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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.

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    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. Nicotine-induced alterations in the expression of nicotinic receptors in primary cultures from human prenatal brain.

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    Hellström-Lindahl, E; Seiger A; Kjaeldgaard, A; Nordberg, A

    2001-01-01

    The nicotinic receptor proteins and gene transcripts for the different nicotinic receptor subunits exist in human prenatal brain already at 4-5 weeks of gestation. The early presence of nicotinic receptors suggests an important role for these receptors in modulating dendritic outgrowth, establishment of neuronal connections and synaptogenesis during development. When measurements of nicotinic receptors using [(3)H]epibatidine (labelling both the alpha3 and alpha4 subtype) and [(3)H]cytisine (labelling the alpha4 subtype) were performed in intact cells from the cortex, subcortical forebrain and mesencephalon (7.5-11 weeks of gestation), the highest specific binding for both ligands was detected in cells from mesencephalon, followed by subcortical forebrain and cortex. The effects of nicotine exposure were studied in primary cultures of prenatal brain (7.5-11 weeks of gestation). Treatment with nicotine (1-100 microM) for 3 days significantly increased the specific binding of [(3)H]epibatidine and [(3)H]cytisine in cortical cells but not in cells from subcortical forebrain and mesencephalon brain regions, indicating region-specific differences in the sensitivity to nicotine exposure. Relative quantification of mRNA showed that the expression of the nicotinic receptor subunits alpha3 and alpha7, but not alpha4, was increased in cortical cells after nicotine treatment. These findings support the assumption of a potential risk of disturbance in the functional role of nicotinic receptors during brain development as a consequence of maternal smoking during pregnancy.

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

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    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.

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

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    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.

  5. Manganese accumulation in the brain: MR imaging

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    Uchino, A.; Nomiyama, K.; Takase, Y.; Nakazono, T.; Nojiri, J.; Kudo, S. [Saga Medical School, Department of Radiology, Saga (Japan); Noguchi, T. [Kyushu University, Department of Clinical Radiology, Graduate School of Medicine, Fukuoka (Japan)

    2007-09-15

    Manganese (Mn) accumulation in the brain is detected as symmetrical high signal intensity in the globus pallidi on T1-weighted MR images without an abnormal signal on T2-weighted images. In this review, we present several cases of Mn accumulation in the brain due to acquired or congenital diseases of the abdomen including hepatic cirrhosis with a portosystemic shunt, congenital biliary atresia, primary biliary cirrhosis, congenital intrahepatic portosystemic shunt without liver dysfunction, Rendu-Osler-Weber syndrome with a diffuse intrahepatic portosystemic shunt, and patent ductus venosus. Other causes of Mn accumulation in the brain are Mn overload from total parenteral nutrition and welding-related Mn intoxication. (orig.)

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

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

    2010-01-01

    The Nicotrol® (Pfizer, USA) nicotine inhaler reduces craving by mimicking the behavioural component of cigarettes and delivering controlled doses of nicotine, which binds to the beta-2 subunit-containing nicotinic acetylcholine receptors (β2*-nAChRs). Previous studies examined β2*-nAChR occupancy after administration of regular and low-nicotine cigarettes. Here, we measured occupancy of β2*-nAChRs after administration of nicotine via inhaler, and the relationship between occupancy and changes...

  7. In vivo PET imaging of brain nicotinic cholinergic receptors

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    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

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

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

    2009-01-01

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

  9. Brain Imaging of Nicotinic Receptors in Alzheimer's Disease

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    Jin Wu

    2010-01-01

    Full Text Available Neuronal nicotinic acetylcholine receptors (nAChRs are a family of ligand-gated ion channels which are widely distributed in the human brain. Several lines of evidence suggest that two major subtypes (α4β2 and α7 of nAChRs play an important role in the pathophysiology of Alzheimer's disease (AD. Postmortem studies demonstrated alterations in the density of these subtypes of nAChRs in the brain of patients with AD. Currently, nAChRs are one of the most attractive therapeutic targets for AD. Therefore, several researchers have made an effort to develop novel radioligands that can be used to study quantitatively the distribution of these two subtypes in the human brain with positron emission tomography (PET and single-photon emission computed tomography (SPECT. In this paper, we discuss the current topics on in vivo imaging of two subtypes of nAChRs in the brain of patients with AD.

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

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    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)

  11. Nicotine enhances but does not normalize visual sustained attention and the associated brain network in schizophrenia.

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    Hong, L Elliot; Schroeder, Matthew; Ross, Thomas J; Buchholz, Brittany; Salmeron, Betty Jo; Wonodi, Ikwunga; Thaker, Gunvant K; Stein, Elliot A

    2011-03-01

    Sustained attention abnormality in schizophrenia is usually refractory to available treatment. Nicotine can transiently improve sustained attention in schizophrenia patients, although its neural mechanisms are unknown. Understanding the neural basis of this effect may lead to new treatment strategies for this cognitive deficit. Twenty schizophrenia patients and 24 healthy comparison smokers participated in a double-blind, placebo-controlled, crossover, randomized functional magnetic resonance imaging study comparing nicotine vs placebo patch on sustained attention, using the rapid visual information-processing task. Schizophrenia patients had impaired visual sustained attention accuracy and processing speed (all P's attention network compared with healthy comparison subjects. Nicotine administration enhanced accuracy and processing speed compared with placebo (all P's ≤.006), with no drug × diagnosis interactions. However, schizophrenia patients' task performance remained impaired during the nicotine condition, even when compared with healthy comparison subjects in the placebo condition (all P's ≤.01). Nicotine exerted no significant reversal of the impaired attention network associated with schizophrenia. Activations in brain regions associated with nicotine-induced behavioral improvement were not significantly different between patients and comparison subjects. Thus, nicotine transiently enhanced sustained attention similarly in schizophrenia patients and in healthy comparison smokers. The neural mechanisms for this nicotinic effect in schizophrenia appear similar to those for healthy comparison subjects. However, nicotine, at least in a single sustained dose, does not normalize impaired sustained attention and its associated brain network in schizophrenia. These findings provide guidance for developing new treatment strategies for the sustained attention deficit in schizophrenia.

  12. Acetamiprid Accumulates in Different Amounts in Murine Brain Regions

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    Hayato Terayama

    2016-09-01

    Full Text Available Neonicotinoids such as acetamiprid (ACE belong to a new and widely used single class of pesticides. Neonicotinoids mimic the chemical structure of nicotine and share agonist activity with the nicotine acetylcholine receptor (nAchR. Neonicotinoids are widely considered to be safe in humans; however, they have recently been implicated in a number of human health disorders. A wide range of musculoskeletal and neuromuscular disorders associated with high doses of neonicotinoids administered to animals have also been reported. Consequently, we used a mouse model to investigate the response of the central nervous system to ACE treatment. Our results show that exposure to ACE-containing water for three or seven days (decuple and centuple of no observable adverse effect level (NOAEL/day caused a decrease in body weight in 10-week old A/JJmsSlc (A/J mice. However, the treatments did not affect brain histology or expression of CD34. ACE concentrations were significantly higher in the midbrain of ACE-treated mice than that of the normal and vehicle groups. Expression levels of α7, α4, and β2 nAChRs were found to be low in the olfactory bulb and midbrain of normal mice. Furthermore, in the experimental group (centuple ACE-containing water for seven days, β2 nAChR expression decreased in many brain regions. Information regarding the amount of accumulated ACE and expression levels of the acetylcholine receptor in each region of the brain is important for understanding any clinical symptoms that may be associated with ACE exposure.

  13. Acetamiprid Accumulates in Different Amounts in Murine Brain Regions

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    Terayama, Hayato; Endo, Hitoshi; Tsukamoto, Hideo; Matsumoto, Koichi; Umezu, Mai; Kanazawa, Teruhisa; Ito, Masatoshi; Sato, Tadayuki; Naito, Munekazu; Kawakami, Satoshi; Fujino, Yasuhiro; Tatemichi, Masayuki; Sakabe, Kou

    2016-01-01

    Neonicotinoids such as acetamiprid (ACE) belong to a new and widely used single class of pesticides. Neonicotinoids mimic the chemical structure of nicotine and share agonist activity with the nicotine acetylcholine receptor (nAchR). Neonicotinoids are widely considered to be safe in humans; however, they have recently been implicated in a number of human health disorders. A wide range of musculoskeletal and neuromuscular disorders associated with high doses of neonicotinoids administered to animals have also been reported. Consequently, we used a mouse model to investigate the response of the central nervous system to ACE treatment. Our results show that exposure to ACE-containing water for three or seven days (decuple and centuple of no observable adverse effect level (NOAEL)/day) caused a decrease in body weight in 10-week old A/JJmsSlc (A/J) mice. However, the treatments did not affect brain histology or expression of CD34. ACE concentrations were significantly higher in the midbrain of ACE-treated mice than that of the normal and vehicle groups. Expression levels of α7, α4, and β2 nAChRs were found to be low in the olfactory bulb and midbrain of normal mice. Furthermore, in the experimental group (centuple ACE-containing water for seven days), β2 nAChR expression decreased in many brain regions. Information regarding the amount of accumulated ACE and expression levels of the acetylcholine receptor in each region of the brain is important for understanding any clinical symptoms that may be associated with ACE exposure. PMID:27669271

  14. ( sup 3 H)cytisine binding to nicotinic cholinergic receptors in brain

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    Pabreza, L.A.; Dhawan, S.; Kellar, K.J. (Georgetown Univ. School of Medicine, Washington, DC (USA))

    1991-01-01

    Cytisine, a ganglionic agonist, competes with high affinity for brain nicotinic cholinergic receptors labeled by any of several nicotinic {sup 3}H-agonist ligands. Here we have examined the binding of ({sup 3}H)cytisine in rat brain homogenates. ({sup 3}H)Cytisine binds with high affinity (Kd less than 1 nM), and specific binding represented 60-90% of total binding at all concentrations examined up to 15 nM. The nicotinic cholinergic agonists nicotine, acetylcholine, and carbachol compete with high affinity for ({sup 3}H)cytisine binding sites, whereas among nicotinic receptor antagonists only dihydro-beta-erythroidine competes with high affinity (in the nanomolar range). Comparison of binding in several brain regions showed that ({sup 3}H)cytisine binding is higher in the thalamus, striatum, and cortex than in the hippocampus, cerebellum, or hypothalamus. The pharmacology and brain regional distribution of ({sup 3}H)cytisine binding sites are those predicted for neuronal nicotinic receptor agonist recognition sites. The high affinity and low nonspecific binding of ({sup 3}H)cytisine should make it a very useful ligand for studying neuronal nicotinic receptors.

