorders. Indeed, BDNF therapies are curre......Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin with important functions in neuronal development and neuroplasticity. Accumulating evidence suggests that alterations in BDNF expression levels underlie a variety of psychiatric and neurological disorders. Indeed, BDNF therapies...

  12. Degradation kinetics of benzyl nicotinate in aqueous solution

    Directory of Open Access Journals (Sweden)

    Mbah C

    2010-01-01

    Full Text Available The degradation of benzyl nicotinate in aqueous solution over a pH range of 2.0-10.0 at 50±0.2 o was studied. The degradation was determined by high performance liquid chromatography. The degradation was observed to follow apparent first-order rate kinetics and the rate constant for the decomposition at 25 o was estimated by extrapolation. The reaction was shown to be hydroxide ion catalyzed and the Arrhenius plots showed the temperature dependence of benzyl nicotinate degradation. A significant increase in the stability of benzyl nicotinate was observed when glycerol or polyethylene glycol 400 was incorporated into the aqueous solution.

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

    Science.gov (United States)

    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. PMID:18988077

  14. Nicotine blocks apomorphine-induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic α7 receptors

    OpenAIRE

    Suemaru, Katsuya; Yasuda, Kayo; Umeda, Kenta; Araki, Hiroaki; Shibata, Kazuhiko; Choshi, Tominari; Hibino, Satoshi; Gomita, Yutaka

    2004-01-01

    Nicotine has been reported to normalize deficits in auditory sensory gating in the cases of schizophrenia, suggesting an involvement of nicotinic acetylcholine receptors in attentional abnormalities. However, the mechanism remains unclear. The present study investigated the effects of nicotine on the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine or phencyclidine in rats.Over the dose range tested, nicotine (0.05–1 mg kg−1, s.c.) did not disrup...

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

    Directory of Open Access Journals (Sweden)

    Zuo Jun Ren

    Full Text Available 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.

  16. The development and testing of new nicotine replacement treatments: from 'nicotine replacement' to 'smoking replacement'.

    Science.gov (United States)

    Hajek, Peter

    2015-07-01

    Griffith Edwards, unusually in the 1970s, saw tobacco use as falling within the remit of addiction research, and brought Michael Russell to the Addiction Research Unit [ARU] to initiate research into smoking. The work of the tobacco section of ARU paved the way to a better understanding of tobacco dependence and to developing nicotine replacement treatments. Michael Russell pioneered the idea of attractive nicotine replacement products with an acceptable safety profile replacing cigarettes on the open market and ending the tobacco epidemic, envisaging a transition from medicinal and temporary 'nicotine replacement' to recreational and potentially permanent 'smoking replacement'. Mike's prediction that the pharmaceutical industry would develop such devices did not materialize. Instead, two such products were generated by the tobacco industry (snus) and independent developers (electronic cigarettes). Another of Mike's hopes was that regulators would adopt rational policies, and that tobacco control activists would become supportive of smoking replacement once they thought through the implications. Until now, the 'smoking replacement' idea has been met with vigorous opposition from some tobacco control activists. The voices of researchers with historical links to ARU are prominent in arguing in favour of harm reduction and e-cigarettes. The most important debate ever to occur in tobacco control is under way and it carries the signature of Griffith Edwards' ARU. PMID:26042563

  17. Structural model of nicotinic acetylcholine receptor isotypes bound to acetylcholine and nicotine

    Directory of Open Access Journals (Sweden)

    Abagyan Ruben

    2002-01-01

    Full Text Available Abstract Background Nicotine is a psychoactive drug presenting a diverse array of biological activities, some positive, such as enhancement of cognitive performances, others negative, such as addiction liability. Ligands that discriminate between the different isotypes of nicotinic acetylcholine receptors (nAChRs could present improved pharmacology and toxicity profile. Results Based on the recent crystal structure of a soluble acetylcholine binding protein from snails, we have built atomic models of acetylcholine and nicotine bound to the pocket of four different human nAChR subtypes. The structures of the docked ligands correlate with available biochemical data, and reveal that the determinants for isotype selectivity are relying essentially on four residues, providing diversity of the ligand binding pocket both in terms of Van der Waals boundary, and electrostatic potential. We used our models to screen in silico a large compound database and identify a new ligand candidate that could display subtype selectivity. Conclusion The nAChR-agonist models should be useful for the design of nAChR agonists with diverse specificity profiles.

  18. Probing into the Interaction of Nicotine and Bovine Submaxillary Mucin: NMR, Fluorescence, and FTIR Approaches

    Directory of Open Access Journals (Sweden)

    Xiaoxiang Liao

    2016-01-01

    Full Text Available Nicotine, the important component of cigarette products, may have an impact on the oral environment after inhalation. The research of interaction between nicotine and bovine submaxillary mucin (BSM contributes to understand the binding mechanism of nicotine and BSM, and the effects of nicotine on the structure and function of the mucin. NMR data demonstrated that the interaction between nicotine and BSM did exist, and it was pyrrolidyl ring of nicotine playing the major role in the binding. The quenching mechanisms of nicotine and BSM in different pH were different: for acidic environment, the quenching was dynamic; while it became static in the alkaline circumstance. Synchronous fluorescence spectra indicated that nicotine had effect on the microenvironment of the Trp rather than Tyr residue. Meanwhile, the impact of nicotine on the conformation of BSM was also confirmed by 3D fluorescence and FTIR spectra.

  19. Animal models of nicotine exposure: relevance to second-hand smoking, electronic cigarette use and compulsive smoking

    Directory of Open Access Journals (Sweden)

    Ami eCohen

    2013-06-01

    Full Text Available 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.

  20. E-Cig Liquid Nicotine Containers Often Mislabeled

    Science.gov (United States)

    ... t child-resistant, which poses a risk to youngsters To use the sharing features on this page, ... e-liquids exposes the user to the harmful effects of nicotine," said study author Kelly Buettner-Schmidt, ...

  1. The impact of nicotine on bone healing and osseointegration

    DEFF Research Database (Denmark)

    Balatsouka, Dimitra; Gotfredsen, Klaus; Lindh, Christian H;

    2005-01-01

    administered via a miniosmotic pump and plasma cotinine levels were measured weekly. The pump delivered 15 mg of nicotine/day for the animals in the test group. All rabbits had three tibial bone preparations. In the proximal and distal bone bed, implants were placed after 4 weeks (right tibia) and after 6......OBJECTIVES: To examine the short-term effect of nicotine on bone healing and osseointegration. MATERIAL AND METHODS: Sixteen female rabbits were divided into two groups. The test group was exposed to nicotine tartrate for 8 weeks and the control group was exposed to placebo. Nicotine or placebo was...... weeks (left tibia). Thus, 2- and 4-week healing groups were created. Removal torque test (RMT) was performed at the distal implants. Ground sections were made from the proximal and the central bone beds. The fraction of mineralized bone in contact to the implant (BIC) and the bone density within the...

  2. Constant exposure to darkness produces supersensitivity to nicotine.

    Science.gov (United States)

    Flemmer, D D; Dilsaver, S C

    1990-03-01

    Treatment with full-spectrum bright artificial light produces subsensitivity to the hypothermic effect of nicotine in the rat. The authors hypothesized that prolonged exposure to darkness would produce the opposite effect. The thermic responsiveness of 11 rats to nicotine (base), 0.25 mg/kg IP, was telemetrically measured at baseline, after 7 days of exposure to constant darkness, and 2, 5, and 12 days after being returned to standard vivarium conditions. Exposure to constant darkness enhanced the hypothermic response to nicotine. The sample exhibited a hyperthermic response to nicotine 2 and 5 days after being returned to the standard vivarium conditions with a 12-hour-light/12-hour-dark cycle. The magnitude of the hyperthermia observed is characteristic of the response to the injection of saline. Twelve days after return to standard vivarium conditions the thermic response of the sample was at baseline. PMID:2339143

  3. Targeted studies on the interaction of nicotine and morin molecules with amyloid β-protein.

    Science.gov (United States)

    Boopathi, Subramaniam; Kolandaivel, Ponmalai

    2014-03-01

    Alzheimer's disease (AD) is a neurodegenerative disorder that occurs due to progressive deposition of amyloid β-protein (Aβ) in the brain. Stable conformations of solvated Aβ₁₋₄₂ protein were predicted by molecular dynamics (MD) simulation using the OPLSAA force field. The seven residue peptide (Lys-Leu-Val-Phe-Phe-Ala-Glu) Aβ₁₆₋₂₂ associated with AD was studied and reported in this paper. Since effective therapeutic agents have not yet been studied in detail, attention has focused on the use of natural products as effective anti-aggregation compounds, targeting the Aβ₁₋₄₂ protein directly. Experimental and theoretical investigation suggests that some compounds extracted from natural products might be useful, but detailed insights into the mechanism by which they might act remains elusive. The molecules nicotine and morin are found in cigarettes and beverages. Here, we report the results of interaction studies of these compounds at each hydrophobic residue of Aβ₁₆₋₂₂ peptide using the hybrid ONIOM (B3LYP/6-31G**:UFF) method. It was found that interaction with nicotine produced higher deformation in the Aβ₁₆₋₂₂ peptide than interaction with morin. MD simulation studies revealed that interaction of the nicotine molecule with the β-sheet of Aβ₁₆₋₂₂ peptide transforms the β-sheet to an α-helical structure, which helps prohibit the aggregation of Aβ-protein. PMID:24567151

  4. Comparison of seven different anesthesia protocols for nicotine pharmacologic magnetic resonance imaging in rat.

    Science.gov (United States)

    Paasonen, Jaakko; Salo, Raimo A; Shatillo, Artem; Forsberg, Markus M; Närväinen, Johanna; Huttunen, Joanna K; Gröhn, Olli

    2016-03-01

    Pharmacologic MRI (phMRI) is a non-invasive in vivo imaging method, which can evaluate the drug effects on the brain and provide complementary information to ex vivo techniques. The preclinical phMRI studies usually require anesthesia to reduce the motion and stress of the animals. The anesthesia, however, is a crucial part of the experimental design, as it may modulate the neural drug-induced (de)activation and hemodynamic coupling. Therefore, the aim of the present study was to address this methodologic question by performing phMRI experiments with five anesthetics (α-chloralose, isoflurane, medetomidine, thiobutabarbital, and urethane) and seven anesthesia protocols. Nicotine, a widely studied psychostimulant, was administered to rats while measuring blood oxygenation level-dependent (BOLD) signals. Notably different responses were observed depending on the anesthetic used. The highest responses were measured in urethane-anesthetized rats whereas the responses were hardly noticeable in α-chloralose group. As urethane is not commonly used in phMRI, hemodynamic coupling under urethane anesthesia was investigated with functional cerebral blood flow (CBF) and volume-weighted (CBVw) imaging, and simultaneous electrophysiologic and BOLD measurements. The BOLD, CBF, and CBVw measurements in response to nicotine were highly correlated (R(2) ≥ 0.70, p<0.001). BOLD values correlated well (R(2)=0.43, p<10(-6)) with local field potential (LFP) spectral power (13-70Hz) during pharmacologic stimulation. These findings indicate that urethane anesthesia combined with BOLD contrast provides a robust protocol for nicotine phMRI studies. As urethane has mild effects to individual receptor systems, and coupling between electrophysiologic activity and hemodynamic response is maintained, this anesthetic may also be suitable for other phMRI studies. PMID:26796682

  5. The α7 nicotinic acetylcholine receptor complex

    DEFF Research Database (Denmark)

    Thomsen, Morten Skøtt; Mikkelsen, Jens D

    2012-01-01

    The α7 nicotinic acetylcholine receptor (nAChR) is a promising drug target for a number of diseases ranging from schizophrenia and Alzheimer's disease to chronic pain and inflammatory diseases. Focusing on the central nervous system, we describe how endogenous and experimental compounds and...... compounds in vivo is highly dependent on α7 nAChR-interacting proteins, such as RIC-3 and lynx1, which modulate expression and function of the receptor. These regulatory proteins are often not expressed in in vitro models used to study α7 nAChR function, and it is not known to what extent they are involved...... in diseases such as schizophrenia and Alzheimer's disease. Furthermore, α7 nAChR agonists and allosteric modulators differentially alter expression and functionality of the α7 nAChR with repeated administration, which suggests that there may be fundamentally different outcomes of long...

  6. Influence of nicotine and caffeine on rat embryonic development

    OpenAIRE

    Nash, J. E.; Persaud, T.V.N.

    1988-01-01

    The influence on embryonic development of nicotine and caffeine at dose levels approximating human consumption was investigated in Sprague- Dawley rats. One group of animals received nicotine administered subcutaneously by an Alzet mini-osmotic pump from gestational day 6 through 12 (25 mg over 7 days; rate 149 pg/hr). Control animals received physiological saline in a similar manner. A second group received a single intravenous injection of caffeine (25 mg/ ...

  7. The effects of acute nicotine on contextual safety discrimination

    OpenAIRE

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

    2014-01-01

    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. Followi...

  8. SLEEP QUALITY AMONG TYPE 2 DIABETICS WITH NICOTINE DEPENDENCE

    OpenAIRE

    Sivaraman; Aarthi; Ismail; Thirumala Kolundu

    2014-01-01

    INTRODUCTION: Sleep disorders are reported due to varied reasons and are on the rise. Diabetes is established as the one of the reasons for alterations in the quality of sleep. Studies have established that nicotine acts on the neurotransmitter system and influence the quality of sleep. Nicotine use by the diabetic patients is an added factor and will interfere with their quality of sleep. The objectives of the study were to assess the quality of sleep among uncontrolled and u...

  9. Differential sensitivity to nicotine among hypothalamic magnocellular neurons

    DEFF Research Database (Denmark)

    Mikkelsen, J D; Jacobsen, Julie; Kiss, Adrian Emil

    2012-01-01

    The magnocellular neurons in the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON) either contain vasopressin or oxytocin. Even though both hormones are released after systemic administration of nicotine, the mechanism through which the two populations of neurons are activated is not...... known. This study was carried out in the rat to investigate the effect of increasing doses of nicotine on subsets of magnocellular neurons containing either oxytocin or vasopressin....

  10. E-cigarettes for the management of nicotine addiction

    OpenAIRE

    Bullen, Chris; Knight-West, Oliver

    2016-01-01

    Oliver Knight-West, Christopher Bullen The National Institute for Health Innovation, School of Population Health, The University of Auckland, Auckland, New Zealand Abstract: In this review, we discuss current evidence on electronic cigarettes (ECs), a rapidly evolving class of nicotine delivery system, and their role in managing nicotine addiction, specifically in helping smokers to quit smoking and/or reduce the amount of tobacco they smoke. The current evidence base is limited to t...

  11. Spectroscopic Characterization of Disulfiram and Nicotinic Acid after Biofield Treatment

    OpenAIRE

    Trivedi, Mahendra Kumar

    2015-01-01

    Disulfiram is being used clinically as an aid in chronic alcoholism, while nicotinic acid is one of a B-complex vitamin that has cholesterol lowering activity. The aim of present study was to investigate the impact of biofield treatment on spectral properties of disulfiram and nicotinic acid. The study was performed in two groups i.e., control and treatment of each drug. The treatment groups were received Mr. Trivedi’s biofield treatment. Subsequently, spectral properties of control and...

  12. Different effects of lobeline on neuronal and muscle nicotinic receptors

    Czech Academy of Sciences Publication Activity Database

    Kaniaková, Martina; Skřenková, Kristýna; Adámek, S.; Vyskočil, František; Krůšek, Jan

    2014-01-01

    Roč. 738, Sep 5 (2014), s. 352-359. ISSN 0014-2999 R&D Projects: GA ČR(CZ) GA202/09/0806; GA AV ČR(CZ) IAA500110905; GA ČR(CZ) GBP304/12/G069 Institutional support: RVO:67985823 Keywords : neuronal nicotinic receptor alpha3beta4 * lobeline * embryonic muscle nicotinic receptor Subject RIV: ED - Physiology Impact factor: 2.532, year: 2014

  13. The endocrine effects of nicotine and cigarette smoke

    OpenAIRE

    Tweed, Jesse Oliver; Hsia, Stanley H.; Lutfy, Kabirullah; Friedman, Theodore C.

    2012-01-01

    With a current prevalence of approximately 20%, smoking continues to impact negatively upon health. Tobacco or nicotine use influences the endocrine system, with important clinical implications. In this review we critically evaluate the literature concerning the impact of nicotine as well as tobacco use on several parameters of the endocrine system and on glucose and lipid homeostasis. Emphasis is on the effect of smoking on diabetes mellitus and obesity and the consequences of smoking cessat...

  14. Transdermal Nicotine Application Attenuates Cardiac Dysfunction after Severe Thermal Injury

    Science.gov (United States)

    Claassen, Leif; Papst, Stephan; Reimers, Kerstin; Stukenborg-Colsman, Christina; Steinstraesser, Lars; Vogt, Peter M.; Kraft, Theresia; Niederbichler, Andreas D.