  15. Pipecolic acid enhances resistance to bacterial infection and primes salicylic acid and nicotine accumulation in tobacco.

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    Vogel-Adghough, Drissia; Stahl, Elia; Návarová, Hana; Zeier, Juergen

    2013-11-01

    Distinct amino acid metabolic pathways constitute integral parts of the plant immune system. We have recently identified pipecolic acid (Pip), a lysine-derived non-protein amino acid, as a critical regulator of systemic acquired resistance (SAR) and basal immunity to bacterial infection in Arabidopsis thaliana. In Arabidopsis, Pip acts as an endogenous mediator of defense amplification and priming. For instance, Pip conditions plants for effective biosynthesis of the phenolic defense signal salicylic acid (SA), accumulation of the phytoalexin camalexin, and expression of defense-related genes. Here, we show that tobacco plants respond to leaf infection by the compatible bacterial pathogen Pseudomonas syringae pv tabaci (Pstb) with a significant accumulation of several amino acids, including Lys, branched-chain, aromatic, and amide group amino acids. Moreover, Pstb strongly triggers, alongside the biosynthesis of SA and increases in the defensive alkaloid nicotine, the production of the Lys catabolites Pip and α-aminoadipic acid. Exogenous application of Pip to tobacco plants provides significant protection to infection by adapted Pstb or by non-adapted, hypersensitive cell death-inducing P. syringae pv maculicola. Pip thereby primes tobacco for rapid and strong accumulation of SA and nicotine following bacterial infection. Thus, our study indicates that the role of Pip as an amplifier of immune responses is conserved between members of the rosid and asterid groups of eudicot plants and suggests a broad practical applicability for Pip as a natural enhancer of plant disease resistance.

  16. Neurodegeneration with Brain Iron Accumulation: An Overview

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    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

  17. Acute and chronic nicotine effects on behaviour and brain activation during intertemporal decision making.

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    Kobiella, Andrea; Ripke, Stephan; Kroemer, Nils B; Vollmert, Christian; Vollstädt-Klein, Sabine; Ulshöfer, Dorothea E; Smolka, Michael N

    2014-09-01

    Previous studies demonstrated higher discount rates for delayed rewards in smokers than non-smokers. We performed this study to determine whether those differences in intertemporal choice are due to pharmacological effects of nicotine and to track related brain regions. Thirty-three non-smokers and 27 nicotine-dependent smokers underwent functional magnetic resonance imaging while performing an intertemporal choice task consisting of 40 sets of monetary reward options that varied by delay to delivery. Smokers were investigated in a state of nicotine satiation. Non-smokers were investigated twice, receiving nicotine (2 mg) and placebo gums in a double-blinded, randomized cross-over design. Smokers displayed steeper temporal discounting than non-smokers. Those behavioural differences were reflected in the brain response during the decision between two alternative money/time pairs: smokers showed less activation in parietal and occipital areas (e.g. precuneus) than non-smokers under placebo. A single dose of nicotine in non-smokers led to a similar effect on brain activation but did not impact behaviour. Processing of the reward magnitude of money/time pairs differed between smokers and non-smokers: smokers showed decreased reactivity of the ventral striatum. Moreover, there was an acute nicotine effect in non-smokers on processing of the reward magnitude: nicotine increased the correlation of blood oxygen level-dependent response and mean amount in the left hippocampus, amygdala and anterior insula. We conclude that cross-sectional differences between smokers and non-smokers are only, in part, due to the acute pharmacological effects of nicotine. Longitudinal studies are needed to investigate pre-drug group characteristics as well as consequences of smoking on discounting behaviour and its neural correlates.

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

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    Biegon, Anat; Alia-Klein, Nelly; Fowler, Joanna S

    2012-01-01

    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 and many effects of nicotine are sexually dimorphic (reviewed by Pogun and Yararbas, 2009). 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.

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

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    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

  20. Structural and functional diversity of native brain neuronal nicotinic receptors.

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    Gotti, Cecilia; Clementi, Francesco; Fornari, Alice; Gaimarri, Annalisa; Guiducci, Stefania; Manfredi, Irene; Moretti, Milena; Pedrazzi, Patrizia; Pucci, Luca; Zoli, Michele

    2009-10-01

    Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gated ion channels present in the central and peripheral nervous systems, that are permeable to mono- and divalent cations. They share a common basic structure but their pharmacological and functional properties arise from the wide range of different subunit combinations making up distinctive subtypes. nAChRs are involved in many physiological functions in the central and peripheral nervous systems, and are the targets of the widely used drug of abuse nicotine. In addition to tobacco dependence, changes in their number and/or function are associated with neuropsychiatric disorders, ranging from epilepsy to dementia. Although some of the neural circuits involved in the acute and chronic effects of nicotine have been identified, much less is known about which native nAChR subtypes are involved in specific physiological functions and pathophysiological conditions. We briefly review some recent findings concerning the structure and function of native nAChRs, focusing on the subtypes identified in the mesostriatal and habenulo-interpeduncular pathways, two systems involved in nicotine reinforcement and withdrawal. We also discuss recent findings concerning the effect of chronic nicotine on the expression of native subtypes.

  1. Inhibition of miRNA-210 reverses nicotine-induced brain hypoxic-ischemic injury in neonatal rats

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    Wang, Lei; Ke, Jun; Li, Yong; Ma, Qinyi; Dasgupta, Chiranjib; Huang, Xiaohui; Zhang, Lubo; Xiao, DaLiao

    2017-01-01

    Maternal tobacco use in pregnancy increases the risk of neurodevelopmental disorders and neurobehavioral deficits in postnatal life. The present study tested the hypothesis that perinatal nicotine exposure exacerbated brain vulnerability to hypoxic-ischemic (HI) injury in neonatal rats through up-regulation of miR-210 expression in the developing brain. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps. Experiments of HI brain injury were performed in 10-day-old pups. Perinatal nicotine treatment significantly decreased neonatal body and brain weights, but increased the brain to body weight ratio. Perinatal nicotine exposure caused a significant increase in HI brain infarct size in the neonates. In addition, nicotine enhanced miR-210 expression and significantly attenuated brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase isoform B (TrkB) protein abundance in the brain. Of importance, intracerebroventricular administration of a miR-210 inhibitor (miR-210-LNA) significantly decreased HI-induced brain infarct size and reversed the nicotine-increased vulnerability to brain HI injury in the neonate. Furthermore, miR-210-LNA treatment also reversed nicotine-mediated down-regulation of BDNF and TrkB protein expression in the neonatal brains. These findings provide novel evidence that the increased miR-210 plays a causal role in perinatal nicotine-induced developmental programming of ischemic sensitive phenotype in the brain. It represents a potential novel therapeutic approach for treatment of brain hypoxic-ischemic encephalopathy in the neonate-induced by fetal stress. PMID:28123348

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

    Directory of Open Access Journals (Sweden)

    Anat eBiegon

    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.

  3. Nicotine and neurodegeneration in ageing.

    Science.gov (United States)

    Zanardi, Alessio; Leo, Giuseppina; Biagini, Giuseppe; Zoli, Michele

    2002-02-28

    Impairment in cholinergic systems is a highly consistent finding in human dementia. Among cholinergic markers, marked decreases in nicotine binding have been most consistently observed in the telencephalic regions of demented patients and are thought to contribute to the cognitive deficits associated with ageing and age-related neurodegenerative diseases. New evidence that the cholinergic system has a specific pathogenic role in the neurodegenerative alterations of aged and, especially, demented patients is fast accumulating. Both in vivo and in culture, nicotine protects striatal, hippocampal and cortical neurons against the neurotoxicity induced by excitotoxic amino acids as well as the toxicity caused by beta-amyloid, the major component of senile plaques. Further support for the implication of nicotinic receptors in brain ageing is come from recent studies on transgenic animals lacking nicotinic receptor subtypes, which shed light on the mechanisms of nicotine neuroprotection and neurotoxicity.

  4. Nicotine Increases Codeine Analgesia Through the Induction of Brain CYP2D and Central Activation of Codeine to Morphine.

    Science.gov (United States)

    McMillan, Douglas M; Tyndale, Rachel F

    2015-06-01

    CYP2D metabolically activates codeine to morphine, which is required for codeine analgesia. Permeability across the blood-brain barrier, and active efflux, suggests that initial morphine in the brain after codeine is due to brain CYP2D metabolism. Human CYP2D is higher in the brains, but not in the livers, of smokers and 7-day nicotine treatment induces rat brain, but not hepatic, CYP2D. The role of nicotine-induced rat brain CYP2D in the central metabolic activation of peripherally administered codeine and resulting analgesia was investigated. Rats received 7-day nicotine (1 mg/kg subcutaneously) and/or a single propranolol (CYP2D mechanism-based inhibitor; 20 μg intracerebroventricularly) pretreatment, and then were tested for analgesia and drug levels following codeine (20 mg/kg intraperitoneally) or morphine (3.5 mg/kg intraperitoneally), matched for peak analgesia. Nicotine increased codeine analgesia (1.59X AUC(0-30 min) vs vehicle; p0.1). Nicotine increased, while propranolol decreased, brain, but not plasma, morphine levels, and analgesia correlated with brain (p0.4), morphine levels after codeine. Pretreatments did not alter baseline or morphine analgesia. Here we show that brain CYP2D alters drug response despite the presence of substantial first-pass metabolism of codeine and further that nicotine induction of brain CYP2D increases codeine response in vivo. Thus variation in brain CYP2D activity, due to genetics or environment, may contribute to individual differences in response to centrally acting substrates. Exposure to nicotine may increase central drug metabolism, not detected peripherally, contributing to altered drug efficacy, onset time, and/or abuse liability.