    2015-01-01

    Background. Severe burn trauma leads to an immediate and strong inflammatory response inciting cardiac dysfunction that is associated with high morbidity and mortality. The aim of this study was to determine whether transdermal application of nicotine could influence the burn-induced cardiac dysfunction via its known immunomodulatory effects. Material and Methods. A standardized rat burn model was used in 35 male Sprague Dawley rats. The experimental animals were divided into a control group, a burn trauma group, a burn trauma group with additional nicotine treatment, and a sham group with five experimental animals per group. The latter two groups received nicotine administration. Using microtip catheterization, functional parameters of the heart were assessed 12 or 24 hours after infliction of burn trauma. Results. Burn trauma led to significantly decreased blood pressure (BP) values whereas nicotine administration normalized BP. As expected, burn trauma also induced a significant deterioration of myocardial contractility and relaxation parameters. After application of nicotine these adverse effects were attenuated. Conclusion. The present study showed that transdermal nicotine administration has normalizing effects on burn-induced myocardial dysfunction parameters. Further research is warranted to gain insight in molecular mechanisms and pathways and to evaluate potential treatment options in humans. PMID:26290866

  15. The effect of transdermal nicotine patches on sleep and dreams.

    Science.gov (United States)

    Page, F; Coleman, G; Conduit, R

    2006-07-30

    This study was undertaken to determine the effect of 24-h transdermal nicotine patches on sleep and dream mentation in 15 smokers aged 20 to 33. Utilising a repeated measures design, it was found that more time awake and more ASDA micro-arousals occurred while wearing the nicotine patch compared to placebo. Also, the percentage of REM sleep decreased, but REM latency and the proportion of time spent in NREM sleep stages did not change significantly. Dream reports containing visual imagery, visual imagery ratings and the number of visualizable nouns were significantly greater from REM compared to Stage 2 awakenings, regardless of patch condition. However, a general interaction effect was observed. Stage 2 dream variables remained equivalent across nicotine and placebo conditions. Within REM sleep, more dream reports containing visual imagery occurred while wearing the nicotine patch, and these were rated as more vivid. The greater frequency of visual imagery reports and higher imagery ratings specifically from REM sleep suggests that previously reported dreaming side effects from 24-h nicotine patches may be specific to REM sleep. Combined with previous animal studies showing that transdermally delivered nicotine blocks PGO activity in REM sleep, the current results do no appear consistent with PGO-based hypotheses of dreaming, such as the Activation-Synthesis (AS) or Activation, Input and Modulation (AIM) models. PMID:16782142

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

    Science.gov (United States)

    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. PMID:27376882

  17. The effect of nicotine on aortic endothelial cell turnover

    International Nuclear Information System (INIS)

    Endothelial injury and increased mitotic activity are early features in the pathogenesis of intimal thickening in arteries. This study examines the effect of systemic nicotine on mitotic activity in endothelial cells. Nine adult mice were given nicotine in their drinking water for 5 weeks. The dose (5 mg/kg body wt/day) was equivalent to a human smoking 50-100 cigarettes/day. A group of 8 similar mice, not exposed to nicotine, was the control. At the end of the exposure period all mice were injected with (3H)thymidine (1uCi/g body wt) and were killed 24 h later. After perfusion fixation, en-face preparations of aortic endothelium were processed for autoradiography. In nicotine-affected endothelium 0.46.+-0.11% (SEM) of cells were labeled, which was significantly higher (P<0.01) than in controls (0.14+-0.06). However, there was no difference in cell density between the groups. On this evidence it was concluded that the rate of cell loss, or cell turnover, was greater in nicotine-affected endothelium. Because other studies have shown that increased mitotic acitivity and cell loss are established features of endothelial injury, the present findings provide evidence in support of the hypothesis that nicotine contributes to the pathogenesis of arterial disease in smokers. (author)

  18. Transdermal Nicotine Application Attenuates Cardiac Dysfunction after Severe Thermal Injury

    Directory of Open Access Journals (Sweden)

    Leif Claassen

    2015-01-01

    Full Text Available Background. Severe burn trauma leads to an immediate and strong inflammatory response inciting cardiac dysfunction that is associated with high morbidity and mortality. The aim of this study was to determine whether transdermal application of nicotine could influence the burn-induced cardiac dysfunction via its known immunomodulatory effects. Material and Methods. A standardized rat burn model was used in 35 male Sprague Dawley rats. The experimental animals were divided into a control group, a burn trauma group, a burn trauma group with additional nicotine treatment, and a sham group with five experimental animals per group. The latter two groups received nicotine administration. Using microtip catheterization, functional parameters of the heart were assessed 12 or 24 hours after infliction of burn trauma. Results. Burn trauma led to significantly decreased blood pressure (BP values whereas nicotine administration normalized BP. As expected, burn trauma also induced a significant deterioration of myocardial contractility and relaxation parameters. After application of nicotine these adverse effects were attenuated. Conclusion. The present study showed that transdermal nicotine administration has normalizing effects on burn-induced myocardial dysfunction parameters. Further research is warranted to gain insight in molecular mechanisms and pathways and to evaluate potential treatment options in humans.

  19. Corticotropin-releasing factor within the central nucleus of the amygdala and the nucleus accumbens shell mediates the negative affective state of nicotine withdrawal in rats

    OpenAIRE

    Marcinkiewcz, Catherine A.; Prado, Melissa M.; Isaac, Shani K.; Marshall, Alex.; Rylkova, Daria; Bruijnzeel, Adrie W.

    2009-01-01

    Tobacco addiction is a chronic disorder that is characterized by a negative affective state upon smoking cessation and relapse after periods of abstinence. Previous research has shown that an increased central release of corticotropin-releasing factor (CRF) at least partly mediates the deficit in brain reward function associated with nicotine withdrawal in rats. The aim of these studies was to investigate the role of CRF in the central nucleus of the amygdala (CeA), the lateral bed nucleus of...

  20. GLUCOSE ATTENUATES IMPAIRMENTS IN MEMORY AND CREB ACTIVATION PRODUCED BY AN α4β2 BUT NOT AN α7 NICOTINIC RECEPTOR ANTAGONIST

    OpenAIRE

    Morris, Ken A.; Li, Sisi; Bui, Duat D.; Gold, Paul E.

    2012-01-01

    Glucose improves memory for a variety of tasks when administered to rats and mice near the time of training. Prior work indicates glucose may enhance memory by increasing the synthesis and release of the neurotransmitter acetylcholine in the brain. To investigate if specific acetylcholine receptor subtypes may mediate some of the memory-enhancing actions of glucose, we examined the effects of subtype-specific nicotinic acetylcholine receptor antagonists on memory in Fischer-344 rats and also ...

  1. Nucleosome Repositioning: A Novel Mechanism for Nicotine- and Cocaine-Induced Epigenetic Changes.

    Directory of Open Access Journals (Sweden)

    Amber N Brown

    Full Text Available Drugs of abuse modify behavior by altering gene expression in the brain. Gene expression can be regulated by changes in DNA methylation as well as by histone modifications, which alter chromatin structure, DNA compaction and DNA accessibility. In order to better understand the molecular mechanisms directing drug-induced changes in chromatin structure, we examined DNA-nucleosome interactions within promoter regions of 858 genes in human neuroblastoma cells (SH-SY5Y exposed to nicotine or cocaine. Widespread, drug- and time-resolved repositioning of nucleosomes was identified at the transcription start site and promoter region of multiple genes. Nicotine and cocaine produced unique and shared changes in terms of the numbers and types of genes affected, as well as repositioning of nucleosomes at sites which could increase or decrease the probability of gene expression based on DNA accessibility. Half of the drug-induced nucleosome positions approximated a theoretical model of nucleosome occupancy based on physical and chemical characteristics of the DNA sequence, whereas the basal or drug naïve positions were generally DNA sequence independent. Thus we suggest that nucleosome repositioning represents an initial dynamic genome-wide alteration of the transcriptional landscape preceding more selective downstream transcriptional reprogramming, which ultimately characterizes the cell- and tissue-specific responses to drugs of abuse.

  2. Intense passionate love attenuates cigarette cue-reactivity in nicotine-deprived smokers: an FMRI study.

    Directory of Open Access Journals (Sweden)

    Xiaomeng Xu

    Full Text Available Self-expanding experiences like falling in love or engaging in novel, exciting and interesting activities activate the same brain reward mechanism (mesolimbic dopamine pathway that reinforces drug use and abuse, including tobacco smoking. This suggests the possibility that reward from smoking is substitutable by self-expansion (through competition with the same neural system, potentially aiding cessation efforts. Using a model of self-expansion in the context of romantic love, the present fMRI experiment examined whether, among nicotine-deprived smokers, relationship self-expansion is associated with deactivation of cigarette cue-reactivity regions. Results indicated that among participants who were experiencing moderate levels of craving, cigarette cue-reactivity regions (e.g., cuneus and posterior cingulate cortex showed significantly less activation during self-expansion conditions compared with control conditions. These results provide evidence that rewards from one domain (self-expansion can act as a substitute for reward from another domain (nicotine to attenuate cigarette cue reactivity.

  3. Nucleosome Repositioning: A Novel Mechanism for Nicotine- and Cocaine-Induced Epigenetic Changes.

    Science.gov (United States)

    Brown, Amber N; Vied, Cynthia; Dennis, Jonathan H; Bhide, Pradeep G

    2015-01-01

    Drugs of abuse modify behavior by altering gene expression in the brain. Gene expression can be regulated by changes in DNA methylation as well as by histone modifications, which alter chromatin structure, DNA compaction and DNA accessibility. In order to better understand the molecular mechanisms directing drug-induced changes in chromatin structure, we examined DNA-nucleosome interactions within promoter regions of 858 genes in human neuroblastoma cells (SH-SY5Y) exposed to nicotine or cocaine. Widespread, drug- and time-resolved repositioning of nucleosomes was identified at the transcription start site and promoter region of multiple genes. Nicotine and cocaine produced unique and shared changes in terms of the numbers and types of genes affected, as well as repositioning of nucleosomes at sites which could increase or decrease the probability of gene expression based on DNA accessibility. Half of the drug-induced nucleosome positions approximated a theoretical model of nucleosome occupancy based on physical and chemical characteristics of the DNA sequence, whereas the basal or drug naïve positions were generally DNA sequence independent. Thus we suggest that nucleosome repositioning represents an initial dynamic genome-wide alteration of the transcriptional landscape preceding more selective downstream transcriptional reprogramming, which ultimately characterizes the cell- and tissue-specific responses to drugs of abuse. PMID:26414157

  4. Nicotinic receptor imaging with F-18 A85380 PET in Alzheimer's disease and normal ageing

    International Nuclear Information System (INIS)

    Full text: Central nicotinic acetylcholine receptors (nAChR) mediate excitatory neurotransmission and contribute to a variety of brain functions including learning and memory. Post mortem studies in patients with Alzheimer's disease have revealed losses of nAChR from the neocortex and hippocampal formation with ligand binding studies showing a reduction of over 50% compared to normal elderly brains in the temporal cortex and hippocampus (Sabbagh 1998). This is consistent with the loss of cholinergic neurones that has been well documented in this condition. Nicotinic AChR are predominantly located presynaptically on the cholinergic neurones. Consequently the ability to image and quantify these receptors may provide a measure of cholinergic loss and therefore a test for the early diagnosis of Alzheimer's disease and for monitoring therapy designed' to preserve cholinergic neurones. Aging is known to effect nAChR (Hellstrom-Lindahl 2000) so this variable must be quantified and incorporated into analysis of the scans. Nicotinic receptors also have important modulatory effects on glutamate, dopamine, serotonin and noradrenaline release and profound receptor loss has been documented in Parkinson's disease and Diffuse Lewy Body disease in addition to AD. Abnormalities in the alpha 7 subtype have been reported in schizophrenia. Imaging studies of nAChR have been hampered by the lack of a suitable tracer for in-vivo imaging. Nicotine itself labelled with carbon-11 for PET imaging has been used but has been shown to reflect regional cerebral blood flow not nAChR due to high nonspecific binding (Nyback et al, 1994). Potent nAChR ligands such as Epibatidine have been very useful for in-vitro studies but are too toxic for routine human use due to strong activation of nAChR including those in the sympathetic ganglia (A3B4 subtype). Recently, the Abbott Laboratories developed A85380 (3-[2(S)-2- azetidinylmethoxyl]pyridine) an azetidine derivative of the 3-pyridyl ethers that has

  5. Nitric oxide-mediated blood flow regulation as affected by smoking and nicotine.

    Science.gov (United States)

    Toda, Noboru; Toda, Hiroshi

    2010-12-15

    Cigarette smoking is a major risk factor for atherosclerosis, cerebral and coronary vascular diseases, hypertension, and diabetes mellitus. Chronic smoking impairs endothelial function by decreasing the formation of nitric oxide and increasing the degradation of nitric oxide via generation of oxygen free radicals. Nitric oxide liberated from efferent nitrergic nerves is also involved in vasodilatation, increased regional blood flow, and hypotension that are impaired through nitric oxide sequestering by smoking-induced factors. Influence of smoking on nitric oxide-induced blood flow regulation is not necessarily the same in all organs and tissues. However, human studies are limited mainly to the forearm blood flow measurement that assesses endothelial function under basal and stimulated conditions and also determination of penile tumescence and erection in response to endothelial and neuronal nitric oxide. Therefore, information about blood flow regulation in other organs, such as the brain and placenta, has been provided mainly from studies on experimental animals. Nicotine, a major constituent of cigarette smoke, acutely dilates cerebral arteries and arterioles through nitric oxide liberated from nitrergic neurons, but chronically interferes with endothelial function in various vasculatures, both being noted in studies on experimental animals. Cigarette smoke constituents other than nicotine also have some vascular actions. Not only active but also passive smoking is undoubtedly harmful for both the smokers themselves and their neighbors, who should bear in mind that they can face serious diseases in the future, which may result in lengthy hospitalization, and a shortened lifespan. PMID:20868673

  6. Mapping of the acetylcholine binding site of the nicotinic acetylcholine receptor: [3H]nicotine as an agonist photoaffinity label

    International Nuclear Information System (INIS)

    The agonist [3H]nicotine was used as a photoaffinity label for the acetylcholine binding sties on the Torpedo nicotinic acetylcholine receptor (AChR). [3H]Nicotine binds at equilibrium with Keq = 0.6 μM to the agonist binding sites. Irradiation with 254-nm light of AChR-rich membranes equilibrated with [3H]nicotine resulted in covalent incorporation into the α- and γ-subunits, which was inhibited by agonists and competitive antagonists but not by noncompetitive antagonists. Inhibition of labeling by d-tubocurarine demonstrated that the α-subunit was labeled via both agonist sites but the γ-subunit was labeled only via the site that binds d-tubocurarine with high affinity. Chymotryptic digestion of the α-subunit confirmed that Try-198 was the principal amino acid labeled by [3H]nicotine. This confirmation required a novel radiosequencing strategy employing o-phthalaldehyde [3H]Nicotine, which is the first photoaffinity agonist used, labels primarily Tyr-198 in contrast to competitive antagonist affinity labels, which label primarily Tyr-190 and Cys-192/Cys-193

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

    Energy Technology Data Exchange (ETDEWEB)

    Menelaou, Evdokia; Paul, Latoya T. [Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803 (United States); Perera, Surangi N. [Joseph J. Zilber School of Public Health, University of Wisconsin — Milwaukee, Milwaukee, WI 53205 (United States); Svoboda, Kurt R., E-mail: svobodak@uwm.edu [Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803 (United States); Joseph J. Zilber School of Public Health, University of Wisconsin — Milwaukee, Milwaukee, WI 53205 (United States)

    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.

  8. Mitochondrial accumulation of APP and Abeta

    DEFF Research Database (Denmark)

    Pavlov, Pavel F; Petersen, Anna Camilla Hansson; Glaser, Elzbieta;

    2009-01-01

    Accumulating evidence suggest that alterations in energy metabolism are among the earliest events that occur in the Alzheimer disease (AD) affected brain. Energy consumption is drastically decreased in the AD-affected regions of cerebral cortex and hippocampus pointing towards compromised...... mitochondrial function of neurons within specific brain regions. This is accompanied by an elevated production of reactive oxygen species contributing to increased rates of neuronal loss in the AD-affected brain regions. In this review, we will discuss the role of mitochondrial function and dysfunction in AD...