  5. The gut-brain axis rewired: adding a functional vagal nicotinic "sensory synapse".

    Science.gov (United States)

    Perez-Burgos, Azucena; Mao, Yu-Kang; Bienenstock, John; Kunze, Wolfgang A

    2014-07-01

    It is generally accepted that intestinal sensory vagal fibers are primary afferent, responding nonsynaptically to luminal stimuli. The gut also contains intrinsic primary afferent neurons (IPANs) that respond to luminal stimuli. A psychoactive Lactobacillus rhamnosus (JB-1) that affects brain function excites both vagal fibers and IPANs. We wondered whether, contrary to its primary afferent designation, the sensory vagus response to JB-1 might depend on IPAN to vagal fiber synaptic transmission. We recorded ex vivo single- and multiunit afferent action potentials from mesenteric nerves supplying mouse jejunal segments. Intramural synaptic blockade with Ca(2+) channel blockers reduced constitutive or JB-1-evoked vagal sensory discharge. Firing of 60% of spontaneously active units was reduced by synaptic blockade. Synaptic or nicotinic receptor blockade reduced firing in 60% of vagal sensory units that were stimulated by luminal JB-1. In control experiments, increasing or decreasing IPAN excitability, respectively increased or decreased nerve firing that was abolished by synaptic blockade or vagotomy. We conclude that >50% of vagal afferents function as interneurons for stimulation by JB-1, receiving input from an intramural functional "sensory synapse." This was supported by myenteric plexus nicotinic receptor immunohistochemistry. These data offer a novel therapeutic target to modify pathological gut-brain axis activity.-Perez-Burgos, A., Mao, Y.-K., Bienenstock, J., Kunze, W. A. The gut-brain axis rewired: adding a functional vagal nicotinic "sensory synapse."

  6. 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.

  7. The effect of alcohol and nicotine abuse on gene expression in the brain.

    Science.gov (United States)

    Flatscher-Bader, Traute; Wilce, Peter A

    2009-12-01

    Alcohol intake at levels posing an acute heath risk is common amongst teenagers. Alcohol abuse is the second most common mental disorder worldwide. The incidence of smoking is decreasing in the Western world but increasing in developing countries and is the leading cause of preventable death worldwide. Considering the longstanding history of alcohol and tobacco consumption in human societies, it might be surprising that the molecular mechanisms underlying alcohol and smoking dependence are still incompletely understood. Effective treatments against the risk of relapse are lacking. Drugs of abuse exert their effect manipulating the dopaminergic mesocorticolimbic system. In this brain region, alcohol has many potential targets including membranes and several ion channels, while other drugs, for example nicotine, act via specific receptors or binding proteins. Repeated consumption of drugs of abuse mediates adaptive changes within this region, resulting in addiction. The high incidence of alcohol and nicotine co-abuse complicates analysis of the molecular basis of the disease. Gene expression profiling is a useful approach to explore novel drug targets in the brain. Several groups have utilised this technology to reveal drug-sensitive pathways in the mesocorticolimbic system of animal models and in human subjects. These studies are the focus of the present review.

  8. A D-peptide ligand of nicotine acetylcholine receptors for brain-targeted drug delivery.

    Science.gov (United States)

    Wei, Xiaoli; Zhan, Changyou; Shen, Qing; Fu, Wei; Xie, Cao; Gao, Jie; Peng, Chunmei; Zheng, Ping; Lu, Weiyue

    2015-03-01

    Lysosomes of brain capillary endothelial cells are implicated in nicotine acetylcholine receptor (nAChR)-mediated transcytosis and act as an enzymatic barrier for the transport of peptide ligands to the brain. A D-peptide ligand of nAChRs (termed (D)CDX), which binds to nAChRs with an IC50 value of 84.5 nM, was developed by retro-inverso isomerization. (D)CDX displayed exceptional stability in lysosomal homogenate and serum, and demonstrated significantly higher transcytosis efficiency in an in vitro blood-brain barrier monolayer compared with the parent L-peptide. When modified on liposomal surface, (D)CDX facilitated significant brain-targeted delivery of liposomes. As a result, brain-targeted delivery of (D)CDX modified liposomes enhanced therapeutic efficiency of encapsulated doxorubicin for glioblastoma. This study illustrates the importance of ligand stability in nAChRs-mediated transcytosis, and paves the way for developing stable brain-targeted entities.

  9. 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...

  10. Solid-phase extraction and HPLC assay of nicotine and cotinine in plasma and brain.

    Science.gov (United States)

    Dawson, Ralph; Messina, S M; Stokes, C; Salyani, S; Alcalay, N; De Fiebre, N C; De Fiebre, C M

    2002-01-01

    The aim of this study was to develop a simple and reliable assay for nicotine (NIC) and its major metabolite, cotinine (COT), in plasma and brain. A method was developed that uses an extraction method compatible with reverse-phase high-performance liquid chromatography (HPLC) separation and ultraviolet (UV) detection. Sequential solid-phase extraction on silica columns followed by extraction using octadecyl (C18) columns resulted in mean percent recovery (n = 5) of 51 +/- 5, 64 +/- 10, and 52 +/- 10% for NIC, COT, and phenylimidazole (PI), respectively, in spiked 1-mL serum samples. Recovery (mean +/- SEM) of the internal standard (PI) from spiked samples of nicotine-injected rats averaged 64.1 +/- 1.5% (n = 138) from plasma, and 20.7+/-0.8% (n = 128) from brain. The limits of detection of NIC in plasma samples were approximately 8 ng per mL, and of COT, 13.6 ng per mL. Further optimization of our extraction method, using slower flow rates and solid-phase extraction on silica columns, followed by C18 column extraction, yielded somewhat better recoveries (38 +/-3%) for 1-mL brain homogenates. Interassay precision (coefficient of variation) was determined on the basis of daily calibrations for 2 months and was found to be 7%, 9%, and 9% for NIC, COT, and PI, respectively, whereas intra-assay variability was 3.9% for both NIC and COT. Limited studies were performed on analytical columns for comparison of retention, resolution, asymmetry, and column capacity. We concluded that a simple two-step solid-phase extraction method, coupled with HPLC separation and UV detection, can be used routinely to measure NIC and COT in biological fluids and tissues.

  11. Regulation of cerebral CYP2D alters tramadol metabolism in the brain: interactions of tramadol with propranolol and nicotine.

    Science.gov (United States)

    Wang, Qiaoli; Han, Xiaotong; Li, Jian; Gao, Xinghui; Wang, Yan; Liu, Mingzhou; Dong, Guicheng; Yue, Jiang

    2015-04-01

    1. Cytochrome P450 2D (CYP2D) protein is widely expressed across brain regions in human and rodents. We investigated the interactions between tramadol, a clinically used analgesic, and brain CYP2D regulators, by establishing concentration-time curves of tramadol and O-desmethyltramadol (M1) in rat cerebrospinal fluid (CSF) and plasma, as well as by analyzing the analgesia-time course of tramadol. 2. Propranolol (20 μg, intracerebroventricular injection), CYP2D inhibitor, prolonged the elimination t1/2 of tramadol (40 mg/kg, intraperitoneal injection) in the CSF; meanwhile, lower Cmax and AUC0-∞ values of M1 were observed. Nicotine (1 mg base/kg, subcutaneous injection, seven days), brain CYP2D inducer, induced a shorter Tmax and elevated Cmax of M1 in CSF. No differences in the peripheral metabolism of tramadol were observed following propranolol and nicotine pretreatment. Nicotine increased areas under the analgesia-time curve (AUC) for 0-45 min and 0-90 min of tramadol, which was attenuated by propranolol administration. The analgesic actions of tramadol positively correlated with cerebral M1 concentration. 3. The results suggest that the regulation of brain CYP2D by xenobiotics may cause drug-drug interactions (DDIs) of tramadol. Brain CYPs may play an important role in DDIs of centrally active substances.

  12. 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.

  13. Dystonia in neurodegeneration with brain iron accumulation : outcome of bilateral pallidal stimulation

    NARCIS (Netherlands)

    Timmermann, L.; Pauls, K. A. M.; Wieland, K.; Jech, R.; Kurlemann, G.; Sharma, N.; Gill, S. S.; Haenggeli, C. A.; Hayflick, S. J.; Hogarth, P.; Leenders, K. L.; Limousin, P.; Malanga, C. J.; Moro, E.; Ostrem, J. L.; Revilla, F. J.; Santens, P.; Schnitzler, A.; Tisch, S.; Valldeoriola, F.; Vesper, J.; Volkmann, J.; Woitalla, D.; Peker, S.

    2010-01-01

    Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty

  14. 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

  15. Evaluation of radioiodinated 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine as a ligand for SPECT investigations of brain nicotinic acetylcholine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Saji, Hideo; Ogawa, Mikako; Ueda, Masashi [Kyoto Univ. (Japan). Graduate School of Pharmaceutical Sciences] [and others

    2002-05-01

    5-Iodo-3-(2(S)-azetidinylmethoxy)pyridine (5IA), an A-85380 analog iodinated at the 5-position of the pyridine ring, was evaluated as a radiopharmaceutical for investigating brain nicotinic acethylcholine receptors (nAChRs) by single photon emission computed tomography (SPECT). [{sup 123/125}I]5IA was synthesized by the iododestannylation reaction under no-carrier-added conditions and purified by high-performance liquid chromatography (HPLC) with high radiochemical yield (50%), high radiochemical purity (>98%), and high specific radioactivity (>55 GBq/{mu}mol). The binding affinity of 5IA for brain nAChRs was measured in terms of displacement of [{sup 3}H]cytisine and [{sup 125}I]5IA from binding sites in rat cortical membranes. The binding data revealed that the affinity of 5IA was the same as that of A-85380 and more than seven fold higher than that of (-)-nicotine, and that 5IA bound selectively to the {alpha}4{beta}2 nAChR subtype. Biodistribution studies in rats indicated that the brain uptake of [{sup 125}I]5IA was rapid and profound. Regional cerebral distribution studies in rats demonstrated that the accumulation of [{sup 125}I]5IA was consistent with the density of high affinity nAChRs with highest uptake observed in the nAChR-rich thalamus, moderate uptake in the cortex and lowest uptake in the cerebellum. Administration of the nAChR agonists and (-)-cytisine (-)-nicotine reduced the uptake of [{sup 125}I]5IA in all regions studied with most pronounced reduction in the thalamus, and resulted in similar levels of radioactivity throughout the brain. [{sup 125}I]5IA binding sites were shown to be saturable with unlabeled 5IA. Behavioral studies in mice demonstrated that 5IA did not show signs of behavioral toxicity. Furthermore, SPECT studies with [{sup 123}I]5IA in the common marmoset demonstrated appropriate brain uptake and regional localization for a high-affinity nAChR imaging radiopharmaceutical. These results suggested that [{sup 123}I]5IA is a

  16. Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms.