  9. Chronic forced swim stress produces subsensitivity to nicotine.

    Science.gov (United States)

    Peck, J A; Dilsaver, S C; McGee, M

    1991-03-01

    Twice daily injections of saline reduce the thermic response to nicotine in the rat. The authors hypothesized that this was due to the stress of twice-daily handling and injection. However, the injection of saline is not a classic stressor. The hypothesis that stress blunts thermic responsiveness to nicotine was, therefore, tested using a classic form of chronic inescapable stress. Rats (n = 12) were subjected to a 14-day, twice daily course of inescapable cold water swim stress using a repeated measures design. Thermic responsiveness of nicotine was measured at baseline and every 7 days thereafter for 49 days. The mean response to nicotine (1.0 mg/kg IP) differed significantly across time, F(7,88) = 10.6, p less than 0.0001. Mean thermic responsiveness (+/- SEM) decreased from -0.75 +/- 0.09 at baseline to -0.41 +/- 0.18 degrees C (54.7% of baseline) following 14 days of forced swim stress. This change was not significant. However, the thermic response to nicotine was -0.14 +/- 0.13 degrees C (p less than 0.05), +0.55 +/- 0.12 degrees C (p less than 0.05), and +0.04 +/- 0.11 degrees C (p less than 0.05) 7, 14, and 21 days following the discontinuation of forced swim stress. The mean response did not differ from baseline 28 days following the last session of forced swim stress. The data suggest that in the recovery phase the animals ceased to be sensitive to nicotine. These findings support the hypothesis that a chronic stressor can produce subsensitivity to nicotine. PMID:2068187

  10. [Stress-protective properties of lithium nicotinate--a new derivative of nicotinic acid].

    Science.gov (United States)

    Kresiun, V I

    1984-03-01

    Experiments were made to study stress-protective properties of a new psychotropic agent lithium nicotinate developed on the basis of natural metabolites. Prophylactic treatment of the drug given in courses entails an increase in the physical endurance and work fitness, improvement of animals' orientation under stress, facilitating the avoidance behavior. These effects were particularly demonstrable in highly emotional animals. In these animals, stress produced a paralyzing action. According to the electro- and ballisto-cardiography, the drug prevented the stress-induced disorders of cardiovascular function. PMID:6538449

  11. Low-dose nicotine does not promote lung tumors in mouse models

    Science.gov (United States)

    Experiments in mice show that low levels of exposure to nicotine, equivalent to those in humans who use nicotine replacement therapy (NRT) to help them quit smoking, did not promote lung tumor growth.

  12. Mechanism of nicotine-induced relaxation in the porcine basilar artery

    DEFF Research Database (Denmark)

    Zhang, W; Edvinsson, L; Lee, T J

    1998-01-01

    The present experiment was designed to examine possible influence of adrenergic nerves on nicotine-induced neurogenic vasodilation in porcine basilar arteries denuded of endothelium. Nicotine and transmural nerve stimulation (TNS) induced relaxation of basilar arteries. Tetrodotoxin (TTX) abolished...... the relaxation elicited by TNS, but only partially blocked that induced by nicotine. Relaxation induced by both nicotine and TNS was abolished by N-nitro-L-arginine. The N-nitro-L-arginine inhibition of both TNS- and nicotine-induced relaxation was reversed by L-arginine but not by D......-arginine. Hexamethonium abolished the relaxation induced by nicotine, but did not affect that elicited by TNS. Relaxation induced by nicotine was diminished by guanethidine, which did not affect the relaxation induced by TNS, suggesting that guanethidine blockade of nicotine-induced relaxation is not due to its local...

  13. Kefir protective effects against nicotine cessation-induced anxiety and cognition impairments in rats

    Directory of Open Access Journals (Sweden)

    Negin Noori

    2014-01-01

    Conclusion: This study revealed that Kefir had a potential effect on the treatment of nicotine cessation-induced depression, anxiety and cognition impairment in the animal model. Kefir may be useful for adjunct therapy for nicotine abandonment treatment protocols.

  14. Interoceptive conditioning with nicotine using extinction and re-extinction to assess stimulus similarity with bupropion

    OpenAIRE

    Charntikov, Sergios; deWit, Nicole R.; Bevins, Rick A.

    2014-01-01

    Bupropion is an atypical antidepressant that increases long-term quit rates of tobacco smokers. A better understanding of the relation between nicotine and this first-line medication may provide insight into improving treatment. For all experiments, rats first had nicotine (0.4 mg base/kg) and saline session intermixed; intermittent access to sucrose only occurred on nicotine session. Nicotine in this protocol comes to differentially control “anticipatory” dipper entries. To more closely exam...

  15. Effects of the α subunit on imidacloprid sensitivity of recombinant nicotinic acetylcholine receptors

    OpenAIRE

    Matsuda, K; Buckingham, S D; Freeman, J.C.; Squire, M D; Baylis, H. A.; Sattelle, D B

    1998-01-01

    Imidacloprid is a new insecticide with selective toxicity for insects over vertebrates. Recombinant (α4β2) chicken neuronal nicotinic acetylcholine receptors (AChRs) and a hybrid nicotinic AChR formed by co-expression of a Drosophila melanogaster neuronal α subunit (SAD) with the chicken β2 subunit were heterologously expressed in Xenopus oocytes by nuclear injection of cDNAs. The agonist actions of imidacloprid and other nicotinic AChR ligands ((+)-epibatidine, (−)-nicotine and acetylcholine...

  16. Minor structural changes in nicotinoid insecticides confer differential subtype selectivity for mammalian nicotinic acetylcholine receptors

    OpenAIRE

    Tomizawa, Motohiro; Casida, John E.

    1999-01-01

    The major nitroimine insecticide imidacloprid (IMI) and the nicotinic analgesics epibatidine and ABT-594 contain the 6-chloro-3-pyridinyl moiety important for high activity and/or selectivity. ABT-594 has considerable nicotinic acetylcholine receptor (AChR) subtype specificity which might carry over to the chloropyridinyl insecticides. This study considers nine IMI analogues for selectivity in binding to immuno-isolated α1, α3 and α7 containing nicotinic AChRs and to purported α4β2 nicotinic ...

  17. Nicotine is Chemotactic for Neutrophils and Enhances Neutrophil Responsiveness to Chemotactic Peptides

    Science.gov (United States)

    Totti, Noel; McCusker, Kevin T.; Campbell, Edward J.; Griffin, Gail L.; Senior, Robert M.

    1984-01-01

    Neutrophils contribute to chronic bronchitis and pulmonary emphysema associated with cigarette smoking. Nicotine was found to be chemotactic for human neutrophils but not monocytes, with a peak activity at ~ 31 micromolar. In lower concentrations (comparable to those in smokers' plasma), nicotine enhanced the response of neutrophils to two chemotactic peptides. In contrast to most other chemoattractants for neutrophils, however, nicotine did not affect degranulation or superoxide production. Nicotine thus may promote inflammation and consequent lung injury in smokers.

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

    OpenAIRE

    Kenney, Justin W.; Gould, Thomas J.

    2008-01-01

    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 ...

  19. Maternal exposure of rats to nicotine via infusion during gestation produces neurobehavioral deficits and elevated expression of glial fibrillary acidic protein in the cerebellum and CA1 subfield in the offspring at puberty

    International Nuclear Information System (INIS)

    increased expression of GFAP in cerebellum and CA1 subfield of hippocampus of the offspring on PND 30 and 60. The results show that although 60-day-old male and female rat offspring of mothers exposed to nicotine during gestation did not differ from control in body weight gain or nicotinic acetylcholine receptors ligand binding, they exhibited significant sensorimotor deficits that were consistent with the neuropathological alterations seen in the brain. These neurobehavioral and pathological deficits indicate that maternal nicotine exposure may produce long-term adverse health effects in the offspring

  20. [3H]imidacloprid: synthesis of a candidate radioligand for the nicotinic acetylcholine receptor

    International Nuclear Information System (INIS)

    Imidacloprid is an exceptionally potent insecticide known from physiological studies to act at the nicotinic acetylcholine receptor. To prepare [3H]imidacloprid as a candidate radioligand, 6-chloronicotinoyl chloride was reduced with NaB2H4 (in model studies) or NaB3H4 in absolute ethanol to 2-chloro-5-pyridinylmethanol which was transformed to 2-chloro-5-chloromethylpyridine on refluxing with thionyl chloride. Coupling with 4,5-dihydro-N-nitro-1H-imidazol-2-amine then gave [2H2]imidacloprid incorporating about 95% of the deuterium or [3H2]imidacloprid (25 Ci/mmol) in 80% radiochemical yield. In studies not detailed here [3H] imidacloprid was found to undergo high affinity, specific and saturable binding to a site in insect brain. (author)

  1. Compensatory nicotine self-administration in rats during reduced access to nicotine: an animal model of smoking reduction.

    Science.gov (United States)

    Harris, Andrew C; Burroughs, Danielle; Pentel, Paul R; LeSage, Mark G

    2008-02-01

    The ability of smoking reduction (e.g., decreasing cigarettes per day) to produce significant reductions in toxin exposure is limited by compensatory increases in smoking behavior. Characterizing factors contributing to the marked individual variability in compensation may be useful for understanding this phenomenon. The goal of the current study was to develop an animal model of smoking reduction and to begin to examine potential behavioral and pharmacokinetic contributors to compensation. Rats trained for nicotine self-administration (NSA) in unlimited access sessions were exposed to a progressive decrease in duration of access to nicotine from 23-hr/day to 10-, 6-, and 2-hr/day. Following a return to 23 hr/day access and extinction, single-dose nicotine pharmacokinetic parameters were determined. Rats exhibited a reduction in total daily nicotine intake during reduced access to NSA, but decreases in nicotine intake were not proportional to decreases in access duration. Compensatory increases in hourly infusion rate were also observed when access was decreased. The magnitude of compensation differed considerably among animals. Early session infusion rate during baseline was significantly correlated, while nicotine clearance was moderately correlated, with 1 measure of compensation. Infusion rates were transiently increased compared to prereduction levels when unlimited access was restored, and this effect was greatest in animals that had exhibited the greatest levels of compensation. These findings indicate that rats exhibit compensatory increases in NSA during reduced access to nicotine, with substantial individual variability. This model may be useful for characterizing underlying factors and potential consequences of compensatory smoking. PMID:18266555

  2. Binding properties of the cerebral α4β2 nicotinic acetylcholine receptor ligand 2-[18F]fluoro-A-85380 to plasma proteins

    International Nuclear Information System (INIS)

    Introduction: To determine the availability of nicotinic acetylcholine receptors in different human brain regions using the positron emission tomography (PET) radioligand 2-[18F]fluoro-A-85380 (2-[18F]FA) and invasive approaches for quantification, it is important to correct the arterial input function as well for plasma protein binding (PPB) of the radioligand as for radiolabeled metabolites accumulating in blood. This study deals with some aspects of PPB of 2-[18F]FA. Methods: Patients with different neurological disorders (n=72), such as Parkinson's disease, Alzheimer's disease and multiple sclerosis, and a group of healthy volunteers (n=15) subjected for PET imaging were analyzed for their PPB level of 2-[18F]FA using ultrafiltration. Protein gel electrophoresis of plasma samples was performed to identify the binding protein of 2-[18F]FA. The dependency of PPB on time and on free ligand concentration was analyzed to obtain the binding parameters B max and K d. Results: Albumin was identified to be the binding protein of 2-[18F]FA. PPB of 2-[18F]FA was low at 17±4% and did not show significant differences between the groups of patients. Corresponding to this, a narrow range of plasma albumin of 0.62±0.05 mM was observed. B max was determined as twice the albumin concentration, which indicates two binding sites for 2-[18F]FA on the protein. No time dependence of the PPB could be observed. By relating PPB to B max, an average K d value of 6.0±1.5 mM was obtained. Conclusion: This study shows the dependency of PPB of 2-[18F]FA on human albumin plasma concentration. An equation utilizing B max and K d to easily estimate PPB is presented

  3. Conversion of nicotinic acid to trigonelline is catalyzed by N-methyltransferase belonged to motif B′ methyltransferase family in Coffea arabica

    Energy Technology Data Exchange (ETDEWEB)

    Mizuno, Kouichi, E-mail: koumno@akita-pu.ac.jp [Faculty of Bioresource Sciences, Akita Prefectural University, Akita City, Akita 010-0195 (Japan); Matsuzaki, Masahiro [Faculty of Bioresource Sciences, Akita Prefectural University, Akita City, Akita 010-0195 (Japan); Kanazawa, Shiho [Graduate School of Humanities and Sciences, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo 112-8610 (Japan); Tokiwano, Tetsuo; Yoshizawa, Yuko [Faculty of Bioresource Sciences, Akita Prefectural University, Akita City, Akita 010-0195 (Japan); Kato, Misako [Graduate School of Humanities and Sciences, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo 112-8610 (Japan)

    2014-10-03

    Graphical abstract: Trigonelline synthase catalyzes the conversion of nicotinic acid to trigonelline. We isolated and characterized trigonelline synthase gene(s) from Coffea arabica. - Highlights: • Trigonelline is a major compound in coffee been same as caffeine is. • We isolated and characterized trigonelline synthase gene. • Coffee trigonelline synthases are highly homologous with coffee caffeine synthases. • This study contributes the fully understanding of pyridine alkaloid metabolism. - Abstract: Trigonelline (N-methylnicotinate), a member of the pyridine alkaloids, accumulates in coffee beans along with caffeine. The biosynthetic pathway of trigonelline is not fully elucidated. While it is quite likely that the production of trigonelline from nicotinate is catalyzed by N-methyltransferase, as is caffeine synthase (CS), the enzyme(s) and gene(s) involved in N-methylation have not yet been characterized. It should be noted that, similar to caffeine, trigonelline accumulation is initiated during the development of coffee fruits. Interestingly, the expression profiles for two genes homologous to caffeine synthases were similar to the accumulation profile of trigonelline. We presumed that these two CS-homologous genes encoded trigonelline synthases. These genes were then expressed in Escherichiacoli, and the resulting recombinant enzymes that were obtained were characterized. Consequently, using the N-methyltransferase assay with S-adenosyl[methyl-{sup 14}C]methionine, it was confirmed that these recombinant enzymes catalyzed the conversion of nicotinate to trigonelline, coffee trigonelline synthases (termed CTgS1 and CTgS2) were highly identical (over 95% identity) to each other. The sequence homology between the CTgSs and coffee CCS1 was 82%. The pH-dependent activity curve of CTgS1 and CTgS2 revealed optimum activity at pH 7.5. Nicotinate was the specific methyl acceptor for CTgSs, and no activity was detected with any other nicotinate derivatives, or

  4. Conversion of nicotinic acid to trigonelline is catalyzed by N-methyltransferase belonged to motif B′ methyltransferase family in Coffea arabica

    International Nuclear Information System (INIS)

    Graphical abstract: Trigonelline synthase catalyzes the conversion of nicotinic acid to trigonelline. We isolated and characterized trigonelline synthase gene(s) from Coffea arabica. - Highlights: • Trigonelline is a major compound in coffee been same as caffeine is. • We isolated and characterized trigonelline synthase gene. • Coffee trigonelline synthases are highly homologous with coffee caffeine synthases. • This study contributes the fully understanding of pyridine alkaloid metabolism. - Abstract: Trigonelline (N-methylnicotinate), a member of the pyridine alkaloids, accumulates in coffee beans along with caffeine. The biosynthetic pathway of trigonelline is not fully elucidated. While it is quite likely that the production of trigonelline from nicotinate is catalyzed by N-methyltransferase, as is caffeine synthase (CS), the enzyme(s) and gene(s) involved in N-methylation have not yet been characterized. It should be noted that, similar to caffeine, trigonelline accumulation is initiated during the development of coffee fruits. Interestingly, the expression profiles for two genes homologous to caffeine synthases were similar to the accumulation profile of trigonelline. We presumed that these two CS-homologous genes encoded trigonelline synthases. These genes were then expressed in Escherichiacoli, and the resulting recombinant enzymes that were obtained were characterized. Consequently, using the N-methyltransferase assay with S-adenosyl[methyl-14C]methionine, it was confirmed that these recombinant enzymes catalyzed the conversion of nicotinate to trigonelline, coffee trigonelline synthases (termed CTgS1 and CTgS2) were highly identical (over 95% identity) to each other. The sequence homology between the CTgSs and coffee CCS1 was 82%. The pH-dependent activity curve of CTgS1 and CTgS2 revealed optimum activity at pH 7.5. Nicotinate was the specific methyl acceptor for CTgSs, and no activity was detected with any other nicotinate derivatives, or with

  5. Craving and nicotine withdrawal in a Spanish smoking cessation sample.

    Science.gov (United States)

    Piñeiro, Bárbara; López-Durán, Ana; Fernández del Río, Elena; Martínez, Úrsula; Brandon, Thomas H; Becoña, Elisardo