    Directory of Open Access Journals (Sweden)

    Sonia eLevi

    2014-05-01

    Full Text Available Perturbation of iron distribution is observed in many neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease, but the comprehension of the metal role in the development and progression of such disorders is still very limited. The combination of more powerful brain imaging techniques and faster genomic DNA sequencing procedures has allowed the description of a set of genetic disorders characterized by a constant and often early accumulation of iron in specific brain regions and the identification of the associated genes; these disorders are now collectively included in the category of Neurodegeneration with Brain Iron Accumulation (NBIA. So far 10 different genetic forms have been described but this number is likely to increase in short time. Two forms are linked to mutations in genes directly involved in iron metabolism: Neuroferritinopathy, associated to mutations in the FTL gene and Aceruloplasminaemia, where the ceruloplasmin gene product is defective. In the other forms the connection with iron metabolism is not evident at all and the genetic data let infer the involvement of other pathways: Pank2, COASY,Pla2G6, C19orf12, and FA2H genes seem to be related to lipid metabolism and to mitochondria functioning, WDR45 and ATP13A2 genes are implicated in lysosomal and autophagosome activity, while the C2orf37 gene encodes a nucleolar protein of unknown function. There is much hope in the scientific community that the study of the NBIA forms may provide important insight as to the link between brain iron metabolism and neurodegenerative mechanisms and eventually pave the way for new therapeutic avenues also for the more common neurodegenerative disorders. In this work we will review the most recent findings in the molecular mechanisms underlining the most common forms of NBIA and analyze their possible link with brain iron metabolism.

  17. α2-Null mutant mice have altered levels of neuronal activity in restricted midbrain and limbic brain regions during nicotine withdrawal as demonstrated by cfos expression.

    Science.gov (United States)

    Upton, Montana; Lotfipour, Shahrdad

    2015-10-15

    Neuronal nicotinic acetylcholine receptors (nAChRs) are the primary binding sites for nicotine within the brain. Using alpha(α)2 nAChR subunit-null mutant mice, the current study evaluates whether the absence of this gene product during mecamylamine-precipitated nicotine withdrawal eliminates neuronal activity within selective midbrain and limbic brain regions, as determined by the expression of the immediate early gene, cfos. Our results demonstrate that nicotine withdrawal enhances neuronal activity within the interpeduncular nucleus and dorsal hippocampus, which is absent in mice null for α2-containing nAChRs. In contrast, we observe that α2-null mutant mice exhibit a suppression of neuronal activity in the dentate gyrus in mice undergoing nicotine withdrawal. Interestingly, α2-null mutant mice display potentiated neuronal activity specifically within the stratum lacunosum moleculare layer of the hippocampus, independent of nicotine withdrawal. Overall, our findings demonstrate that α2-null mutant mice have altered cfos expression in distinct populations of neurons within selective midbrain and limbic brain structures that mediate baseline and nicotine withdrawal-induced neuronal activity.

  18. 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

  19. Transcranial sonography in brain disorders with trace metal accumulation.

    Science.gov (United States)

    Walter, Uwe

    2010-01-01

    Transcranial sonography (TCS) can detect trace metal accumulation in deep brain structures with higher sensitivity than conventional MRI. Especially, increased iron content in the substantia nigra in Parkinson's disease, increased copper content in the lenticular nucleus (LN) in Wilson's disease and idiopathic dystonia, and increased manganese content in the LN in manganese-induced Parkinsonism were detected with TCS, even in subjects with normal MRI. TCS, therefore, might be useful to detect an increased risk of developing neurological symptoms in relatives of patients with Parkinson's or Wilson's disease. The exact mechanism of how an elevated trace metal content leads to an increased echogenicity needs to be further elucidated.

  20. Modulation of Tyrosine Hydroxylase, Neuropeptide Y, Glutamate, and Substance P in Ganglia and Brain Areas Involved in Cardiovascular Control after Chronic Exposure to Nicotine

    Directory of Open Access Journals (Sweden)

    Merari F. R. Ferrari

    2011-01-01

    Full Text Available Considering that nicotine instantly interacts with central and peripheral nervous systems promoting cardiovascular effects after tobacco smoking, we evaluated the modulation of glutamate, tyrosine hydroxylase (TH, neuropeptide Y (NPY, and substance P (SP in nodose/petrosal and superior cervical ganglia, as well as TH and NPY in nucleus tractus solitarii (NTS and hypothalamic paraventricular nucleus (PVN of normotensive Wistar Kyoto (WKY and spontaneously hypertensive rats (SHR after 8 weeks of nicotine exposure. Immunohistochemical and in situ hybridization data demonstrated increased expression of TH in brain and ganglia related to blood pressure control, preferentially in SHR, after nicotine exposure. The alkaloid also increased NPY immunoreactivity in ganglia, NTS, and PVN of SHR, in spite of decreasing its receptor (NPY1R binding in NTS of both strains. Nicotine increased SP and glutamate in ganglia. In summary, nicotine positively modulated the studied variables in ganglia while its central effects were mainly constrained to SHR.

  1. 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.

  2. 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.

  3. Chronic exposure to nicotine and saquinavir decreases endothelial Notch-4 expression and disrupts blood-brain barrier integrity.

    Science.gov (United States)

    Manda, Vamshi K; Mittapalli, Rajendar K; Geldenhuys, Werner J; Lockman, Paul R

    2010-10-01

    Since the advent of HAART, there have been substantial improvements in HIV patient survival; however, the prevalence of HIV associated dementia has increased. Importantly, HIV positive individuals who smoke progress to HIV associated neurological conditions faster than those who do not. Recent in vitro data have shown that pharmacological levels of saquinavir causes endothelial oxidative stress and significantly decreases Notch-4 expression, a primary protein involved in maintaining stability of blood-brain barrier (BBB) endothelium. This is concerning as nicotine can also generate reactive oxygen species in endothelium. It is largely unknown if pharmacological doses of these drugs can cause a similar in vivo down-regulation of Notch-4 and if there is a concurrent destabilization of the integrity of the BBB. The data herein show: (i) nicotine and protease inhibitors cause an additive oxidative stress burden in endothelium; (ii) that the integrity of the BBB is disrupted after concurrent chronic nicotine and protease inhibitor administration; and (iii) that BBB endothelial dysfunction is correlated with a decrease in Notch-4 and ZO-1 expression. Considering the high prevalence of smoking in the HIV infected population (3- to 4-fold higher than in the general population) this data must be followed up to determine if all protease inhibitors cause a similar BBB disruption or if there is a safer alternative. In addition, this data may suggest that the induced BBB disruption may allow foreign molecules to gain access to brain and be a contributing factor to the slow progression of HIV associated dementia.

  4. Nicotine Dependence

    Science.gov (United States)

    Nicotine dependence Overview By Mayo Clinic Staff Nicotine dependence ― also called tobacco dependence ― is an addiction to tobacco products caused by the drug nicotine. Nicotine dependence means you can't stop using the substance, ...

  5. 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

  6. Postsynaptic action of brain-derived neurotrophic factor attenuates alpha7 nicotinic acetylcholine receptor-mediated responses in hippocampal interneurons.

    Science.gov (United States)

    Fernandes, Catarina C; Pinto-Duarte, António; Ribeiro, Joaquim Alexandre; Sebastião, Ana M

    2008-05-21

    Nicotinic mechanisms acting on the hippocampus influence attention, learning, and memory and constitute a significant therapeutic target for many neurodegenerative, neurological, and psychiatric disorders. Here, we report that brain-derived neurotrophic factor (BDNF) (1-100 ng/ml), a member of the neurotrophin gene family, rapidly decreases alpha7 nicotinic acetylcholine receptor responses in interneurons of the hippocampal CA1 stratum radiatum. Such effect is dependent on the activation of the TrkB receptor and involves the actin cytoskeleton; noteworthy, it is compromised when the extracellular levels of the endogenous neuromodulator adenosine are reduced with adenosine deaminase (1 U/ml) or when adenosine A(2A) receptors are blocked with SCH 58261 (2-(2-furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine) (100 nm). The intracellular application of U73122 (1-[6[[(17beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione) (5 mum), a broad-spectrum inhibitor of phospholipase C, or GF 109203X (bisindolylmaleimide I) (2 mum), a general inhibitor of protein kinase C isoforms, blocks BDNF-induced inhibition of alpha7 nicotinic acetylcholine receptor function. Moreover, in conditions of simultaneous intracellular dialysis of the fast Ca(2+) chelator BAPTA (10 mm) and removal of extracellular Ca(2+) ions, the inhibitory action of BDNF is further prevented. The present findings disclose a novel target for rapid actions of BDNF that might play important roles on synaptic transmission and plasticity in the brain.

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

    Science.gov (United States)

    Orellana, Juan A; Busso, Dolores; Ramírez, Gigliola; Campos, Marlys; Rigotti, Attilio; Eugenín, Jaime; von Bernhardi, Rommy

    2014-01-01

    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 (HCs) 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 connexin 43 (Cx43) and pannexin 1 (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 HCs in astrocytes, and Panx1 channels in microglia and neurons only if offspring mice were fed with HFC diet. Blockade of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2) and prostaglandin E receptor 1 (EP1), ionotropic ATP receptor type 7 (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 adenosine triphosphate (ATP) and glutamate release from hippocampal slices of prenatally nicotine-exposed offspring. We propose that unregulated gliotransmitter

  8. Oxidative and pro-inflammatory impact of regular and denicotinized cigarettes on blood brain barrier endothelial cells: is smoking reduced or nicotine-free products really safe?