    2014-01-01

    Craving and nicotine withdrawal syndrome (NWS) are components of the tobacco use disorder in DSM-5. They both appear after smoking cessation or an abrupt reduction in tobacco use, and they are associated with both short and long-term smoking-cessation outcomes. The aim of the present study was to examine the association of craving and withdrawal with smoking cessation at the end of the treatment and relapse at 3 months follow-up in a Spanish sample of smokers. The sample comprised 342 smokers (37.7% men; 62.3% women) receiving a cognitive-behavioral treatment for smoking cessation. The assessments of craving and withdrawal were conducted using the Minnesota Nicotine Withdrawal Scale. Abstainers at the end of the treatment, compared to non abstainers, showed significantly lower post-treatment withdrawal, and post-treatment craving. Furthermore, they had lower scores in pre-treatment nicotine dependence. Among abstainers, craving decreased significantly from pre-cessation levels, while in those participants who did not quit smoking it remained on the same levels. High nicotine dependence was a predictor of smoking at the end of the treatment, whereas high nicotine withdrawal predicted relapse at 3 months. Findings support the robust role of craving and NWS in smoking cessation and relapse, although they differ in their specific patterns of change over time. PMID:25314038

  6. Clarifying the relationship between impulsive delay discounting and nicotine dependence.

    Science.gov (United States)

    Amlung, Michael; MacKillop, James

    2014-09-01

    Impulsive delayed reward discounting (DRD) has been linked to nicotine dependence, but with some inconsistency. This may be related to the considerable variability in the literature with regard to the DRD assessments used, particularly in the case of the reward magnitudes assessed. In addition, previous studies have often not considered concurrent substance use when examining the relationship between DRD and nicotine dependence. The current study sought to further clarify the relationship between DRD and nicotine dependence by characterizing DRD across diverse reward magnitudes and incorporating other substance use. Daily smokers (N = 933) were assessed for DRD preferences across nine reward magnitudes (delayed reward range: $2.50-$850), comorbid substance use, and relevant demographic variables (age, education, income). A significant large effect size magnitude effect was found for DRD, reflecting steeper discounting for smaller delayed rewards, but significant correlations across magnitudes also suggested similar relative levels of discounting. Principal components analysis (PCA) was used to generate a single latent index of discounting across all magnitudes that accounted for 69% of the total variance. In correlation and regression analyses, steeper composite DRD was significantly associated with nicotine dependence severity. This relationship remained statistically significant after incorporating demographic variables and alcohol and illicit drug use. These findings provide evidence of a specific link between impulsive DRD and nicotine dependence and reveal that this association is robust across a broad range of monetary rewards. The study also demonstrates the utility of using PCA to generate latent indices of delay discounting across multiple magnitudes of delayed reward. PMID:24841186

  7. Antibacterial activity of nicotine and its copper complex

    International Nuclear Information System (INIS)

    Nicotine and its metal complex; Cu(II)-nicotine was isolated from leaves of Nicotiana tabacum using metal ions following the method of Munir et al., 1994. Their antibacterial activity against ten different species of gram positive and gram negative bacteria were studied. For comparative study, pure sample of nicotine and metal salts used for complexation; Copper(II) chloride were also subjected to antibacterial tests with the same species of bacteria under similar conditions. Results indicated that nicotine had no effect on all the bacteria tested except Escherichia coli, Pseudomonas aeroginosa and Enterococcus faecalis, which showed 14 mm zone of inhibition at 200 mu g l00 mul/sup -1/ Copper(II) chloride was found to be effective against seven species and ineffective against three species of selected bacteria. On the other hand, Cu(II)-nicotine complex was ineffective against five species of bacteria at lower level while at higher level, only one species of bacteria showed resistance against this complex. The complex was compared with three standard antibiotics. Thus, this complex can be used against a variety of microorganisms at higher level. (author)

  8. Effect of MK-801 on the development of nicotine sensitization of nucleus accumbens dopamine release

    International Nuclear Information System (INIS)

    We have previously found that MK-801, a noncompetitive NMDA receptor antagonist, prevents behavioral sensitization to nicotine. This study aimed to investigate the effect of MK-801 on a neurochemical component of nicotine sensitization by evaluating the effect of the drug on nicotine sensitization of nucleus accumbens dopamine (DA) release. Sprague-Dawley rats were pretreated with MK-801 (0.3 mg/kg, i.p.) or saline 30 min before injection of nicotine (0.4 mg/kg, s.c., once daily) for 7 consecutive days. Twenty-four hours after the last drug injection, animals were challenged with local perfusion of 5 mM nicotine into the shell of nucleus accumbens and DA release was monitored using in vivo microdialysis. In rats pretreated with chronic nicotine, local nicotine challenge induced a greater increase of accumbal DA release than in saline-treated animals (maximal DA response 969 ± 235% (mean ± SEM) of basal level vs. 520 ± 93%, P < 0.05). Co-administration of MK-801 with nicotine attenuated an increase of DA release elicited by local nicotine challenge, compared with nicotine alone (maximal DA response 427 ± 83% of basal level vs. 969 ± 235%, P < 0.01). These results suggest that MK-801 blocks the development of nicotine sensitization of nucleus accumbens DA release, further supporting the involvement of NMDA receptors in the development of behavioral sensitization to nicotine

  9. ENVIRONMENTAL TOBACCO SMOKE EXPOSURE OF YOUNG CHILDREN AS ASSESSED USING A PASSIVE DIFFUSION DEVICE FOR NICOTINE

    Science.gov (United States)

    Indoor air nicotine concentrations in the homes of young children (ages 1-3) were monitored for 48 hours as part of a study to assess uptake, metabolism and urinary excretion of nicotine and its metabolites including cotinine. otinine, a metabolite of nicotine, has been used as a...

  10. Involvement of the rostral agranular insular cortex in nicotine self-administration in rats.

    Science.gov (United States)

    Pushparaj, Abhiram; Kim, Aaron S; Musiol, Martin; Trigo, Jose M; Le Foll, Bernard

    2015-09-01

    Our prior work demonstrated the involvement of the caudal granular subregion of the insular cortex in a rat model of nicotine self-administration. Recent studies in various animal models of addiction for nicotine and other drugs have identified a role for the rostral agranular subregion (RAIC). The current research was undertaken to examine the involvement of the RAIC in a rat model of nicotine self-administration. We investigated the inactivating effects of local infusions of a γ-aminobutyric acid agonist mixture (baclofen/muscimol) into the RAIC on nicotine self-administration under a fixed-ratio 5 (FR-5) schedule and on reinstatement of nicotine seeking induced by nicotine-associated cues in rats. We also evaluated the effects of RAIC inactivation on food self-administration under an FR5 schedule as a control. Inactivation of the RAIC decreased nicotine, but not food, self-administration. RAIC inactivation also prevented the reinstatement, after extinction, of nicotine seeking induced by nicotine-associated cues. Our study indicates that the RAIC is involved in nicotine-taking and nicotine-seeking in rats. Modulating insular cortex function appears to be a promising approach for nicotine dependence treatment. PMID:25934486

  11. Genetic Relationship between Schizophrenia and Nicotine Dependence.

    Science.gov (United States)

    Chen, Jingchun; Bacanu, Silviu-Alin; Yu, Hui; Zhao, Zhongming; Jia, Peilin; Kendler, Kenneth S; Kranzler, Henry R; Gelernter, Joel; Farrer, Lindsay; Minica, Camelia; Pool, Rene; Milaneschi, Yuri; Boomsma, Dorret I; Penninx, Brenda W J H; Tyndale, Rachel F; Ware, Jennifer J; Vink, Jacqueline M; Kaprio, Jaakko; Munafò, Marcus; Chen, Xiangning

    2016-01-01

    It is well known that most schizophrenia patients smoke cigarettes. There are different hypotheses postulating the underlying mechanisms of this comorbidity. We used summary statistics from large meta-analyses of plasma cotinine concentration (COT), Fagerström test for nicotine dependence (FTND) and schizophrenia to examine the genetic relationship between these traits. We found that schizophrenia risk scores calculated at P-value thresholds of 5 × 10(-3) and larger predicted FTND and cigarettes smoked per day (CPD), suggesting that genes most significantly associated with schizophrenia were not associated with FTND/CPD, consistent with the self-medication hypothesis. The COT risk scores predicted schizophrenia diagnosis at P-values of 5 × 10(-3) and smaller, implying that genes most significantly associated with COT were associated with schizophrenia. These results implicated that schizophrenia and FTND/CPD/COT shared some genetic liability. Based on this shared liability, we identified multiple long non-coding RNAs and RNA binding protein genes (DA376252, BX089737, LOC101927273, LINC01029, LOC101928622, HY157071, DA902558, RBFOX1 and TINCR), protein modification genes (MANBA, UBE2D3, and RANGAP1) and energy production genes (XYLB, MTRF1 and ENOX1) that were associated with both conditions. Further analyses revealed that these shared genes were enriched in calcium signaling, long-term potentiation and neuroactive ligand-receptor interaction pathways that played a critical role in cognitive functions and neuronal plasticity. PMID:27164557

  12. Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.

    Science.gov (United States)

    Schindler, Charles W; Redhi, Godfrey H; Vemuri, Kiran; Makriyannis, Alexandros; Le Foll, Bernard; Bergman, Jack; Goldberg, Steven R; Justinova, Zuzana

    2016-08-01

    Nicotine, the main psychoactive component of tobacco, and (-)-Δ(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior. Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC, but their clinical use is hindered by potentially serious side effects. The recently developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence. Here we compare attenuation of nicotine and THC reinforcement and reinstatement in squirrel monkeys by the CB1-receptor inverse agonist rimonabant and by the recently developed CB1-receptor neutral antagonist AM4113. Both rimonabant and AM4113 reduced two effects of nicotine and THC that play major roles in tobacco and marijuana dependence: (1) maintenance of high rates of drug-taking behavior, and (2) priming- or cue-induced reinstatement of drug-seeking behavior in abstinent subjects (models of relapse). In contrast, neither rimonabant nor AM4113 modified cocaine-reinforced or food-reinforced operant behavior under similar experimental conditions. However, both rimonabant and AM4113 reduced cue-induced reinstatement in monkeys trained to self-administer cocaine, suggesting the involvement of a common cannabinoid-mediated mechanism in the cue-induced reinstatement for different drugs of abuse. These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence. PMID:26888056

  13. Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: implications for the heightened adolescent susceptibility to nicotine addiction

    DEFF Research Database (Denmark)

    Christensen, Mark Holm; Ishibashi, Masaru; Nielsen, Michael Linnemann;

    2014-01-01

    The younger an individual starts smoking, the greater the likelihood that addiction to nicotine will develop, suggesting that neurobiological responses vary across age to the addictive component of cigarettes. Cholinergic neurons of the laterodorsal tegmental nucleus (LDT) are importantly involved...... in the development of addiction, however, the effects of nicotine on LDT neuronal excitability across ontogeny are unknown. Nicotinic effects on LDT cells across different age groups were examined using calcium imaging and whole-cell patch clamping. Within the youngest age group (P7–P15), nicotine...... cells to target regions involved in development of addiction. Such output would be expected to be promotive of addiction; therefore, ontogenetic differences in nicotine-mediated increases in the excitability of the LDT could contribute to the differential susceptibility to nicotine addiction seen across...

  14. Ameliorative effect of black tea on nicotine induced cardiovascular pathogenesis in rat

    OpenAIRE

    Gholamhoseinian, Ahmad; Joukar, Farzin; Joukar, Siyavash; Najafipour, Hamid; Shahouzehi, Beydolah

    2012-01-01

    Regarding the role of nicotine in the development of cardiovascular complications of smoking, we investigated whether black tea has a modulatory effect on cardiovascular pathogenesis of nicotine in rat. Animals were randomized to control, tea, nicotine and tea plus nicotine groups. Test groups received black tea brewed (adding 400 ml boiling water to 10 g Lipton black tea for 5 min) orally alone or with nicotine 2 mg/kg/day, s.c. separately or combined for four weeks. On 28th day, lipids p...

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

    OpenAIRE

    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 (n...

  16. Synthesis and nicotinic receptor activity of a hydroxylated tropane

    DEFF Research Database (Denmark)

    Bremner, John B; Godfrey, Colette A; Jensen, Anders A.; Smith, Reginald J

    2004-01-01

    (+/-)-3alpha-hydroxy homoepibatidine 4 has been synthesized from the alkaloid scopolamine 5 and its properties as a nicotinic agonist assessed. While still binding strongly, the compound showed reduced agonist potency for the alpha(4)beta(2) nAChR compared with the parent compound epibatidine 1....... Compound 4 also displayed generally similar binding and selectivity profiles at alpha(4)beta(2), alpha(2)beta(4), alpha(3)beta(4), and alpha(4)beta(4) nAChR subtypes to those for nicotine....

  17. Concise synthesis of new bridged-nicotine analogues

    DEFF Research Database (Denmark)

    Crestey, François; Hooyberghs, Geert; Kristensen, Jesper Langgaard

    2012-01-01

    This study describes a very efficient strategy for the synthesis of two new bridged-nicotine analogues. Starting from either 4- or 3-chloropyridine the desired tricyclic ring systems are accessed in just three steps in 23% and 40% overall yield, respectively.......This study describes a very efficient strategy for the synthesis of two new bridged-nicotine analogues. Starting from either 4- or 3-chloropyridine the desired tricyclic ring systems are accessed in just three steps in 23% and 40% overall yield, respectively....

  18. Differential Effects of Nicotine on Discrete Components of Visual Attention

    DEFF Research Database (Denmark)

    Vangkilde, Signe Allerup; Bundesen, Claus; Coull, Jennifer T.

    2009-01-01

    present pilot study was to identify at which point in the attentional process nicotine exerts its effects. Participants and Methods: In a double-blind, counterbalanced, crossover design, nine healthy nonsmokers (mean age 26 years) completed two sessions (45 minutes each) after chewing 2 mg nicotine gum or...... a placebo gum. The experimental paradigm was a letter recognition task with varied stimulus durations terminated by pattern masks. The temporal threshold of conscious perception (t0), visual processing speed (C), storage capacity of visual short-term memory (K), and attentional selectivity (alpha...

  19. Nicotine as a mitogenic stimulus for pancreatic acinar cell proliferation

    Institute of Scientific and Technical Information of China (English)

    Parimal Chowdhury; Kodetthoor B Udupa

    2006-01-01

    Cell proliferation is an important process in life for growth of normal and cancer cells. The signal transduction pathways activated during this process are strictly regulated. This editorial focuses on the role of nicotine,a mitogen, in the induction of signaling pathways resulting in proliferation of pancreatic tumor cells and compares these events with those in normal acinar cells isolated from the rat pancreas. The data shows striking similarities between these two cellular systems.In addition, the editorial reviews very recent literature of the contribution of MAPK signaling in cell lines associated with human diseases. A prospective cellular model of nicotine induced activation of MAPK cascade is presented.

  20. Placebo controlled trial of nicotine chewing gum in general practice.

    OpenAIRE

    Jamrozik, K; Fowler, G; Vessey, M; Wald, N

    1984-01-01

    Of 2110 adult cigarette smokers originally recruited to a study of the effect of antismoking advice in general practice, 429 who reported at follow up after one year that they had tried unsuccessfully to stop smoking were offered "a special antismoking chewing gum," either nicotine gum or a placebo gum, in a double blind study. Of 200 who were willing to try the gum, 101 were randomly allocated to the nicotine gum and 99 to the placebo gum. They were followed up at six months by an unannounce...

  1. Randomised controlled trial of nicotine chewing-gum.

    OpenAIRE

    Jarvis, M. J.; Raw, M.; Russell, M A; Feyerabend, C

    1982-01-01

    The effectiveness of 2 mg nicotine chewing-gum as an aid to stopping smoking was compared with a placebo containing 1 mg nicotine, but unbuffered, in a double-blind randomised trial. Of 58 subjects given the active gum, 27 (47%) were not smoking at one-year follow-up compared with 12 (21%) of the 58 subjects treated with placebo (p less than 0.025). By the most stringent criterion of outcome, 18 (31%) subjects in the active treatment group and eight (14%) in the placebo group had not smoked a...

  2. Intelligent biomembranes for nicotine releases by radiation curing

    International Nuclear Information System (INIS)

    The authors have studied stimuli-responsive polyelectrolyte and polyampholyte hydrogels. Thermo-responsive copolymer hydrogels have also been studied. Recently, the authors have applied those hydrogels to radiation curable intelligent coatings for the gating of drug release channel. One way of this application is the coating on a drug including membrane to initiate and stop the drug release by on-off switching of stimulations. Some results of application to practical intelligent biomembranes such as glucose-responsive nicotine release membrane and temperature-responsive nicotine release membrane were investigated and their functions as well as of some effective factors on the release profiles were proved

  3. The nicotine paradox: effect of smoking on autonomic discrimination.

    Science.gov (United States)

    Lombardo, T W; Epstein, L H

    1986-01-01

    Smoking reduces negative affect while it increases sympathetic nervous system activity. However, theories of emotion predict that increased autonomic arousal should increase rather than reduce negative affect. One explanation for this paradox is that nicotine interferes with perception of autonomic activity. We evaluated the effect of smoking on autonomic activity perception by measuring performance on a heartbeat detection task after a high or low dose of nicotine or not smoking. A group of nonsmokers also completed the task. Results failed to support the hypothesis. In light of previous research, the results suggest EMG perception may be more important to the negative affect reduction phenomenon than perception of autonomic activity. PMID:3739820

  4. Brain Basics

    Medline Plus

    Full Text Available ... News About Us Home > Health & Education > Educational Resources Brain Basics Introduction The Growing Brain The Working Brain ... to mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are ...

  5. Brain Basics

    Science.gov (United States)

    ... News About Us Home > Health & Education > Educational Resources Brain Basics Introduction The Growing Brain The Working Brain ... to mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are ...

  6. Brain Basics

    Medline Plus

    Full Text Available ... Brain Basics provides information on how the brain works, how mental illnesses are disorders of the brain, ... learning more about how the brain grows and works in healthy people, and how normal brain development ...

  7. Covalent Trapping of Methyllycaconitine at the α4-α4 Interface of the α4β2 Nicotinic Acetylcholine Receptor

    DEFF Research Database (Denmark)

    Absalom, Nathan L; Quek, Gracia; Lewis, Trevor M;

    2013-01-01

    The α4β2 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the brain and are implicated in a variety of physiological processes. There are two stoichiometries of the α4β2 nAChR, (α4)2(β2)3 and (α4)3(β2)2, with different sensitivities to acetylcholine (ACh), but their pharmacologi......The α4β2 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the brain and are implicated in a variety of physiological processes. There are two stoichiometries of the α4β2 nAChR, (α4)2(β2)3 and (α4)3(β2)2, with different sensitivities to acetylcholine (ACh), but their...... competitive antagonism and an apparently insurmountable mechanism that only occurs after preincubation with MLA. We hypothesized an additional MLA binding site in the α4-α4 interface that is unique to this stoichiometry. To prove this, we covalently trapped a cysteine-reactive MLA analog at an α4β2 receptor...... containing an α4(D204C) mutation predicted by homology modeling to be within reach of the reactive probe. We demonstrate that covalent trapping results in irreversible reduction of ACh-elicited currents in the (α4)3(β2)2 stoichiometry, indicating that MLA binds to the α4-α4 interface of the (α4)3(β2)2 and...

  8. Nicotine Inhibits Clostridium difficile Toxin A-Induced Colitis but Not Ileitis in Rats

    Science.gov (United States)

    Vigna, Steven R.

    2016-01-01

    Nicotine is protective in ulcerative colitis but not Crohn's disease of the small intestine, but little is known about the effects of nicotine on Clostridium difficile toxin A-induced enteritis. Isolated ileal or colonic segments in anesthetized rats were pretreated with nicotine bitartrate or other pharmacological agents before intraluminal injection of toxin A. After 3 hours, the treated segments were removed and inflammation was assessed. Nicotine biphasically inhibited toxin A colitis but not ileitis. Pretreatment with the nicotinic receptor antagonist, hexamethonium, blocked the effects of nicotine. Pretreating the colonic segments with hexamethonium before toxin A administration resulted in more inflammation than seen with toxin A alone, suggesting that a tonic nicotinic anti-inflammatory condition exists in the colon. Nicotine also inhibited toxin A-induced increased colonic concentrations of the TRPV1 (transient receptor potential vanilloid subtype 1) agonist, leukotriene B4 (LTB4), and release of the proinflammatory neuropeptide, substance P. Pretreatment with nicotine did not protect against direct TRPV1-mediated colitis caused by intraluminal capsaicin. Nicotinic cholinergic receptors tonically protect the colon against inflammation and nicotine inhibits toxin A colitis but not toxin A ileitis in rats in part by inhibition of toxin A-induced activation of TRPV1 by endogenous TRPV1 agonists such as LTB4. PMID:26881175

  9. 18-Methoxycoronaridine acts in the medial habenula to attenuate behavioral and neurochemical sensitization to nicotine.

    Science.gov (United States)

    Eggan, Branden L; McCallum, Sarah E

    2016-07-01

    Systemic 18-methoxycoronaridine, an alpha3beta4 nicotinic antagonist, slows the rate of induction of behavioral sensitization to nicotine (Glick et al., 1996; 2011). The primary mechanism of action of 18-MC is believed to be the inhibition of α3β4 nicotinic acetylcholine receptors which are densely expressed in the medial habenula and interpeduncular nucleus (Pace et al., 2004; Glick et al., 2012). Recently, these habenular nicotinic receptors and their multiple roles in nicotine aversion and withdrawal have been increasingly emphasized (Antolin-Fontes et al., 2015). Here, we investigated the effects of 18-MC on both behavioral and neurochemical sensitization to nicotine. Daily systemic administration of 18-MC slowed the rate of induction of behavioral sensitization to nicotine but failed to block the expression of a sensitized locomotor response when absent. In contrast, in nicotine sensitized animals, systemic 18-MC significantly reduced the expression of behavioral sensitization. Results from intra-habenular administration of 18-MC paralleled these findings in that the expression of behavioral sensitization was also reduced in sensitized animals. Consistent with its effects on behavioral sensitization, intra-MHb treatment with 18-MC completely abolished sensitized dopamine responses in the nucleus accumbens in nicotine sensitized animals. These results show that α3β4 nicotinic receptors in the MHb contribute to nicotine sensitization, a phenomenon associated with drug craving and relapse. PMID:27059333

  10. Uncoupling nicotine mediated motoneuron axonal pathfinding errors and muscle degeneration in zebrafish

    International Nuclear Information System (INIS)

    Zebrafish embryos offer a unique opportunity to investigate the mechanisms by which nicotine exposure impacts early vertebrate development. Embryos exposed to nicotine become functionally paralyzed by 42 hpf suggesting that the neuromuscular system is compromised in exposed embryos. We previously demonstrated that secondary spinal motoneurons in nicotine-exposed embryos were delayed in development and that their axons made pathfinding errors (Svoboda, K.R., Vijayaraghaven, S., Tanguay, R.L., 2002. Nicotinic receptors mediate changes in spinal motoneuron development and axonal pathfinding in embryonic zebrafish exposed to nicotine. J. Neurosci. 22, 10731-10741). In that study, we did not consider the potential role that altered skeletal muscle development caused by nicotine exposure could play in contributing to the errors in spinal motoneuron axon pathfinding. In this study, we show that an alteration in skeletal muscle development occurs in tandem with alterations in spinal motoneuron development upon exposure to nicotine. The alteration in the muscle involves the binding of nicotine to the muscle-specific AChRs. The nicotine-induced alteration in muscle development does not occur in the zebrafish mutant (sofa potato, [sop]), which lacks muscle-specific AChRs. Even though muscle development is unaffected by nicotine exposure in sop mutants, motoneuron axonal pathfinding errors still occur in these mutants, indicating a direct effect of nicotine exposure on nervous system development.

  11. Chronic nicotine modifies skeletal muscle Na,K-ATPase activity through its interaction with the nicotinic acetylcholine receptor and phospholemman.

    Directory of Open Access Journals (Sweden)

    Alexander V Chibalin

    Full Text Available Our previous finding that the muscle nicotinic acetylcholine receptor (nAChR and the Na,K-ATPase interact as a regulatory complex to modulate Na,K-ATPase activity suggested that chronic, circulating nicotine may alter this interaction, with long-term changes in the membrane potential. To test this hypothesis, we chronically exposed rats to nicotine delivered orally for 21-31 days. Chronic nicotine produced a steady membrane depolarization of ∼3 mV in the diaphragm muscle, which resulted from a net change in electrogenic transport by the Na,K-ATPase α2 and α1 isoforms. Electrogenic transport by the α2 isoform increased (+1.8 mV while the activity of the α1 isoform decreased (-4.4 mV. Protein expression of Na,K-ATPase α1 or α2 isoforms and the nAChR did not change; however, the content of α2 subunit in the plasma membrane decreased by 25%, indicating that its stimulated electrogenic transport is due to an increase in specific activity. The physical association between the nAChR, the Na,K-ATPase α1 or α2 subunits, and the regulatory subunit of the Na,K-ATPase, phospholemman (PLM, measured by co-immuno precipitation, was stable and unchanged. Chronic nicotine treatment activated PKCα/β2 and PKCδ and was accompanied by parallel increases in PLM phosphorylation at Ser(63 and Ser(68. Collectively, these results demonstrate that nicotine at chronic doses, acting through the nAChR-Na,K-ATPase complex, is able to modulate Na,K-ATPase activity in an isoform-specific manner and that the regulatory range includes both stimulation and inhibition of enzyme activity. Cholinergic modulation of Na,K-ATPase activity is achieved, in part, through activation of PKC and phosphorylation of PLM.

  12. Developmental Implications for Prenatal Exposure to Environmental Toxins: Consumption Habits of Pregnant Women and Prenatal Nicotine Exposure in a Mouse Model

    Science.gov (United States)

    Santiago, Sarah Emily

    This dissertation provides a discussion of the effects of maternal consumption of environmental toxins, and will hopefully contribute to the prevention and understanding of developmental disorders and physiological deficits. Developing systems are particularly susceptible to toxic insults, and small changes in utero can result in long-term deficits. Chapter one of this dissertation reviews the potential teratogenicity of nicotine, alcohol, caffeine, MeHg, PCBs, BPA, and tap water contaminants, so as to characterize the current body of literature detailing the effects and implications of prenatal exposure to toxins. In chapter two, research on maternal consumption habits is presented, with an emphasis on commonly-consumed, potentially-teratogenic substances. Occurrences and frequencies of maternal intake of healthy and unhealthy foods, beverages, and medications in a population of predominantly Hispanic women in Southern California were assessed using the Food, Beverage, and Medication Intake Questionnaire (FBMIQ). The described study reveals that a proportion of pregnant women consumed BPA, MeHg, caffeine, and alcohol at varied levels during pregnancy. The following chapters provide an in-depth analysis of the postnatal effects of a particular neuroteratogen, nicotine, which has been shown to impart various detrimental postnatal effects on exposed offspring. A CD-1 mouse model of prenatal nicotine exposure (PNE) was used to analyze aspects of the brain and neocortex that may underly some of the cognitive and behavioral phenotypes seen with PNE. Analyses included postnatal measurements of brain weight, brain widths and lengths, development of neocortical circuitry, and cortical thickness measures. Exposed mice were found to exhibit reduced brain and body weights at birth, a phenotype that recovered by postnatal day 10. No changes in neocortical circuity or thickness in sensory and motor areas were found. PNE also resulted in persistent behavioral effects, including

  13. Decay kinetics of nicotine/NNK-DNA adducts in vivo studied by accelerator mass spectrometry

    International Nuclear Information System (INIS)

    The decay kinetics of nicotine-DNA adducts and NNK-DNA adducts in mice liver after single dosing was studied by accelerator mass spectrometry (AMS). The decay is characterized by a two-stage process. The half-lives of nicotine-DNA adducts are 1.3 d (4-24 h) and 7.0 d (1-21 d), while for NNK-DNA adducts are 0.7 d (4-24 h) and 18.0 d (1-21 d). The relatively faster decay of nicotine-DNA adducts suggests that the genotoxicity of nicotine is weaker than that of NNK. The in vitro study shows that the metabolization of nicotine is necessary for the final formation of nicotine-DNA adducts, and nicotine Δ1'(5') iminium ion is a probable metabolite species that binds to DNA molecule covalently

  14. Generation of tobacco lines with widely different reduction in nicotine levels via RNA silencing approaches

    Indian Academy of Sciences (India)

    Peng Wang; Zhifeng Liang; Jia Zeng Wenchao; Wenchao Li; Xiaofen Sun; Zhiqi Miao; Kexuan Tang

    2008-06-01

    Issues related to the nicotine content of tobacco have been public concerns. Several reports have described decreasing nicotine levels by silencing the putrescine N-methyltransferase (PMT) genes, but the reported variations of nicotine levels among transgenic lines are relatively low in general. Here we describe the generation in tobacco (Nicotiana tabacum) lines with widely different, reduced nicotine levels using three kinds of RNA-silencing approaches. The relative efficacies of suppression were compared among the three approaches regarding the aspect of nicotine level in tobacco leaves. By suppressing expression of the PMT genes, over 200 transgenic lines were obtained with nicotine levels reduced by 9.1–96.7%. RNA interference (RNAi) was the most efficient method of reducing the levels of nicotine, whereas cosuppression and antisense methods were less effective. This report gives clues to the efficient generation of plants with a variety of metabolite levels, and the results demonstrate the relative efficiencies of various RNA-silencing methods.

  15. Rapid deterioration of externally induced neuroplasticity in non-smoking subjects by nicotine

    Directory of Open Access Journals (Sweden)

    JessicaGrundey

    2012-10-01

    Full Text Available In various studies nicotine has been shown to alter cognitive functions in non-smoking subjects, which might be due to nicotine-generated modulation of cortical functions, excitability and activity, as mainly described in animal experiments. In non-smoking humans application of nicotine for hours via nicotine patch abolishes inhibitory plasticity both after cathodal transcranial direct current stimulation (tDCS or paired associative stimulation (PAS-10. Excitatory anodal tDCS after-effects were reduced whereas excitatory PAS-25 was prolonged. These results are compatible with the view that prolonged nicotine administration facilitates focal synapse-specific excitatory plasticity as induced with excitatory PAS as focusing effect. However, since nicotine receptors undergo rapid adaption processes within minutes, the results cannot distinguish between an impact of the substance alone or a compensatory receptor adaption. Thus in the present study we replicated the experiments however using nicotine spray, which enhances blood concentration of nicotine within minutes. 48 non-smokers received nicotine spray respectively placebo spray combined with either facilitatory or inhibitory tDCS or PAS. Corticospinal excitability was monitored via motor-evoked potentials elicited by transcranial magnetic stimulation (TMS. Nicotine spray abolished all types of plasticity except synapse-unspecific non-focal tDCS-derived excitability reduction, which was delayed and also weakened. Thus, the effects of short-term nicotine application differ from those of prolonged nicotine application, which might be due to missing adaptive nicotinic receptor alterations. These results enhance our knowledge about the dynamic impact of nicotine on plasticity, which might be relevant to its heterogeneous effect on cognition.

  16. The efficacy and safety of a nicotine conjugate vaccine (NicVAX® or placebo co-administered with varenicline (Champix® for smoking cessation: study protocol of a phase IIb, double blind, randomized, placebo controlled trial

    Directory of Open Access Journals (Sweden)

    Hoogsteder Philippe HJ

    2012-12-01

    Full Text Available Abstract Background A potential new treatment in smoking cessation and relapse prevention is nicotine vaccination which is based on active immunization against the nicotine molecule. This immunization will elicit the immune system to produce nicotine-specific antibodies that sequester nicotine in the blood stream, after inhaling tobacco products. The resulting antibody-antigen is too large to cross the blood–brain barrier and is therefore postulated to attenuate the rewarding effect of nicotine by preventing the latter from reaching its receptors in the brain and causing the release of dopamine. The aim of this paper is to describe the design of a phase IIb, multi-center, double blind, randomized, placebo controlled trial to assess the efficacy of the nicotine vaccine NicVAX® co-administered with varenicline (Champix® and intensive counseling as an aid in smoking cessation and relapse prevention. Methods/design Two centers will include a total of 600 smokers who are motivated to quit smoking. At week −2 these smokers will be randomized, in a 1:1 ratio, to either 6 injections of NicVAX® or placebo, both co-administered with 12-weeks of varenicline treatment, starting at week 0. The target quit day will be set after 7 days of varenicline treatment at week 1. Smokers will be followed up for 54 weeks. The primary outcome is defined as biochemically validated prolonged smoking abstinence from week 9 to 52. Secondary outcomes include safety, immunogenicity, smoking abstinence from week 37 to 52, abstinence from week 9 to 24, abstinence in the subset of subjects with the highest antibody response, and lapse/relapse rate. Discussion This is the first study to assess the efficacy of a nicotine conjugate vaccine in combination with an evidence-based smoking cessation pharmacotherapy (varenicline to quit smoking. Although NicVAX® is primarily designed as an aid to smoking cessation, our study is designed to explore its potential to maintain

  17. E-cigarettes for the management of nicotine addiction

    Science.gov (United States)

    Knight-West, Oliver; Bullen, Christopher

    2016-01-01

    In this review, we discuss current evidence on electronic cigarettes (ECs), a rapidly evolving class of nicotine delivery system, and their role in managing nicotine addiction, specifically in helping smokers to quit smoking and/or reduce the amount of tobacco they smoke. The current evidence base is limited to three randomized trials (only one compares ECs with nicotine replacement therapy) and a growing number of EC user surveys (n=6), case reports (n=4), and cohort studies (n=8). Collectively, these studies suggest modest cessation efficacy and a few adverse effects, at least with the short-term use. On this basis, we provide advice for health care providers on providing balanced information for patients who enquire about ECs. More research, specifically well-conducted large efficacy trials comparing ECs with standard smoking cessation management (eg, nicotine replacement therapy plus behavioral support) and long-term prospective studies for adverse events, are urgently needed to fill critical knowledge gaps on these products. PMID:27574480

  18. Nicotine Modulates the Long-Lasting Storage of Fear Memory

    Science.gov (United States)

    Lima, Ramon H.; Radiske, Andressa; Kohler, Cristiano A.; Gonzalez, Maria Carolina; Bevilaqua, Lia R.; Rossato, Janine I.; Medina, Jorge H.; Cammarota, Martin

    2013-01-01

    Late post-training activation of the ventral tegmental area (VTA)-hippocampus dopaminergic loop controls the entry of information into long-term memory (LTM). Nicotinic acetylcholine receptors (nAChR) modulate VTA function, but their involvement in LTM storage is unknown. Using pharmacological and behavioral tools, we found that…

  19. Single molecule transistor based nanopore for the detection of nicotine

    Energy Technology Data Exchange (ETDEWEB)

    Ray, S. J., E-mail: ray.sjr@gmail.com [Institute of Materials Science, Technical University of Darmstadt, Alarich-Weiss-Str. 2, 64287 Darmstadt (Germany)

    2014-12-28

    A nanopore based detection methodology was proposed and investigated for the detection of Nicotine. This technique uses a Single Molecular Transistor working as a nanopore operational in the Coulomb Blockade regime. When the Nicotine molecule is pulled through the nanopore area surrounded by the Source(S), Drain (D), and Gate electrodes, the charge stability diagram can detect the presence of the molecule and is unique for a specific molecular structure. Due to the weak coupling between the different electrodes which is set by the nanopore size, the molecular energy states stay almost unaffected by the electrostatic environment that can be realised from the charge stability diagram. Identification of different orientation and position of the Nicotine molecule within the nanopore area can be made from specific regions of overlap between different charge states on the stability diagram that could be used as an electronic fingerprint for detection. This method could be advantageous and useful to detect the presence of Nicotine in smoke which is usually performed using chemical chromatography techniques.