    Science.gov (United States)

    2014-01-01

    Background Both active and passive tobacco smoke (TS) potentially impair the vascular endothelial function in a causative and dose-dependent manner, largely related to the content of reactive oxygen species (ROS), nicotine, and pro-inflammatory activity. Together these factors can compromise the restrictive properties of the blood–brain barrier (BBB) and trigger the pathogenesis/progression of several neurological disorders including silent cerebral infarction, stroke, multiple sclerosis and Alzheimer’s disease. Based on these premises, we analyzed and assessed the toxic impact of smoke extract from a range of tobacco products (with varying levels of nicotine) on brain microvascular endothelial cell line (hCMEC/D3), a well characterized human BBB model. Results Initial profiling of TS showed a significant release of reactive oxygen (ROS) and reactive nitrogen species (RNS) in full flavor, nicotine-free (NF, “reduced-exposure” brand) and ultralow nicotine products. This release correlated with increased oxidative cell damage. In parallel, membrane expression of endothelial tight junction proteins ZO-1 and occludin were significantly down-regulated suggesting the impairment of barrier function. Expression of VE-cadherin and claudin-5 were also increased by the ultralow or nicotine free tobacco smoke extract. TS extract from these cigarettes also induced an inflammatory response in BBB ECs as demonstrated by increased IL-6 and MMP-2 levels and up-regulation of vascular adhesion molecules, such as VCAM-1 and PECAM-1. Conclusions In summary, our results indicate that NF and ultralow nicotine cigarettes are potentially more harmful to the BBB endothelium than regular tobacco products. In addition, this study demonstrates that the TS-induced toxicity at BBB ECs is strongly correlated to the TAR and NO levels in the cigarettes rather than the nicotine content. PMID:24755281

  9. 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.

  10. Brain-derived neurotrophic factor (BDNF) and TrkB in the piglet brainstem after post-natal nicotine and intermittent hypercapnic hypoxia.

    Science.gov (United States)

    Tang, Samantha; Machaalani, Rita; Waters, Karen A

    2008-09-26

    Brain-derived neurotrophic factor (BDNF) and its receptor TrkB play a significant role in the regulation of cell growth, survival and death during central nervous system development. The expression of BDNF and TrkB is affected by noxious insults. Two insults during the early post-natal period that are of interest to our laboratory are exposure to nicotine and to intermittent hypercapnic hypoxia (IHH). Piglet models were used to mimic the conditions associated with the risk factors for the sudden infant death syndrome (SIDS) including post-natal cigarette smoke exposure (nicotine model) and prone sleeping where the infant is subjected to re-breathing of expired gases (IHH model). We aimed to determine the effects of nicotine and IHH, alone or in combination, on pro- and rhBDNF and TrkB expression in the developing piglet brainstem. Four piglet groups were studied, with equal gender ratios in each: control (n=14), nicotine (n=14), IHH (n=10) and nic+IHH (n=14). Applying immunohistochemistry, and studying six nuclei of the caudal medulla, we found that compared to controls, TrkB was the only protein significantly decreased after nicotine and nic+IHH exposure regardless of gender. For pro-BDNF and rhBDNF however, observed changes were more evident in males than females exposed to nicotine and nic+IHH. The implications of these findings are that a prior nicotine exposure makes the developing brainstem susceptible to greater changes in the neurotrophic effects of BDNF and its receptor TrkB in the face of a hypoxic insult, and that the effects are greater in males than females.

  11. The exposure to nicotine affects expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in neonate rats.

    Science.gov (United States)

    Xiaoyu, Wang

    2015-02-01

    In the current study effect of nicotine on expression of neurotrophins, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) has been studied in hippocampus and frontal cortex during development of brain in rats. Neurotrophins are factors that help in development of brain among which BDNF and NGF are very important, expressed at different stages during the developmental process. Different sedatives are reported to alter the expression of these factors. In this study, three groups of neonate rats (1-5, 5-10 and 10-15 days age) were used each having 20 rats. Ten were subjected to a dose of 66 μg of nicotine while other ten received the same amount of saline at the same time interval. Then expression of the BDNF and NGF was observed in hippocampus and frontal cortex tissue using immunoassay. Western blotting was used to observe the presence of BDNF in hippocampus as well as frontal cortex. In all groups there was a significant decrease in concentration of neurotrophic factors where nicotine was applied as compared to control. The highest expression of BDNF and NGF in hippocampus and frontal cortex was observed in 10-15 days group (G3) and in 5-10 group (G2) as compared to the control, P BDNF and it effects the development of brain in neonates that can further impair brain functions.

  12. Effect of the Nicotinic α4β2-receptor Partial Agonist Varenicline on Non-invasive Brain Stimulation-Induced Neuroplasticity in the Human Motor Cortex.

    Science.gov (United States)

    Batsikadze, Giorgi; Paulus, Walter; Grundey, Jessica; Kuo, Min-Fang; Nitsche, Michael A

    2015-09-01

    Nicotine alters cognitive functions in animals and humans most likely by modification of brain plasticity. In the human brain, it alters plasticity induced by transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS), probably by interference with calcium-dependent modulation of the glutamatergic system. We aimed to test this hypothesis further by exploring the impact of the α4β2-nicotinic receptor partial agonist varenicline on focal and non-focal plasticity, induced by PAS and tDCS, respectively. We administered low (0.1 mg), medium (0.3 mg), and high (1.0 mg) single doses of varenicline or placebo medication before PAS or tDCS on the left motor cortex of 25 healthy non-smokers. Corticospinal excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor evoked potential amplitudes up to 36 h after plasticity induction. Whereas low-dose varenicline had no impact on stimulation-induced neuroplasticity, medium-dose abolished tDCS-induced facilitatory after-effects, favoring focal excitatory plasticity. High-dose application preserved cathodal tDCS-induced excitability diminution and focal excitatory PAS-induced facilitatory plasticity. These results are comparable to the impact of nicotine receptor activation and might help to further explain the involvement of specific receptor subtypes in the nicotinic impact on neuroplasticity and cognitive functions in healthy subjects and patients with neuropsychiatric diseases.

  13. Nanoparticle accumulation and transcytosis in brain endothelial cell layers

    NARCIS (Netherlands)

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

    2013-01-01

    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 juncti

  14. Localization of [3H]nicotine, [3H]cytisine, [3H]epibatidine, and [125I]alpha-bungarotoxin binding sites in the brain of Macaca mulatta.

    Science.gov (United States)

    Han, Zhi-Yan; Zoli, Michele; Cardona, Ana; Bourgeois, Jean-Pierre; Changeux, Jean-Pierre; Le Novère, Nicolas

    2003-06-16

    We determined the localization of [(3)H]nicotine, [(3)H]cytisine, [(3)H]epibatidine, and [(125)I]alpha-bungarotoxin binding sites in the brain of rhesus monkey by means of receptor autoradiography. The labelings by [(3)H]nicotine, [(3)H]cytisine, and [(3)H]epibatidine were highly concordant, except for epibatidine. Layer IV of some cortical areas, most thalamic nuclei, and presubiculum displayed high levels of labeling for the three ligands. Moderate levels of binding were detected in the subiculum, the septum, and the mesencephalon. Low levels were present in layers I-II and VI of the cortex, the cornu Ammonis, the dentate gyrus, and the amygdala. In addition, the level of epibatidine labeling was very high in the epithalamic nuclei and the interpeduncular nucleus, whereas labeling by nicotine and cytisine was very weak in the same regions. The distribution of [(125)I]alpha-bungarotoxin binding differed from the binding of the three agonists. The labeling was dense in layer I of most cortical areas, dentate gyrus, stratum lacunosum-moleculare of CA1 field, several thalamic nuclei, and medial habenula. A moderate labeling was found in layers V and VI of the prefrontal and frontal cortices, layer IV of primary visual cortex, amygdala, septum, hypothalamus, and some mesencenphalic nuclei. A weak signal was also detected in subiculum, claustrum, stratum oriens, and stratum lucidum of cornu Ammonis and also in some mesencephalic nuclei. The distribution of nicotine, cytisine, and epibatidine bindings corresponds broadly to the patterns observed in rodents, with the marked exception of the epithalamus. However, in monkey, those distributions match the distribution of alpha2 messenger RNA, rather than that of alpha4 transcripts as it exists in rodent brains. The distribution of the binding sites for alpha-bungarotoxin is larger in the brain of rhesus monkeys than in rodent brain, suggesting a more important role of alpha7 receptors in primates.

  15. 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.

  16. 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.

  17. 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.)

  18. A positive relationship between harm avoidance and brain nicotinic acetylcholine receptor availability.

    Science.gov (United States)

    Storage, Steven; Mandelkern, Mark A; Phuong, Jonathan; Kozman, Maggie; Neary, Meaghan K; Brody, Arthur L

    2013-12-30

    Prior research indicates that disturbance of cholinergic neurotransmission reduces anxiety, leading to the hypothesis that people with heightened cholinergic function have a greater tendency toward anxiety-like and/or harm-avoidant behavior. We sought to determine if people with elevated levels of harm avoidance (HA), a dimension of temperament from the Temperament and Character Inventory (TCI), have high α4β2* nicotinic acetylcholine receptor (nAChR) availability. Healthy adults (n=105; 47 non-smokers and 58 smokers) underwent bolus-plus-continuous infusion positron emission tomography (PET) scanning using the radiotracer 2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (abbreviated as 2-FA). During the uptake period of 2-FA, participants completed the TCI. The central study analysis revealed a significant association between total HA and mean nAChR availability, with higher total HA scores being linked with greater nAChR availability. In examining HA subscales, both 'Fear of Uncertainty' and 'Fatigability' were significant, based on higher levels of these characteristics being associated with greater nAChR availabilities. This study adds to a growing body of knowledge concerning the biological basis of personality and may prove useful in understanding the pathophysiology of psychiatric disorders (such as anxiety disorders) that have similar characteristics to HA. Study findings may indicate that heightened cholinergic neurotransmission is associated with increased anxiety-like traits.