  20. Effect of transdermal nicotine administration on exercise endurance in men.

    Science.gov (United States)

    Mündel, Toby; Jones, David A

    2006-07-01

    Nicotine is widely reported to increase alertness, improve co-ordination and enhance cognitive performance; however, to our knowledge there have been no attempts to replicate these findings in relation to exercise endurance. The purpose of this study was to determine the effects nicotine might have on cycling endurance, perception of exertion and a range of physiological variables. With local ethics committee approval and having obtained informed consent, 12 healthy, non-smoking men (22 +/- 3 years; maximal O2 uptake, 56 +/- 6 ml kg(-1) min(-1), mean +/- s.d.) cycled to exhaustion at 18 degrees C and 65% of their peak aerobic power, wearing either a 7 mg transdermal nicotine patch (NIC) or a colour-matched placebo (PLA) in a randomized cross-over design; water was available ad libitum. Subjects were exercising at approximately 75% of their maximal O2 uptake with no differences in cadence between trials. Ten out of 12 subjects cycled for longer with NIC administration, and this resulted in a significant 17 +/- 7% improvement in performance (P effect on peripheral markers, we conclude that nicotine prolongs endurance by a central mechanism. Possible modes of action are suggested. PMID:16627574

  1. E-cigarettes for the management of nicotine addiction.

    Science.gov (United States)

    Knight-West, Oliver; Bullen, Christopher

    2016-01-01

    In this review, we discuss current evidence on electronic cigarettes (ECs), a rapidly evolving class of nicotine delivery system, and their role in managing nicotine addiction, specifically in helping smokers to quit smoking and/or reduce the amount of tobacco they smoke. The current evidence base is limited to three randomized trials (only one compares ECs with nicotine replacement therapy) and a growing number of EC user surveys (n=6), case reports (n=4), and cohort studies (n=8). Collectively, these studies suggest modest cessation efficacy and a few adverse effects, at least with the short-term use. On this basis, we provide advice for health care providers on providing balanced information for patients who enquire about ECs. More research, specifically well-conducted large efficacy trials comparing ECs with standard smoking cessation management (eg, nicotine replacement therapy plus behavioral support) and long-term prospective studies for adverse events, are urgently needed to fill critical knowledge gaps on these products. PMID:27574480

  2. Brain herniation

    Science.gov (United States)

    ... herniation; Uncal herniation; Subfalcine herniation; Tonsillar herniation; Herniation - brain ... Brain herniation occurs when something inside the skull produces pressure that moves brain tissues. This is most ...

  3. NICOTINE-RECEPTOR BLOCKADE AND THE EFFECTS OF ANATOXIN-A ON THE MOTOR ACTIVITY OF RATS: COMPARISON WITH NICOTINE.

    Science.gov (United States)

    Anatoxin-a is produced by several species of freshwater cyanobacteria and has caused several poisoning episodes in terrestrial and aquatic wildlife, livestock and domestic animals. Anatoxin-a is also a potent nicotinic agonist in the nervous system and at the neuromuscular juncti...

  4. Nicotine-specific and non-specific effects of cigarette smoking on endogenous opioid mechanisms.

    Science.gov (United States)

    Nuechterlein, Emily B; Ni, Lisong; Domino, Edward F; Zubieta, Jon-Kar

    2016-08-01

    This study investigates differences in μ-opioid receptor mediated neurotransmission in healthy controls and overnight-abstinent smokers, and potential effects of the OPRM1 A118G genotype. It also examines the effects of smoking denicotinized (DN) and average nicotine (N) cigarettes on the μ-opioid system. Positron emission tomography with (11)C-carfentanil was used to determine regional brain μ-opioid receptor (MOR) availability (non-displaceable binding potential, BPND) in a sample of 19 male smokers and 22 nonsmoking control subjects. Nonsmokers showed greater MOR BPND than overnight abstinent smokers in the basal ganglia and thalamus. BPND in the basal ganglia was negatively correlated with baseline craving levels and Fagerström scores. Interactions between group and genotype were seen in the nucleus accumbens bilaterally and the amygdala, with G-allele carriers demonstrating lower BPND in these regions, but only among smokers. After smoking the DN cigarette, smokers showed evidence of MOR activation in the thalamus and nucleus accumbens. No additional activation was observed after the N cigarette, with a mean effect of increases in MOR BPND (i.e., deactivation) with respect to the DN cigarette effects in the thalamus and left amygdala. Changes in MOR BPND were related to both Fagerström scores and changes in craving. This study showed that overnight-abstinent smokers have lower concentrations of available MORs than controls, an effect that was related to both craving and the severity of addiction. It also suggests that nicotine non-specific elements of the smoking experience have an important role in regulating MOR-mediated neurotransmission, and in turn modulating withdrawal-induced craving ratings. PMID:27095017

  5. Impact of prenatal nicotine on the structure of midbrain dopamine regions in the rat.

    Science.gov (United States)

    Omelchenko, Natalia; Roy, Priya; Balcita-Pedicino, Judith Joyce; Poloyac, Samuel; Sesack, Susan R

    2016-05-01

    In utero exposure of rats to nicotine (NIC) provides a useful animal model for studying the impact of smoking during pregnancy on human offspring. Certain sequelae of prenatal NIC exposure suggest an impact on the development of the midbrain dopamine (DA) system, which receives a robust cholinergic innervation from the mesopontine tegmentum. We therefore investigated whether prenatal NIC induced structural changes in cells and synapses within the midbrain that persisted into adulthood. Osmotic minipumps delivering either sodium bitartrate (vehicle; VEH) or NIC bitartrate at 2 mg/kg/day were implanted into nine timed-pregnant dams at E4. At birth, rat pups were culled to litters of six males each, and the litters were cross-fostered. Plasma levels of NIC and cotinine from killed pups provided evidence of NIC exposure in utero. Pups separated from dams at weaning showed a trend toward reduced locomotor activity at this time point but not when tested again in adulthood. Adult rats were killed for anatomical studies. Estimates of brain size and volume did not vary with NIC treatment. Midbrain sections stained for Nissl or by immunoperoxidase for tyrosine hydroxylase and analyzed using unbiased stereology revealed no changes in volume or cell number in the substantia nigra compacta or ventral tegmental area as a result of NIC exposure. Within the ventral tegmental area, electron microscopic physical disector analysis showed no significant differences in the number of axon terminals or the number of asymmetric (putative excitatory) or symmetric (putative inhibitory) synapses. Although too infrequent to estimate by unbiased stereology, no obvious difference in the proportion of cholinergic axons was noted in NIC- versus VEH-treated animals. These data suggest that activation of nicotinic receptors during prenatal development induces no significant modifications in the structure of cells in the ventral midbrain when assessed in adulthood. PMID:25716298

  6. Crocin Improves Damage Induced by Nicotine on A Number of Reproductive Parameters in Male Mice

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Salahshoor

    2016-05-01

    Full Text Available Background: Crocin, a carotenoid isolated from Crocus sativus L. (saffron, is a pharmacologically active component of saffron. Nicotine consumption can decrease fertility in males through induction of oxidative stress and DNA damage. The aim of this study is to determine the effects of crocin on reproductive parameter damages in male mice exposed to nicotine. Materials and Methods: In this experimental study, we divided 48 mice into 8 groups (n=6 per group: control (normal saline, nicotine (2.5 mg/kg, crocin (12.5, 25 and 50 mg/kg and crocin (12.5, 25 and 50 mg/kg+nicotine (2.5 mg/kg. Mice received once daily intraperitoneal injections of crocin, nicotine and crocin+nicotine for 4 weeks. Sperm parameters (count, motility, and viability, testis weight, seminiferous tube diameters, testosterone, and serum nitric oxide levels were analyzed and compared. Results: Nicotine administration significantly decreased testosterone level; sperm count, viability, and motility; testis weight and seminiferous tubule diameters compared to the control group (P<0.05. However, increasing the dose of crocin in the crocin and crocin+nicotine groups significantly boosted sperm motility and viability; seminiferous tubule diameters; testis weight; and testosterone levels in all groups compared to the nicotine group (P<0.05. Conclusion: Crocin improves nicotine-induced adverse effects on reproductive parameters in male mice.

  7. Analysis of effect of nicotine on microbial community structure in sediment using PCR-DGGE fingerprinting

    Directory of Open Access Journals (Sweden)

    Ai-dong Ruan

    2015-10-01

    Full Text Available Solid or liquid waste containing a high concentration of nicotine can pollute sediment in rivers and lakes, and may destroy the ecological balance if it is directly discharged into the environment without any treatment. In this study, the polymerase chain reaction (PCR and denaturing gradient gel electrophoresis (DGGE method was used to analyze the variation of the microbial community structure in the control and nicotine-contaminated sediment samples with nicotine concentration and time of exposure. The results demonstrated that the growth of some bacterial species in the nicotine-contaminated sediment samples was inhibited during the exposure. Some bacteria decreased in species diversity and in quantity with the increase of nicotine concentration or time of exposure, while other bacteria were enriched under the effect of nicotine, and their DGGE bands changed from undertones to deep colors. The microbial community structure, however, showed a wide variation in the nicotine-contaminated sediment samples, especially in the sediment samples treated with high-concentration nicotine. The Jaccard index was only 35.1% between the initial sediment sample and the sediment sample with a nicotine concentration of 0.030 μg/g after 28 d of exposure. Diversity indices showed that the contaminated groups had a similar trend over time. The diversity indices of contaminated groups all decreased in the first 7 d after exposure, then increased until day 42. It has been found that nicotine decreased the diversity of the microbial community in the sediment.

  8. Antenatal Antioxidant Prevents Nicotine-Mediated Hypertensive Response in Rat Adult Offspring.

    Science.gov (United States)

    Xiao, DaLiao; Huang, Xiaohui; Li, Yong; Dasgupta, Chiranjib; Wang, Lei; Zhang, Lubo

    2015-09-01

    Previous studies have demonstrated that perinatal nicotine exposure increased blood pressure (BP) in adult offspring. However, the underlying mechanisms were unclear. The present study tested the hypothesis that perinatal nicotine-induced programming of hypertensive response is mediated by enhanced reactive oxygen species (ROS) in the vasculature. Nicotine was administered to pregnant rats via subcutaneous osmotic mini-pumps from Day 4 of gestation to Day 10 after birth, in the absence or presence of the ROS inhibitor N-acetyl-cysteine (NAC) in the drinking water. Experiments were conducted in 8-mo-old male offspring. Perinatal nicotine treatment resulted in a significant increase in arterial ROS production in offspring, which was abrogated by NAC. Angiotensin II (Ang II)-induced BP responses were significantly higher in nicotine-treated group than in saline-treated control group, and NAC treatment blocked the nicotine-induced increase in BP response. Consistent with that, the nicotine treatment significantly increased both Ang II-induced and phorbol [12, 13]-dibutyrate (PDBu, a Prkc activator)-induced arterial contractions in adult offspring, which were blocked by NAC treatment. In addition, perinatal nicotine treatment significantly attenuated acetylcholine-induced arterial relaxation in offspring, which was also inhibited by NAC treatment. Results demonstrate that inhibition of ROS blocks the nicotine-induced increase in arterial reactivity and BP response to vasoconstrictors in adult offspring, suggesting a key role for increased oxidative stress in nicotine-induced developmental programming of hypertensive phenotype in male offspring. PMID:26224008

  9. Nicotine reinforcement is reduced by cannabinoid CB1 receptor blockade in the ventral tegmental area.

    Science.gov (United States)

    Simonnet, Amelie; Cador, Martine; Caille, Stephanie

    2013-11-01

    Cannabinoid type 1 (CB1) receptors control the motivational properties and reinforcing effects of nicotine. Indeed, peripheral administration of a CB1 receptor antagonist dramatically decreases both nicotine taking and seeking. However, the neural substrates through which the cannabinoid CB1 receptors regulate the voluntary intake of nicotine remain to be elucidated. In the present study, we sought to determine whether central injections of a CB1 receptor antagonist delivered either into the ventral tegmental area (VTA) or the nucleus accumbens (NAC) may alter nicotine intravenous self-administration (IVSA). Rats were first trained to self-administer nicotine (30 μg/kg/0.1 ml). The effect of central infusions of the CB1 antagonist AM 251 (0, 1 and 10 μg/0.5 μl/side) on nicotine-taking behavior was then tested. Intra-VTA infusions of AM 251 dose dependently reduced IVSA with a significant decrease for the dose 10 μg/0.5 μl/side. Moreover, operant responding for water was unaltered by intra-VTA AM 251 at the same dose. Surprisingly, intra-NAC delivery of AM 251 did not alter nicotine behavior at all. These data suggest that in rats chronically exposed to nicotine IVSA, the cannabinoid CB1 receptors located in the VTA rather than in the NAC specifically control nicotine reinforcement and, subsequently, nicotine-taking behavior. PMID:22784230

  10. Tobacco extract but not nicotine impairs the mechanical strength of fracture healing in rats.

    Science.gov (United States)

    Skott, Martin; Andreassen, Troels T; Ulrich-Vinther, Michael; Chen, X; Keyler, Dan E; LeSage, Mark G; Pentel, Paul R; Bechtold, Joan E; Soballe, Kjeld

    2006-07-01

    The influence of nicotine and tobacco extract (without nicotine) alone and in combination on and mechanical strength of closed femoral fractures in rats was investigated. One hundred four male Sprague-Dawley rats were divided into four groups receiving: nicotine, tobacco extract, tobacco extract plus nicotine, and saline. One week prior to fracture, osmotic pumps were implanted subcutaneously in all animals to administer nicotine equivalent to the serum level of nicotine observed in a smoker consuming one to two packs of cigarettes daily. An equivalent volume of saline was administered to the control animals. Tobacco extract was administered orally. A closed transverse femoral diaphysial fracture was performed, and stabilized with an intramedullary pin. The fractures were mechanically tested after 21 days of healing. Tobacco extract alone decreased the mechanical strength. Ultimate torque and torque at yield point of the tobacco extract group were decreased by 21% (p=0.010) and 23% (p=0.056), respectively, compared with the vehicle (saline) group, and by 20% (p=0.023) and 26% (p=0.004), respectively, compared with the nicotine group. No difference was found between the tobacco extract and tobacco extract plus nicotine groups. An 18% (p=0.013) reduction in torque at yield point was observed in the tobacco extract plus nicotine group compared with the nicotine group. No differences in ultimate stiffness, energy absorption, and callus bone mineral content at the fracture line were found between any of the groups. Serum levels of nicotine were between 40-50 ng/mL in the group given nicotine alone and the group given tobacco extract plus nicotine (equivalent to serum levels observed in persons smoking one to two packs of cigarettes per day). PMID:16705735

  11. Early adolescent nicotine exposure affects later-life cocaine reward in mice.

    Science.gov (United States)

    Alajaji, Mai; Lazenka, Matthew F; Kota, Dena; Wise, Laura E; Younis, Rabha M; Carroll, F Ivy; Levine, Amir; Selley, Dana E; Sim-Selley, Laura J; Damaj, M Imad