  19. Changes of learning and memory ability and brain nicotinic receptors of rat offspring with coal burning fluorosis

    Energy Technology Data Exchange (ETDEWEB)

    Gui, C.Z.; Ran, L.Y.; Li, J.P.; Guan, Z.Z. [Guiyang Medical College, Guiyang (China). Dept. of Pathology

    2010-09-15

    The purpose of the investigation is to reveal the mechanism of the decreased ability of learning and memory induced by coal burning fluorosis. Ten offspring SD rats aged 30 days, who were born from the mothers with chronic coal burning fluorosis, and ten offspring with same age from the normal mothers as controls were selected. Spatial learning and memory of the rats were evaluated by Morris Water Maze test. Cholinesterase activity was detected by photometric method. The expressions of nicotinic acetylcholine receptors (nAChRs) at protein and mRNA levels were detected by Western blotting and Real-time PCR, respectively. The results showed that in the rat offspring exposed to higher fluoride as compared to controls, the learning and memory ability declined; the cholinesterase activities in the brains were inhibited; the protein levels of alpha 3, alpha 4 and alpha 7 nAChR subunits were decreased which showed certain significant correlations with the declined learning and memory ability; and the mRNA levels of alpha 3 and alpha 4 nAChRs were decreased, whereas the alpha 7 mRNA increased. The data indicated that coal burning fluorosis can induce the decreased ability of learning and memory of rat offspring, in which the mechanism might be connected to the changed nAChRs and cholinesterase.

  20. Late Onset Neurodegeneration with Brain-Iron Accumulation Presenting as Parkinsonism

    Directory of Open Access Journals (Sweden)

    Robert Fekete

    2012-01-01

    Full Text Available Neurodegeneration with brain-iron accumulation (NBIA encompasses a family of neurodegenerative disorders connected by evidence of abnormal brain iron deposition. Advances in imaging and genetic testing expanded the clinical spectrum of these disorders. Here, a case of parkinsonism and dystonia with orofacial stereotypies is presented. While the patient was initially diagnosed with Parkinson’s disease and placed on levodopa therapy, dopamine transporter imaging via (123I-FP-CIT SPECT (DaTSCAN was normal. MRI brain showed “eye of the tiger” sign on T2 weighted imaging. NBIA should be considered in the differential diagnosis of atypical parkinsonism.

  1. 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

    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...... and degradation of NAPE, respectively. The results showed that 1) the ability to accumulate NAPE during post-decapitative ischemia is especially high in the youngest rats and is markedly reduced in older brains [in 1-day-old rat brains NAPE accumulated to 1.5% of total phospholipids, while in 30-day-old rat......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...

  2. Hepcidin Suppresses Brain Iron Accumulation by Downregulating Iron Transport Proteins in Iron-Overloaded Rats.

    Science.gov (United States)

    Du, Fang; Qian, Zhong-Ming; Luo, Qianqian; Yung, Wing-Ho; Ke, Ya

    2015-08-01

    Iron accumulates progressively in the brain with age, and iron-induced oxidative stress has been considered as one of the initial causes for Alzheimer's disease (AD) and Parkinson's disease (PD). Based on the role of hepcidin in peripheral organs and its expression in the brain, we hypothesized that this peptide has a role to reduce iron in the brain and hence has the potential to prevent or delay brain iron accumulation in iron-associated neurodegenerative disorders. Here, we investigated the effects of hepcidin expression adenovirus (ad-hepcidin) and hepcidin peptide on brain iron contents, iron transport across the brain-blood barrier, iron uptake and release, and also the expression of transferrin receptor-1 (TfR1), divalent metal transporter 1 (DMT1), and ferroportin 1 (Fpn1) in cultured microvascular endothelial cells and neurons. We demonstrated that hepcidin significantly reduced brain iron in iron-overloaded rats and suppressed transport of transferrin-bound iron (Tf-Fe) from the periphery into the brain. Also, the peptide significantly inhibited expression of TfR1, DMT1, and Fpn1 as well as reduced Tf-Fe and non-transferrin-bound iron uptake and iron release in cultured microvascular endothelial cells and neurons, while downregulation of hepcidin with hepcidin siRNA retrovirus generated opposite results. We concluded that, under iron-overload, hepcidin functions to reduce iron in the brain by downregulating iron transport proteins. Upregulation of brain hepcidin by ad-hepcidin emerges as a new pharmacological treatment and prevention for iron-associated neurodegenerative disorders.

  3. Accumulation of 23 kDa lipocalin during brain development and injury in Hyphantria cunea.

    Science.gov (United States)

    Kim, Hong Ja; Je, Hyun Jeong; Cheon, Hyang Mi; Kong, Sun Young; Han, JikHyun; Yun, Chi Young; Han, Yeon Su; Lee, In Hee; Kang, Young Jin; Seo, Sook Jae

    2005-10-01

    The cDNA corresponding to a novel lipocalin was identified from the fall webworm, Hyphantria cunea. This lipocalin cDNA encodes a 194 residue protein with a calculated molecular mass of 23 kDa. Sequence analyses revealed that the 23 kDa lipocalin cDNA is most similar to Drosophila lazarillo, human apolipoprotein D, and Bombyrin. Northern blot analyses showed that 23 kDa lipocalin transcript is expressed in the whole body only in 4- and 6-day-old pupae. By Western blot analysis it was confirmed that 23 kDa lipocalin is mainly accumulated in brain and subesophageal ganglion, though it is detected in a small amount in fat body and epidermis of Hyphantria cunea. The accumulation of 23 kDa lipocalin in brain tissue was upregulated in response to injury. The putative function of 23 kDa lipocalin in brain is discussed.

  4. Brain beta-amyloid accumulation in transgenic mice expressing mutant superoxide dismutase 1.

    Science.gov (United States)

    Turner, Bradley J; Li, Qiao-Xin; Laughton, Katrina M; Masters, Colin L; Lopes, Elizabeth C; Atkin, Julie D; Cheema, Surindar S

    2004-12-01

    Oxidative stress is implicated in both the deposition and pathogenesis of beta-amyloid (Abeta) protein in Alzheimer's disease (AD). Accordingly, overexpression of the antioxidant enzyme superoxide dismutase 1 (SOD1) in neuronal cells and transgenic AD mice reduces Abeta toxicity and accumulation. In contrast, mutations in SOD1 associated with amyotrophic lateral sclerosis (ALS) confer enhanced pro-oxidative enzyme activities. We therefore examined whether ALS-linked mutant SOD1 overexpression in motor neuronal cells or transgenic ALS mice modulates Abeta toxicity or its accumulation in the brain. Aggregated, but not freshly solubilised, substrate-bound Abeta peptides induced degenerative morphology and cytotoxicity in motor neuron-like NSC-34 cells. Transfection of NSC-34 cells with human wild-type SOD1 attenuated Abeta-induced toxicity, however this neuroprotective effect was also observed for ALS-linked mutant SOD1. Analysis of the cerebral cortex, brainstem, cerebellum and olfactory bulb from transgenic SOD1G93A mice using enzyme-linked immunosorbent assay of acid-guanidine extracts revealed age-dependent elevations in Abeta levels, although not significantly different from wild-type mouse brain. In addition, brain amyloid protein precursor (APP) levels remained unaltered as a consequence of mutant SOD1 expression. We therefore conclude that mutant SOD1 overexpression promotes neither Abeta toxicity nor brain accumulation in these ALS models.

  5. Glucose-6-phosphate reduces calcium accumulation in rat brain endoplasmic reticulum

    Directory of Open Access Journals (Sweden)

    Jeffrey Thomas Cole

    2012-04-01

    Full Text Available Brain cells expend large amounts of energy sequestering calcium (Ca2+, while loss of Ca2+ compartmentalization leads to cell damage or death. Upon cell entry, glucose is converted to glucose-6-phosphate (G6P, a parent substrate to several metabolic major pathways, including glycolysis. In several tissues, G6P alters the ability of the endoplasmic reticulum to sequester Ca2+. This led to the hypothesis that G6P regulates Ca2+ accumulation by acting as an endogenous ligand for sarco-endoplasmic reticulum calcium ATPase (SERCA. Whole brain ER microsomes were pooled from adult male Sprague-Dawley rats. Using radio-isotopic assays, 45Ca2+ accumulation was quantified following incubation with increasing amounts of G6P, in the presence or absence of thapsigargin, a potent SERCA inhibitor. To qualitatively assess SERCA activity, the simultaneous release of inorganic phosphate (Pi coupled with Ca2+ accumulation was quantified. Addition of G6P significantly and decreased Ca2+ accumulation in a dose-dependent fashion (1-10 mM. The reduction in Ca2+ accumulation was not significantly different that seen with addition of thapsigargin. Addition of glucose-1-phosphate or fructose-6-phosphate, or other glucose metabolic pathway intermediates, had no effect on Ca2+ accumulation. Further, the release of Pi was markedly decreased, indicating G6P-mediated SERCA inhibition as the responsible mechanism for reduced Ca2+ uptake. Simultaneous addition of thapsigargin and G6P did decrease inorganic phosphate in comparison to either treatment alone, which suggests that the two treatments have different mechanisms of action. Therefore, G6P may be a novel, endogenous regulator of SERCA activity. Additionally, pathological conditions observed during disease states that disrupt glucose homeostasis, may be attributable to Ca2+ dystasis caused by altered G6P regulation of SERCA activity

  6. Nicotinic involvement in memory function in zebrafish.

    Science.gov (United States)

    Levin, Edward D; Chen, Elaine

    2004-01-01

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

  7. Arsenic and nicotine co-exposure lead to some synergistic effects on oxidative stress and apoptotic markers in young rat blood, liver, kidneys and brain

    Directory of Open Access Journals (Sweden)

    Anshu Jain

    2015-01-01

    Full Text Available Arsenic and nicotine exposure has been a major health concern globally. Individually both these toxicants increase the risk to various diseases including cancers. However, limited information exists on the co-exposure. In this study, we evaluate the effects of their individual and combined exposure and if co-exposure to these toxicants might have a synergism or antagonism. Male rats were exposed to a very low dose of arsenic (25 ppm in drinking water or nicotine (0.25 mg/kg, sub-cutaneously for a period of 5 months and post exposure various biochemical variables indicative of oxidative stress and apoptosis evaluated. Almost all glutathione linked enzymes showed marked alteration in individual as well as co-exposure treated groups. While serum creatinine and apoptosis indicator, lactate dehydrogenase (LDH were significantly increased in both treatments, an additive effect was noted in co-exposure group. A similar trend was also seen in brain and liver but not in kidneys. Gene expression studies showed marked reduction in catalase, Cu-Zn SOD, GST, there was a significant up regulation in Bax, caspase 3 in various tissues along with urinary 8-OHdG levels, indicative of DNA damage and apoptosis. Interestingly, a decrease in liver arsenic concentration was noted in co-exposed group compared to arsenic alone exposed group. In conclusion, the present study suggests that arsenic and nicotine exhibited significant toxicity during individual exposure whereas co-exposure to these toxins showed variable conditions (indicative of both synergism and antagonism in male rats.