    2016-06-01

    Adolescence represents a unique developmental period associated with increased risk-taking behavior and experimentation with drugs of abuse, in particular nicotine. We hypothesized that exposure to nicotine during early adolescence might increase the risk for drug reward in adulthood. To test this hypothesis, male ICR mice were treated with a subchronic regimen of nicotine or saline during adolescence, and their preference for cocaine, morphine and amphetamine was examined using the conditioned place preference (CPP) test in adulthood. Long-term behavioral changes induced by nicotine suggested a possible role of altered gene transcription. Thus, immunoblot for ΔFosB, a member of the Fos family of transcription factors, was conducted in the nucleus accumbens of these mice. Mice treated with nicotine during early but not late adolescence showed an increase in CPP for cocaine, morphine and amphetamine later in adulthood. This effect was not seen in mice pretreated with a subchronic regimen of nicotine as adults, suggesting that exposure to nicotine specifically during early adolescence increases the rewarding effects of other drugs in adulthood. However, adolescent nicotine exposure did not alter highly palatable food conditioning in mice. The enhancement of cocaine CPP by nicotine was strain-dependent and was blocked by pretreatment with nicotinic antagonists. In addition, nicotine exposure during early adolescence induced ΔFosB expression to a greater extent than identical nicotine exposure in adulthood, and enhanced cocaine-induced locomotor sensitization later in adulthood. These results suggest that nicotine exposure during early adolescence increases drug-induced reward in adulthood through mechanisms that may involve the induction of ΔFosB. PMID:26808314

  12. Adolescent alcohol exposure decreased sensitivity to nicotine in adult Wistar rats.

    Science.gov (United States)

    Boutros, Nathalie; Semenova, Svetlana; Markou, Athina

    2016-07-01

    Many adolescents engage in heavy alcohol use. Limited research in humans indicates that adolescent alcohol use predicts adult tobacco use. The present study investigated whether adolescent intermittent ethanol (AIE) exposure alters nicotine sensitivity in adulthood. Adolescent male Wistar rats (postnatal day 28-53) were exposed to AIE exposure that consisted of 5 g/kg of 25 percent ethanol three times per day in a 2 days on/2 days off regimen. Control rats received water with the same exposure regimen. In adulthood, separate groups of rats were tested for nicotine intravenous self-administration (IVSA), drug discrimination and conditioned taste aversion (CTA). The dose-response function for nicotine IVSA under a fixed-ratio schedule of reinforcement was similar in AIE-exposed and control rats. However, AIE-exposed rats self-administered less nicotine at the lowest dose, suggesting that low-dose nicotine was less reinforcing in AIE-exposed, compared with control rats. AIE-exposed rats self-administered less nicotine under a progressive-ratio schedule, suggesting decreased motivation for nicotine after AIE exposure. The discriminative stimulus effects of nicotine were diminished in AIE-exposed rats compared with control rats. No group differences in nicotine CTA were observed, suggesting that AIE exposure had no effect on the aversive properties of nicotine. Altogether, these results demonstrate that AIE exposure decreases sensitivity to the reinforcing, motivational and discriminative properties of nicotine while leaving the aversive properties of nicotine unaltered in adult rats. These findings suggest that drinking during adolescence may result in decreased sensitivity to nicotine in adult humans, which may in turn contribute to the higher rates of tobacco smoking. PMID:25950618

  13. Endothelial disruptive proinflammatory effects of nicotine and e-cigarette vapor exposures

    Science.gov (United States)

    Schweitzer, Kelly S.; Chen, Steven X.; Law, Sarah; Van Demark, Mary; Poirier, Christophe; Justice, Matthew J.; Hubbard, Walter C.; Kim, Elena S.; Lai, Xianyin; Wang, Mu; Kranz, William D.; Carroll, Clinton J.; Ray, Bruce D.; Bittman, Robert; Goodpaster, John

    2015-01-01

    The increased use of inhaled nicotine via e-cigarettes has unknown risks to lung health. Having previously shown that cigarette smoke (CS) extract disrupts the lung microvasculature barrier function by endothelial cell activation and cytoskeletal rearrangement, we investigated the contribution of nicotine in CS or e-cigarettes (e-Cig) to lung endothelial injury. Primary lung microvascular endothelial cells were exposed to nicotine, e-Cig solution, or condensed e-Cig vapor (1–20 mM nicotine) or to nicotine-free CS extract or e-Cig solutions. Compared with nicotine-containing extract, nicotine free-CS extract (10–20%) caused significantly less endothelial permeability as measured with electric cell-substrate impedance sensing. Nicotine exposures triggered dose-dependent loss of endothelial barrier in cultured cell monolayers and rapidly increased lung inflammation and oxidative stress in mice. The endothelial barrier disruptive effects were associated with increased intracellular ceramides, p38 MAPK activation, and myosin light chain (MLC) phosphorylation, and was critically mediated by Rho-activated kinase via inhibition of MLC-phosphatase unit MYPT1. Although nicotine at sufficient concentrations to cause endothelial barrier loss did not trigger cell necrosis, it markedly inhibited cell proliferation. Augmentation of sphingosine-1-phosphate (S1P) signaling via S1P1 improved both endothelial cell proliferation and barrier function during nicotine exposures. Nicotine-independent effects of e-Cig solutions were noted, which may be attributable to acrolein, detected along with propylene glycol, glycerol, and nicotine by NMR, mass spectrometry, and gas chromatography, in both e-Cig solutions and vapor. These results suggest that soluble components of e-Cig, including nicotine, cause dose-dependent loss of lung endothelial barrier function, which is associated with oxidative stress and brisk inflammation. PMID:25979079

  14. Manganese: Brain Species and Mechanisms of Brain Injury

    OpenAIRE

    Neth, Katharina

    2016-01-01

    Manganism is a Parkinson-related disease, which can arise by accumulation of the essential trace element manganese (Mn) in the brain by overexposure. Versatile Mn-species and imbalances of trace elements in serum and brain tissue of Mn-exposed rats were analyzed by methods of metallomics. Additionally, non-targeted metabolomics of brain tissue served for analysis of the multilateral mechanisms, which can lead to the neuronal injury. Finally, results from metallomics were correlated to the fin...

  15. Nicotinate-Curcumin Impedes Foam Cell Formation from THP-1 Cells through Restoring Autophagy Flux.

    Science.gov (United States)

    Gu, Hong-Feng; Li, Hai-Zhe; Tang, Ya-Ling; Tang, Xiao-Qing; Zheng, Xi-Long; Liao, Duan-Fang

    2016-01-01

    Our previous studies have indicated that a novel curcumin derivate nicotinate-curcumin (NC) has beneficial effects on the prevention of atherosclerosis, but the precise mechanisms are not fully understood. Given that autophagy regulates lipid metabolism, the present study was designed to investigate whether NC decreases foam cell formation through restoring autophagy flux in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 cells. Our results showed that ox-LDL (100 μg/ml) was accumulated in THP-1 cells and impaired autophagy flux. Ox-LDL-induced impairment of autophagy was enhanced by treatment with the autophagy inhibitor chloroquine (CQ) and rescued by the autophagy inducer rapamycin. The aggregation of ox-LDL was increased by CQ, but decreased by rapamycin. In addition, colocalization of lipid droplets with LC3-II was remarkably reduced in ox-LDL group. In contrast, NC (10 μM) rescued the impaired autophagy flux by significantly increasing level of LC3-II, the number of autophagolysosomes, and the degradation of p62 in ox-LDL-treated THP-1 cells. Inhibition of the PI3K-Akt-mTOR signaling was required for NC-rescued autophagy flux. Notably, our results showed that NC remarkably promoted the colocalization of lipid droplets with autophagolysosomes, increased efflux of cholesterol, and reduced ox-LDL accumulation in THP-1 cells. However, treatment with 3-methyladenine (3-MA) or CQ reduced the protective effects of NC on lipid accumulation. Collectively, the findings suggest that NC decreases lipid accumulation in THP-1 cells through restoring autophagy flux, and further implicate that NC may be a potential therapeutic reagent to reverse atherosclerosis. PMID:27128486

  16. Nicotinate-Curcumin Impedes Foam Cell Formation from THP-1 Cells through Restoring Autophagy Flux

    Science.gov (United States)

    Gu, Hong-Feng; Li, Hai-Zhe; Tang, Ya-Ling; Tang, Xiao-Qing; Zheng, Xi-Long; Liao, Duan-Fang

    2016-01-01

    Our previous studies have indicated that a novel curcumin derivate nicotinate-curcumin (NC) has beneficial effects on the prevention of atherosclerosis, but the precise mechanisms are not fully understood. Given that autophagy regulates lipid metabolism, the present study was designed to investigate whether NC decreases foam cell formation through restoring autophagy flux in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 cells. Our results showed that ox-LDL (100 μg/ml) was accumulated in THP-1 cells and impaired autophagy flux. Ox-LDL-induced impairment of autophagy was enhanced by treatment with the autophagy inhibitor chloroquine (CQ) and rescued by the autophagy inducer rapamycin. The aggregation of ox-LDL was increased by CQ, but decreased by rapamycin. In addition, colocalization of lipid droplets with LC3-II was remarkably reduced in ox-LDL group. In contrast, NC (10 μM) rescued the impaired autophagy flux by significantly increasing level of LC3-II, the number of autophagolysosomes, and the degradation of p62 in ox-LDL-treated THP-1 cells. Inhibition of the PI3K-Akt-mTOR signaling was required for NC-rescued autophagy flux. Notably, our results showed that NC remarkably promoted the colocalization of lipid droplets with autophagolysosomes, increased efflux of cholesterol, and reduced ox-LDL accumulation in THP-1 cells. However, treatment with 3-methyladenine (3-MA) or CQ reduced the protective effects of NC on lipid accumulation. Collectively, the findings suggest that NC decreases lipid accumulation in THP-1 cells through restoring autophagy flux, and further implicate that NC may be a potential therapeutic reagent to reverse atherosclerosis. PMID:27128486

  17. CXCL9 Is Important for Recruiting Immune T Cells into the Brain and Inducing an Accumulation of the T Cells to the Areas of Tachyzoite Proliferation to Prevent Reactivation of Chronic Cerebral Infection with Toxoplasma gondii

    OpenAIRE

    Ochiai, Eri; Sa, Qila; Brogli, Morgan; Kudo, Tomoya; Wang, Xisheng; Dubey, Jitender P; Suzuki, Yasuhiro

    2015-01-01

    T cells are required to maintain the latency of chronic infection with Toxoplasma gondii in the brain. Here, we examined the role of non–glutamic acid-leucine-arginine CXC chemokine CXCL9 for T-cell recruitment to prevent reactivation of infection with T. gondii. Severe combined immunodeficient (SCID) mice were infected and treated with sulfadiazine to establish a chronic infection. Immune T cells from infected wild-type mice were transferred into the SCID mice in combination with treatment w...

  18. Injury of Mouse Brain Mitochondria Induced by Cigarette Smoke Extract and Effect of Vitamin C on It in vitro

    Institute of Scientific and Technical Information of China (English)

    YU-MEI YANG; GENG-TAO LIU

    2003-01-01

    To investigate the toxicity of cigarette smoke extract (CSE) and nicotine on mouse brain mitochondria as well as the protective effect of vitamin C in vitro. Method Mouse brain mitochondria in vitro was incubated with CSE or nicotine in the absence or presence of vitamin C for 60 minutes, and the changes of mitochondrial function and structure were measured. Results CSE inhibited mitochondrial ATPase and cytochrome C oxidase activities in a dose-dependent manner.However, no significant changes in the peroxidation indices were observed when mitochondrial respiratory enzymes activity was inhibited, and protection of mitochondria from CSE-induced injury by vitamin C was not displayed in vitro. The effect of CSE on mouse brain mitochondria swelling response to calcium stimulation was dependent on calcium concentrations. CSE inhibited swelling of mitochondria at 6.5 μmol/L Ca2+, but promoted swelling response at 250 μmol/L Ca2+. Nicotine, the major component of cigarette smoke, showed no significant damage in mouse brain mitochondria in vitro. The CSE treatment induced mitochondrial inner membrane damage and vacuolization of the matrix, whereas the outer mitochondrial membrane appeared to be preserved. Conclusion The toxic effect of CSE on brain mitochondria may be due to its direct action on enzymatic activity rather than through oxygen free radical injury. Nicotine is not the responsible component for the toxicity of CSE to brain mitochondria.

  19. Beta-cryptoxanthin restores nicotine-reduced lung SIRT1 to normal levels and inhibits nicotine-promoted lung tumorigenesis and emphysema in A/J mice

    Science.gov (United States)

    Nicotine, a large constituent of cigarette smoke, is associated with an increased risk of lung cancer, but the data supporting this relationship are inconsistent. Here, we found that nicotine treatment not only induced emphysema but also increased both lung tumor multiplicity and volume in 4-nitrosa...

  20. Nicotine promotes cell proliferation via α7-nicotinic acetylcholine receptor and catecholamine-synthesizing enzymes-mediated pathway in human colon adenocarcinoma HT-29 cells

    International Nuclear Information System (INIS)

    Cigarette smoking has been implicated in colon cancer. Nicotine is a major alkaloid in cigarette smoke. In the present study, we showed that nicotine stimulated HT-29 cell proliferation and adrenaline production in a dose-dependent manner. The stimulatory action of nicotine was reversed by atenolol and ICI 118,551, a β1- and β2-selective antagonist, respectively, suggesting the role of β-adrenoceptors in mediating the action. Nicotine also significantly upregulated the expression of the catecholamine-synthesizing enzymes [tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DβH) and phenylethanolamine N-methyltransferase]. Inhibitor of TH, a rate-limiting enzyme in the catecholamine-biosynthesis pathway, reduced the actions of nicotine on cell proliferation and adrenaline production. Expression of α7-nicotinic acetylcholine receptor (α7-nAChR) was demonstrated in HT-29 cells. Methyllycaconitine, an α7-nAChR antagonist, reversed the stimulatory actions of nicotine on cell proliferation, TH and DβH expression as well as adrenaline production. Taken together, through the action on α7-nAChR nicotine stimulates HT-29 cell proliferation via the upregulation of the catecholamine-synthesis pathway and ultimately adrenaline production and β-adrenergic activation. These data reveal the contributory role α7-nAChR and β-adrenoceptors in the tumorigenesis of colon cancer cells and partly elucidate the carcinogenic action of cigarette smoke on colon cancer

  1. Evaluation of the Nicotinic Acetylcholine Receptor-Associated Proteome at Baseline and Following Nicotine Exposure in Human and Mouse Cortex

    Science.gov (United States)

    Esterlis, Irina; Stone, Kathryn L.; Grady, Sharon R.; Lindstrom, Jon M.; Marks, Michael J.

    2016-01-01

    Abstract Nicotinic acetylcholine receptors (nAChRs) support the initiation and maintenance of smoking, but the long-term changes occurring in the protein complex as a result of smoking and the nicotine in tobacco are not known. Human studies and animal models have also demonstrated that increasing cholinergic tone increases behaviors related to depression, suggesting that the nAChR-associated proteome could be altered in individuals with mood disorders. We therefore immunopurified nAChRs and associated proteins for quantitative proteomic assessment of changes in protein–protein interactions of high-affinity nAChRs containing the β2 subunit (β2*-nAChRs) from either cortex of mice treated with saline or nicotine, or postmortem human temporal cortex tissue from tobacco-exposed and nonexposed individuals, with a further comparison of diagnosed mood disorder to control subjects. We observed significant effects of nicotine exposure on the β2*-nAChR-associated proteome in human and mouse cortex, particularly in the abundance of the nAChR subunits themselves, as well as putative interacting proteins that make up core components of neuronal excitability (Na/K ATPase subunits), presynaptic neurotransmitter release (syntaxins, SNAP25, synaptotagmin), and a member of a known nAChR protein chaperone family (14-3-3ζ). These findings identify candidate-signaling proteins that could mediate changes in cholinergic signaling via nicotine or tobacco use. Further analysis of identified proteins will determine whether these interactions are essential for primary function of nAChRs at presynaptic terminals. The identification of differences in the nAChR-associated proteome and downstream signaling in subjects with various mood disorders may also identify novel etiological mechanisms and reveal new treatment targets.

  2. Gut Microbiota: The Brain Peacekeeper

    OpenAIRE

    Mu, Chunlong; Yang, Yuxiang; Zhu, Weiyun

    2016-01-01

    Gut microbiota regulates intestinal and extraintestinal homeostasis. Accumulating evidence suggests that the gut microbiota may also regulate brain function and behavior. Results from animal models indicate that disturbances in the composition and functionality of some microbiota members are associated with neurophysiological disorders, strengthening the idea of a microbiota–gut–brain axis and the role of microbiota as a “peacekeeper” in the brain health. Here, we review recent discoveries on...