  8. Enhanced behavioral response by decreasing brain oxidative stress to 6-hydroxy-l-nicotine in Alzheimer's disease rat model.

    Science.gov (United States)

    Hritcu, Lucian; Stefan, Marius; Brandsch, Roderich; Mihasan, Marius

    2015-03-30

    6-Hydroxy-l-nicotine (6HLN) is a nicotine metabolite resulted from nicotine degradation within Arthrobacter nicotinovorans with positive effects on spatial memory and oxidative stress damage. In the present study, the effects of 6HLN on spatial memory performance were assessed in scopolamine-treated rats. Scopolamine-induced memory impairments were observed, as measured by the Y-maze and radial arm-maze tasks. Decreased activities of superoxide dismutase, glutathione peroxidase and catalase along with decrease of total content of reduced glutathione were observed in the rat hippocampal homogenates of scopolamine-treated animals as compared with control. Production of malondialdehyde (lipid peroxidation) significantly increased in the rat hippocampal homogenates of scopolamine-treated animals as compared with control, as a consequence of impaired antioxidant enzymes activities. Additionally, in scopolamine-treated rats 6HLN significantly improved memory formation and decreased oxidative stress, suggesting memory-enhancing and antioxidant effects. Therefore, our results suggest that administration of 6HLN ameliorates scopolamine-induced spatial memory impairment by attenuation of the oxidative stress in the rat hippocampus.

  9. Baclofen prevented the changes in c-Fos and brain-derived neutrophic factor expressions during mecamylamine-precipitated nicotine withdrawal in mice.

    Science.gov (United States)

    Varani, Andrés P; Moutinho Machado, Lirane; Balerio, Graciela N

    2014-11-01

    Previous studies from our laboratory showed that baclofen (BAC, GABAB receptor agonist) prevented the behavioral and neurochemical alterations of nicotine (NIC) withdrawal syndrome. To further investigate the mechanisms underlying these effects, we analyzed the c-Fos and brain-derived neutrophic factor (BDNF) expression during NIC withdrawal and its prevention with BAC. Swiss-Webster mice received NIC (2.5 mg/kg, sc) four times daily, for 7 days. On the 8th day, NIC-treated mice received the nicotinic antagonist mecamylamine (MEC; 2 mg/kg, i.p.) 1 h after the last dose of NIC. A second group of NIC-treated mice received BAC (2 mg/kg, i.p.) prior to MEC administration. Thirty minutes after MEC, mice were sacrificed and the immunohistochemistry assays (c-Fos and BDNF) were performed at different anatomical levels. c-Fos expression decreased in the dentate gyrus of the hippocampus (DG) and the bed nucleus of the stria terminalis (BST), and increased in the habenular (Hb), accumbens shell (AcbSh) nuclei during NIC withdrawal. BAC re-established the modified c-Fos expression only in the DG, BST and AcbSh during NIC withdrawal. Conversely, BDNF expression decreased in the CA1 and CA3 area of the hippocampus, the Hb, and caudate putamen (CPu) during NIC withdrawal. Finally, BAC restored the decreased BDNF expression during NIC withdrawal in the CA1, CA3, Hb, and CPu. The results suggest a relationship between BAC's preventive effect of the expression of NIC withdrawal signs, and its ability to restore the changes in c-Fos and BDNF expression, observed in specific brain areas of NIC-withdrawn mice.

  10. 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

  11. Blood-brain barrier to peptides: (/sup 3/H)gonadotropin-releasing hormone accumulation by eighteen regions of the rat brain and by anterior pituitary

    Energy Technology Data Exchange (ETDEWEB)

    Ermisch, A.; Ruehle, H.J. (Karl-Marx-Universitaet, Leipzig (German Democratic Republic). Sektion Biowissenschaften); Klauschenz, E.; Kretzschmar, R. (Akademie der Wissenschaften der DDR, Berlin. Inst. fuer Wirkstofforschung)

    1984-01-01

    After intracarotid injection of (/sup 3/H)gonadotropin-releasing hormone ((/sup 3/H)GnRH) the mean accumulation of radioactivity per unit wet weight of 18 brain samples investigated and the anterior pituitary was 0.38 +- 0.11% g/sup -1/ of the injected tracer dose. This indicates a low but measurable brain uptake of the peptide. The brain uptake of (/sup 3/H)GnRH in blood-brain barrier (BBB)-protected regions is 5% of that of separately investigated (/sup 3/H)OH. In BBB-free regions the accumulation of radioactivity was more than 25-fold higher than in BBB-protected regions. The accumulation of (/sup 3/H)GnRH among regions with BBB varies less than among regions with leaky endothelia. The data presented for (/sup 3/H)GnRH are similar to those for other peptides so far investigated.

  12. Nicotinic Acetylcholine Receptor Signalling: Roles in Alzheimer's Disease and Amyloid Neuroprotection

    OpenAIRE

    2009-01-01

    Alzheimer's disease (AD), the major contributor to dementia in the elderly, involves accumulation in the brain of extracellular plaques containing the β-amyloid protein (Aβ) and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is also characterized by a loss of neurons, particularly those expressing nicotinic acetylcholine receptors (nAChRs), thereby leading to a reduction in nAChR numbers. The Aβ1–42 protein, which is toxic to neurons, is critical to the onset and...

  13. Protracted treatment with MDMA induces heteromeric nicotinic receptor up-regulation in the rat brain: an autoradiography study.

    Science.gov (United States)

    Ciudad-Roberts, Andrés; Camarasa, Jorge; Pubill, David; Escubedo, Elena

    2014-08-04

    Previous studies indicate that 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) can induce a heteromeric nicotinic acetylcholine receptor (nAChR, mainly of α4β2 subtype) up-regulation. In this study we treated male Sprague-Dawley rats twice-daily for 10 days with either saline or MDMA (7 mg/kg) and sacrificed them the day after to perform [(125)I]Epibatidine binding autoradiograms on serial coronal slices. MDMA induced significant increases in nAChR density in the substantia nigra, ventral tegmental area, nucleus accumbens, olfactory tubercle, anterior caudate-putamen, somatosensory, motor, auditory and retrosplenial cortex, laterodorsal thalamus nuclei, amygdala, postsubiculum and pontine nuclei. These increases ranged from 3% (retrosplenial cortex) to 30 and 34% (amygdala and substantia nigra). No increased α4 subunit immunoreactivity was found in up-regulated areas compared with saline-treated rats, suggesting a post-translational mechanism as occurs with nicotine. The heteromeric nAChR up-regulation in certain areas could account, at least in part, for the reinforcing, sensitizing and psychiatric disorders observed after long-term consumption of MDMA.

  14. Temporal course of cerebrospinal fluid dynamics and amyloid accumulation in the aging rat brain from three to thirty months

    Directory of Open Access Journals (Sweden)

    Chiu Catherine

    2012-01-01

    Full Text Available Abstract Background Amyloid accumulation in the brain parenchyma is a hallmark of Alzheimer's disease (AD and is seen in normal aging. Alterations in cerebrospinal fluid (CSF dynamics are also associated with normal aging and AD. This study analyzed CSF volume, production and turnover rate in relation to amyloid-beta peptide (Aβ accumulation in the aging rat brain. Methods Aging Fischer 344/Brown-Norway hybrid rats at 3, 12, 20, and 30 months were studied. CSF production was measured by ventriculo-cisternal perfusion with blue dextran in artificial CSF; CSF volume by MRI; and CSF turnover rate by dividing the CSF production rate by the volume of the CSF space. Aβ40 and Aβ42 concentrations in the cortex and hippocampus were measured by ELISA. Results There was a significant linear increase in total cranial CSF volume with age: 3-20 months (p p p p -1 to 12 months (11.30 day-1 and then a decrease to 20 months (10.23 day-1 and 30 months (6.62 day-1. Aβ40 and Aβ42 concentrations in brain increased from 3-30 months (p Conclusions In young rats there is no correlation between CSF turnover and Aβ brain concentrations. After 12 months, CSF turnover decreases as brain Aβ continues to accumulate. This decrease in CSF turnover rate may be one of several clearance pathway alterations that influence age-related accumulation of brain amyloid.

  15. Differential modulation of brain nicotinic acetylcholine receptor function by cytisine, varenicline, and two novel bispidine compounds: emergent properties of a hybrid molecule.

    Science.gov (United States)

    Peng, Can; Stokes, Clare; Mineur, Yann S; Picciotto, Marina R; Tian, Chengju; Eibl, Christoph; Tomassoli, Isabelle; Guendisch, Daniela; Papke, Roger L

    2013-11-01

    Partial agonist therapies for the treatment of nicotine addiction and dependence depend on both agonistic and antagonistic effects of the ligands, and side effects associated with other nAChRs greatly limit the efficacy of nicotinic partial agonists. We evaluated the in vitro pharmacological properties of four partial agonists, two current smoking cessation drugs, varenicline and cytisine, and two novel bispidine compounds, BPC and BMSP, by using defined nAChR subtypes expressed in Xenopus laevis oocytes and human embryonic kidney 293 cells. Similar to varenicline and cytisine, BPC and BMSP are partial agonists of α4β2 nAChRs, although BMSP produced very little activation of these receptors. Unlike varenicline and cytisine, BPC and BMSP showed desired low activity. BPC produced mecamylamine-sensitive steady-state activation of α4* receptors that was not evident with BMSP. We evaluated the modulation of α4*- and α7-mediated responses in rat lateral geniculate nucleus (LGN) neurons and hippocampal stratum radiatum (SR) interneurons, respectively. The LGN neurons were sensitive to a very low concentration of varenicline, and the SR interneuron responses were also sensitive to varenicline at a submicromolar concentration. Although 300 nM BPC strongly inhibited the ACh-evoked responses of LGN neurons, it did not inhibit the α7 currents of SR interneurons. Similar results were observed with 300 nM BMSP. Additionally, the bispidine compounds were efficacious in the mouse tail suspension test, demonstrating that they affect receptors in the brain when delivered systemically. Our data indicate that BPC and BMSP are promising α4β2* partial agonists for pharmacotherapeutics.