  3. Brain Basics

    Medline Plus

    Full Text Available ... Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures of the brain's structure, studies show that brain growth in children with autism ...

  4. The antidepressant-like activity of nicotine, but not of 3-furan-2-yl-N-p-tolyl-acrylamide, is regulated by the nicotinic receptor β4 subunit.

    Science.gov (United States)

    Arias, Hugo R; Targowska-Duda, Katarzyna M; Feuerbach, Dominik; Jozwiak, Krzysztof

    2015-08-01

    The current study compares the antidepressant-like effect elicited by nicotine between wild-type (β4+/+) and knockout (β4-/-) mice, and subsequently, the effect of 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a positive allosteric modulator of α7 nicotinic receptors, on the previously determined activity of nicotine. Mice from each sex were injected daily with nicotine base (0.2 mg/kg; s.c.) or co-administered with PAM-2 (1.0 mg/kg; i.p.) for 3 weeks. Forced swim tests were performed to determine the acute (day 1), subchronic (day 7), and chronic (days 14 and 21) effects of the drugs, as well as their residual effects after treatment cessation (days 28 and 35). Our results indicate that nicotine mediates antidepressant-like activity after acute, subchronic, and chronic treatments in β4+/+, but not β4-/-, mice, and that these effects are not mediated by unspecific locomotor stimulation. Nicotine co-administered with PAM-2 produces antidepressant-like activity in both β4+/+ and β4-/- mice, except after the acute treatment of β4-/- mice, and decreases locomotor activity. This suggests that although the β4 subunit regulates the antidepressant-like activity of nicotine it does not affect the activity elicited by PAM-2 when is co-administered with nicotine. The residual antidepressant-like activity of PAM-2 + nicotine was observed only in female mice, suggesting gender-specific differences. Our findings clearly indicate that β4-containing nAChRs play an important role in the antidepressant-like activity elicited by nicotine but they are not essential for the modulatory activity of PAM-2. In fact, PAM-2 inhibits α4β4 and α3β4 AChRs at higher concentration ranges compared to that for the PAM activity previously found at the α7 AChR. PMID:26116439

  5. Predictive model of nicotine dependence based on mental health indicators and self-concept

    Directory of Open Access Journals (Sweden)

    Hamid Kazemi Zahrani

    2014-12-01

    Full Text Available Background: The purpose of this research was to investigate the predictive power of anxiety, depression, stress and self-concept dimensions (Mental ability, job efficiency, physical attractiveness, social skills, and deficiencies and merits as predictors of nicotine dependency among university students in Isfahan. Methods: In this correlational study, 110 male nicotine-dependent students at Isfahan University were selected by convenience sampling. All samples were assessed by Depression Anxiety Stress Scale (DASS, self-concept test and Nicotine Dependence Syndrome Scale. Data were analyzed by Pearson correlation and stepwise regression. Results: The result showed that anxiety had the highest strength to predict nicotine dependence. In addition, the self-concept and its dimensions predicted only 12% of the variance in nicotine dependence, which was not significant. Conclusion: Emotional processing variables involved in mental health play an important role in presenting a model to predict students’ dependence on nicotine more than identity variables such as different dimensions of self-concept.

  6. Effects of fatty acid amide hydrolase inhibition on neuronal responses to nicotine, cocaine and morphine in the nucleus accumbens shell and ventral tegmental area: involvement of PPAR-α nuclear receptors

    OpenAIRE

    Luchicchi, Antonio; Lecca, Salvatore; Carta, Stefano; Pillolla, Giuliano; Muntoni, Anna Lisa; Yasar, Sevil; Goldberg, Steven R.; Pistis, Marco

    2010-01-01

    The endocannabinoid system regulates neurotransmission in brain regions relevant to neurobiological and behavioral actions of addicting drugs. We recently demonstrated that inhibition by URB597 of fatty acid amide hydrolase (FAAH), the main enzyme which degrades the endogenous cannabinoid N-acylethanolamine (NAE) anandamide and the endogenous non-cannabinoid NAEs oleoylethanolamide and palmitoylethanolamide, blocks nicotine-induced excitation of ventral tegmental area (VTA) dopamine (DA) neur...

  7. Comparative In Vitro Toxicity Profile of Electronic and Tobacco Cigarettes, Smokeless Tobacco and Nicotine Replacement Therapy Products: E-Liquids, Extracts and Collected Aerosols

    Directory of Open Access Journals (Sweden)

    Manoj Misra

    2014-10-01

    Full Text Available The use of electronic cigarettes (e-cigs continues to increase worldwide in parallel with accumulating information on their potential toxicity and safety. In this study, an in vitro battery of established assays was used to examine the cytotoxicity, mutagenicity, genotoxicity and inflammatory responses of certain commercial e-cigs and compared to tobacco burning cigarettes, smokeless tobacco (SLT products and a nicotine replacement therapy (NRT product. The toxicity evaluation was performed on e-liquids and pad-collected aerosols of e-cigs, pad-collected smoke condensates of tobacco cigarettes and extracts of SLT and NRT products. In all assays, exposures with e-cig liquids and collected aerosols, at the doses tested, showed no significant activity when compared to tobacco burning cigarettes. Results for the e-cigs, with and without nicotine in two evaluated flavor variants, were very similar in all assays, indicating that the presence of nicotine and flavors, at the levels tested, did not induce any cytotoxic, genotoxic or inflammatory effects. The present findings indicate that neither the e-cig liquids and collected aerosols, nor the extracts of the SLT and NRT products produce any meaningful toxic effects in four widely-applied in vitro test systems, in which the conventional cigarette smoke preparations, at comparable exposures, are markedly cytotoxic and genotoxic.

  8. Intravenous Nicotine Self-Administration in Smokers: Dose-Response Function and Sex Differences.

    Science.gov (United States)

    Jensen, Kevin P; DeVito, Elise E; Valentine, Gerald; Gueorguieva, Ralitza; Sofuoglu, Mehmet

    2016-07-01

    Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration. PMID:26717881

  9. Nicotine Treatment Induces Expression of Matrix Metalloproteinases in Human Osteoblastic Saos-2 Cells

    Institute of Scientific and Technical Information of China (English)

    Tomoko KATONO; Takayuki KAWATO; Natsuko TANABE; Naoto SUZUKI; Kazuhiro YAMANAKA; Hitoshi OKA; Masafumi MOTOHASHI; Masao MAENO

    2006-01-01

    Tobacco smoking is an important risk factor for the development of severe periodontitis.Recently, we showed that nicotine affected mineralized nodule formation, and that nicotine and lipopolysaccharide stimulated the formation of osteoclast-like cells by increasing production of macrophage colony-stimulating factor (M-CSF) and prostaglandin E2 (PGE2) by human osteoblastic Saos-2 cells. In the present study, we examined the effects of nicotine on the expression of matrix metalloproteinases (MMPs),tissue inhibitors of matrix metalloproteinases (TIMPs), the plasminogen activation system including the component of tissue-type plasminogen activator (tPA), urokinase-type PA (uPA), and PA inhibitor type 1(PAI- 1), α7 nicotine receptor, and c-fos. We also examined the effect of the nicotine antagonist D-tubocurarine on nicotine-induced expression of MMP-1. Gene expression was examined using real-time polymerase chain reaction (PCR) to estimate mRNA levels. In addition, expression of the MMP, TIMP, uPA, tPA, and PAI-1proteins was determined by Western blotting analysis. Nicotine treatment caused expression of MMP-1, 2, 3,and 13, but not MMP-14, to increase significantly after 5 or 10 d of culture; MMP-14 expression did not change through day 14. Enhancement of MMP-1 expression by nicotine treatment was eliminated by simultaneous treatment with D-tubocurarine. In the presence of nicotine, expression of uPA, PAI-1, or TIMP-1, 2, 3, or 4 did not change over 14 d of culture, whereas expression of tPA increased significantly by day 7. Nicotine also increased expression of the α7 nicotine receptor and c-fos genes. These results suggest that nicotine stimulates bone matrix turnover by increasing production of tPA and MMP-1, 2, 3, and 13,thereby tipping the balance between bone matrix formation and resorption toward the latter process.

  10. Relationship between nicotine dependence and temperament and character traits in adults with cigarette smoking

    OpenAIRE

    Zincir, Selma Bozkurt; Zincir, Nihat; Sünbül, Esra Aydın; Kaymak, Esra

    2012-01-01

    Objective: Cigarette smoking is one of the most important health problems today. Nicotine dependence and difficulty to cessate smoking are assumed to be originating both from psychopharmacological effects of nicotine and genetic and environmental factors. The other possible factor which mediates to keep on smoking behavior may be personality traits. Aims: To find out the associations between temperament and character traits and nicotine dependence levels among the adult outpatients presen...

  11. Bupropion Differentially Alters the Aversive, Locomotor and Rewarding Properties of Nicotine in CD-1 Mice

    OpenAIRE

    Rauhut, Anthony S.; Hawrylak, Michael; Mardekian, Stacey K.

    2008-01-01

    The present experiments determined the effects of bupropion on the motivational (aversive and rewarding) and locomotor properties of nicotine in CD-1 mice. Preliminary experiments determined effective nicotine doses (0.1 – 2.0 mg/kg) to produce a conditioned taste aversion (CTA) or conditioned place preference (CPP; Experiments 1a and 2a, respectively). Mice were administered vehicle or bupropion (1 – 20 mg/kg) followed by vehicle or nicotine after drinking saccharin during CTA training (Expe...

  12. An investigation of bupropion substitution for the interoceptive stimulus effects of nicotine

    OpenAIRE

    Wilkinson, Jamie L.; Carroll, F. Ivy; Bevins, Rick A.

    2009-01-01

    Although the exact mechanism that makes bupropion hydrochloride (ZybanR) effective as a smoking cessation aid has not been fully elucidated, studies have found that bupropion and nicotine share behavioral and neurophysiological properties suggesting that bupropion might serve as a substitute for nicotine. In fact, bupropion prompts nicotine-appropriate responding in operant and Pavlovian drug discrimination studies with rats. A majority of the literature examining this substitution pattern ha...

  13. Nicotine Contents in Some Commonly Used Toothpastes and Toothpowders: A Present Scenario

    OpenAIRE

    S. S. Agrawal; Ray, R. S.

    2012-01-01

    The use of tobacco products as dentifrices is still prevalent in various parts of India. Tobacco use in dentifrices is a terrible scourge which motivates continued use despite its harmful effects. Indian legislation prohibits the use of nicotine in dentifrices. Nicotine is primarily injurious to people because it is responsible for tobacco addiction and is dependence forming. The present study was motivated by an interest in examining the presence of nicotine in these dentifrices. Our earlier...

  14. Expression of the α7 nicotinic acetylcholine receptor in human lung cells

    OpenAIRE

    Schuller Hildegard M; Dhar Madhu; Plummer Howard K

    2005-01-01

    Abstract Background We and others have shown that one of the mechanisms of growth regulation of small cell lung cancer cell lines and cultured pulmonary neuroendocrine cells is by the binding of agonists to the α7 neuronal nicotinic acetylcholine receptor. In addition, we have shown that the nicotine-derived carcinogenic nitrosamine, 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is a high affinity agonist for the α7 nicotinic acetylcholine receptor. In the present study, our goal was t...

  15. Developing a model of limited-access nicotine consumption in C57Bl/6J mice.

    Science.gov (United States)

    Kasten, C R; Frazee, A M; Boehm, S L

    2016-09-01

    Although United States smoking rates have been on the decline over the past few decades, cigarette smoking still poses a critical health and economic threat. Very few treatment options for smoking exist, and many of them do not lead to long-term abstinence. Preclinical models are necessary for understanding the effects of nicotine and developing treatments. Current self-administration models of nicotine intake may require surgical procedures and often result in low levels of intake. Further, they do not lend themselves to investigating treatments. The current study sought to develop a limited-access model of nicotine intake using the Drinking-in-the-Dark paradigm, which results in high levels of binge-like ethanol consumption that can be pharmacologically manipulated. The present study found that mice will consume nicotine under a range of parameters. Intakes under the preferred condition of 0.14mg/ml nicotine in 0.2% saccharin reached over 6mg/kg in two hours and were reduced by an injection of R(+)-baclofen. Mecamylamine did not significantly affect nicotine consumption. As nicotine and ethanol are often co-abused, nicotine intake was also tested in the presence of ethanol. When presented in the same bottle, mice altered nicotine intake under various concentrations to maintain consistent levels of ethanol intake. When nicotine and ethanol were presented in separate bottles, mice greatly reduced their nicotine intake while maintaining ethanol intake. In conclusion, these studies characterize a novel model of limited-access nicotine intake that can be pharmacologically manipulated. PMID:27242276

  16. Effects of Nicotine Exposure on In Vitro Metabolism of Chlorpyrifos in Male Sprague-Dawley Rats

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sookwang; Busby, Andrea L.; Timchalk, Charles; Poet, Torka S.

    2009-01-30

    Chlorpyrifos (CPF) is a common organophosphate (OP) insecticide which is metabolized by CYP450s to the neurotoxic metabolite, chlorpyrifos-oxon (CPF-oxon) and a non-toxic metabolite, 3,5,6-trichloro-2-pyridinol (TCP). The objective of this study was to quantify the effect of repeated in vivo nicotine exposures on CPF in vitro metabolism and marker substrate activities in rats. Male Sprague-Dawley rats were dosed subcutaneously with 1 mg nicotine/kg/, for up to 10 days. Animals showed signs of cholinergic crisis after the initial nicotine doses, but exhibited adaptation after a couple days of treatment. Rats were sacrificed on selected days 4 or 24 hr after the last nicotine-treatment. While CYP450 reduced CO spectra were not different across the treatments, the single nicotine dose group showed a 2-fold increase in CYP2E1 marker substrate (p-nitrophenol) activity 24 hr after a single nicotine treatment compared to saline controls. Conversely, repeated nicotine treatments resulted in decreased EROD marker substrate activity 4 hr after the 7th day of treatment. CPF-oxon Vmax and Km did not show significant changes across the different nicotine treatment groups. The Vmax describing the metabolism of CPF to TCP was increased on all groups (days 1, 7, and 10) 24 hr after nicotine treatment but were unchanged 4 hr after nicotine treatment. Results of this in vitro study suggest that repeated nicotine exposure (i.e., from smoking) may result in altered metabolism of CPF. Future in vivo experiments based on these results will be conducted to ascertain the impact of in vivo nicotine exposures on CPF metabolism in rats.

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

    OpenAIRE

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

    2008-01-01

    Neurochemical studies suggest that baclofen, an agonist at GABAB 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 3 mg/kg on nicotine-induced conditioned place preferences (CPP), nicotine discrimination, locomotor activity and food-reinforced behavior in male Sprague Dawley rats. The high dose of baclofen (3 mg/kg) ...

  18. Overexpression of ??3/??5/??4 nicotinic receptor subunits modifies impulsive-like behavior

    OpenAIRE

    Vi??als, Xavier; Molas Casacuberta, Susanna, 1985-; Gallego, Xavier; Fern??ndez Montes, Rub??n D.; Robledo, Patr??cia, 1958-; Dierssen, Mara; Maldonado, Rafael

    2012-01-01

    Recent studies have revealed that sequence variants in genes encoding the ??3/??5/??4 nicotinic acetylcholine receptor subunits are associated with nicotine dependence. In this study, we evaluated two specific aspects of executive functioning related to drug addiction (impulsivity and working memory) in transgenic mice over expressing ??3/??5/??4 nicotinic receptor subunits. Impulsivity and working memory were evaluated in an operant delayed alternation task, where mice must inhibit respondin...

  19. Role of Progesterone in Nicotine Addiction: Evidence From Initiation to Relapse

    OpenAIRE

    Lynch, Wendy J; Sofuoglu, Mehmet

    2010-01-01

    Nicotine addiction continues to be the main cause of preventable death in developed countries. Women and teen girls appear to be more vulnerable on certain aspects of nicotine addiction compared with men and boys. While the mechanism of gender differences in nicotine addiction is not yet clear, evidence suggests that while estrogen may underlie enhanced vulnerability in females, progesterone may protect females. Thus, progesterone may have therapeutic use for tobacco addiction, especially in ...

  20. Nicotinic Receptors in the Dorsal and Ventral Hippocampus Differentially Modulate Contextual Fear Conditioning

    OpenAIRE

    Kenney, Justin W.; Raybuck, Jonathan D.; Gould, Thomas J.

    2012-01-01

    Nicotine administration alters various forms of hippocampus-dependent learning and memory. Increasing work has found that the dorsal and ventral hippocampus differentially contribute to multiple behaviors. Thus, the present study examined whether the effects of nicotine in the dorsal and ventral hippocampus have distinct influences on contextual fear learning in male C57BL/6J mice. Direct infusion of nicotine into the dorsal hippocampus resulted in an enhancement of contextual fear learning, ...