  16. Synthesis of a [2-pyridinyl-18F]-labelled fluoro derivative of (-)-cytisine as a candidate radioligand for brain nicotinic alpha4beta2 receptor imaging with PET.

    Science.gov (United States)

    Roger, Gaëlle; Lagnel, Béatrice; Rouden, Jacques; Besret, Laurent; Valette, Héric; Demphel, Stéphane; Gopisetti, JaganMohan; Coulon, Christine; Ottaviani, Michele; Wrenn, Lori A; Letchworth, Sharon R; Bohme, Georg A; Benavides, Jesus; Lasne, Marie-Claire; Bottlaender, Michel; Dollé, Frédéric

    2003-12-01

    In recent years, there has been considerable effort to design and synthesize radiotracers suitable for use in Positron Emission Tomography (PET) imaging of the alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR) subtype. A new fluoropyridinyl derivative of (-)-cytisine (1), namely (-)-9-(2-fluoropyridinyl)cytisine (3, K(i) values of 24 and 3462 nM for the alpha4beta2 and alpha7 nAChRs subtypes, respectively) has been synthesized in four chemical steps from (-)-cytisine and labelled with fluorine-18 (T(1/2): 119.8 min) using an efficient two-step radiochemical process [(a). nucleophilic heteroaromatic ortho-radiofluorination using the corresponding N-Boc-protected nitro-derivative, (b). TFA removal of the Boc protective group]. Typically, 20-45 mCi (0.74-1.67 GBq) of (-)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3, 2-3 Ci/micromol or 74-111 GBq/micromol) were easily obtained in 70-75 min starting from a 100 mCi (3.7 GBq) aliquot of a cyclotron-produced [18F]fluoride production batch (20-45% non decay-corrected yield based on the starting [18F]fluoride). The in vivo pharmacological profile of (-)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3) was evaluated in rats with biodistribution studies and brain radioactivity monitoring using intracerebral radiosensitive beta-microprobes. The observed in vivo distribution of the radiotracer in brain was rather uniform, and did not match with the known regional densities of nAChRs. It was also significantly different from that of the parent compound (-)-[3H]cytisine. Moreover, competition studies with (-)-nicotine (5 mg/kg, 5 min before the radiotracer injection) did not reduce brain uptake of the radiotracer. These experiments clearly indicate that (-)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3) does not have the required properties for imaging nAChRs using PET.

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

    Science.gov (United States)

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

    2011-12-01

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

  18. 6-hydroxy-L-nicotine from Arthrobacter nicotinovorans sustain spatial memory formation by decreasing brain oxidative stress in rats.

    Science.gov (United States)

    Hritcu, Lucian; Stefan, Marius; Brandsch, Roderich; Mihasan, Marius

    2013-03-01

    Male Wistar rats were subjected to chronic 6-hydroxy-L-nicotine treatment (6HLN, 0.3 mg/kg, i.p., seven consecutive days) and their memory performance was studied by means of Y-maze and radial arm-maze tasks. 6HLN significantly increased spontaneous alternations in Y-maze task and working memory in radial arm-maze task, suggesting effects on short-term memory, without affecting long-term memory, explored by reference memory in radial arm-maze task. In addition, 6HLN increased antioxidant enzymes activity and decreased production of lipid peroxidation, suggesting antioxidant effects. Also, the linear regression between behavioral measures and oxidative stress markers resulted in significant correlations. Therefore, positive effects of 6HLN on spatial memory may occur by antioxidant actions.

  19. Kynurenic acid as an antagonist of α7 nicotinic acetylcholine receptors in the brain: facts and challenges.

    Science.gov (United States)

    Albuquerque, Edson X; Schwarcz, Robert

    2013-04-15

    Kynurenic acid (KYNA), a major tryptophan metabolite, is a glutamate receptor antagonist, which is also reported to inhibit α7 nicotinic acetylcholine receptors (α7nAChRs). Due to variations in experimental approaches, controversy has arisen regarding the ability of KYNA to directly influence α7nAChR function. Here we summarize current concepts of KYNA neurobiology and review evidence pertaining to the proposed role of KYNA as an endogenous modulator of α7nAChRs and synaptic transmission. As dysfunction of α7nAChRs plays a major role in the pathophysiology of central nervous system disorders, elucidation of KYNA's action on this receptor subtype has significant therapeutic implications.

  20. Alteration of the coenzyme A biosynthetic pathway in neurodegeneration with brain iron accumulation syndromes.

    Science.gov (United States)

    Venco, Paola; Dusi, Sabrina; Valletta, Lorella; Tiranti, Valeria

    2014-08-01

    NBIA (neurodegeneration with brain iron accumulation) comprises a heterogeneous group of neurodegenerative diseases having as a common denominator, iron overload in specific brain areas, mainly basal ganglia and globus pallidus. In the past decade a bunch of disease genes have been identified, but NBIA pathomechanisms are still not completely clear. PKAN (pantothenate kinase-associated neurodegeneration), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA. It is caused by mutations in the PANK2 (pantothenate kinase 2) gene, coding for a mitochondrial enzyme that phosphorylates vitamin B5 in the first reaction of the CoA (coenzyme A) biosynthetic pathway. A distinct form of NBIA, denominated CoPAN (CoA synthase protein-associated neurodegeneration), is caused by mutations in the CoASY (CoA synthase) gene coding for a bifunctional mitochondrial enzyme, which catalyses the final steps of CoA biosynthesis. These two inborn errors of CoA metabolism further support the concept that dysfunctions in CoA synthesis may play a crucial role in the pathogenesis of NBIA.

  1. Mitochondria: A crossroads for lipid metabolism defect in neurodegeneration with brain iron accumulation diseases.

    Science.gov (United States)

    Aoun, Manar; Tiranti, Valeria

    2015-06-01

    Neurodegeneration with brain iron accumulation (NBIA) comprises a group of brain iron deposition syndromes that lead to mixed extrapyramidal features and progressive dementia. Exact pathologic mechanism of iron deposition in NBIA remains unknown. However, it is becoming increasingly evident that many neurodegenerative diseases are hallmarked by metabolic dysfunction that often involves altered lipid profile. Among the identified disease genes, four encode for proteins localized in mitochondria, which are directly or indirectly implicated in lipid metabolism: PANK2, CoASY, PLA2G6 and C19orf12. Mutations in PANK2 and CoASY, both implicated in CoA biosynthesis that acts as a fatty acyl carrier, lead, respectively, to PKAN and CoPAN forms of NBIA. Mutations in PLA2G6, which plays a key role in the biosynthesis and remodeling of membrane phospholipids including cardiolipin, lead to PLAN. Mutations in C19orf12 lead to MPAN, a syndrome similar to that caused by mutations in PANK2 and PLA2G6. Although the function of C19orf12 is largely unknown, experimental data suggest its implication in mitochondrial homeostasis and lipid metabolism. Altogether, the identified mutated proteins localized in mitochondria and associated with different NBIA forms support the concept that dysfunctions in mitochondria and lipid metabolism play a crucial role in the pathogenesis of NBIA. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies.

  2. 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.

  3. Study on effect of flue-cured tobacco nicotine accumulation and distribution in fermented soybean cake%大豆饼肥对烤烟烟碱积累和含量影响的研究

    Institute of Scientific and Technical Information of China (English)

    王鹏; 张吉立; 彭友; 李洋; 叶义; 张云贵

    2012-01-01

    To determine the ermented soybean cake best use ratio in Heilongjiang tobacco chernozem, the test studied flue-cured tobacco effect of flue-cured tobacco nicotine accumulation and distribution in ermented soybean cake in different uses proportion. The test with random block design in the field, three treatments were applied for the pure inorganic fertilizer, 50% of the ermented soybean cake and 50% inorganic fertilizer application, 100% use ermented soybean cake, repeat 3 times. The results showed that: Flue-cured tobacco total nicotine accumulation with growth period delay became increasing and when harvest that 3 treatment accumulation respectively 89. 80 kg · hm -2, 92. 22 kg · hm-2, 117. 49 kg · hm -2, between 50% fermented soybean cake treatment and control have no significant difference and 100% fermented soybean cake treatment have significant difference with the control; 100% fermented soybean cake treatment stem, lower leaves, middle leaves nicotine content was significantly higher than the control, 50% fermented soybean cake treatment all organs nicotine content with the control were not significantly different; Smoking results showed that 50% fermented soybean cake treatment was highest score that was 31. 50 points, control the lowest was 29. 00 points. Comprehensive analysis that fermented soybean cake used ratio in 50% ~ 100% was appropriate in Heilongjiang smoke area.%为了确定黑龙江省黑钙土烟区大豆饼肥的最佳施用比例,试验研究不同大豆饼肥使用比例对烤烟烟碱积累以及分配的影响,从而为大豆饼肥的合理施用提供参考依据.采用田间小区试验,设3个处理,分别为纯施无机化肥(对照)、50%大豆饼肥与50%无机化肥混合施用、100%施用大豆饼肥,3次重复.结果表明:烤烟烟碱总积累量随生育期延后逐渐增加,收获时3个处理积累量分别达到89.80、92.22、117.49kg ·hm-2,50%比例大豆饼肥处理与对照之间无显著差异,100%饼肥

  4. 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.

  5. Fish eyes and brain as primary targets for mercury accumulation - a new insight on environmental risk assessment.

    Science.gov (United States)

    Pereira, Patrícia; Raimundo, Joana; Araújo, Olinda; Canário, João; Almeida, Armando; Pacheco, Mário

    2014-10-01

    Fish eyes and brain are highly susceptible to environmental Hg exposure but this issue is still scarcely investigated, mainly regarding methylmercury (MeHg) accumulation. Yet, Hg levels in fish lens have not been previously examined under field conditions. Total Hg (tHg), MeHg and inorganic Hg (iHg) levels were assessed in the brain, eye wall and lens of the golden grey mullet (Liza aurata) from an Hg contaminated area, both in winter and summer, together with water and sediment levels. Sampling was performed at Aveiro lagoon (Portugal) where a confined area (LAR) is severely contaminated by Hg. Fish brain, eye wall and lens accumulated higher levels of tHg, MeHg and iHg at LAR than the reference site, reflecting faithfully environmental spatial differences. The brain and eye wall responded also to the winter-summer changes found in water and sediment, accumulating higher levels of MeHg (and tHg) in winter. Contrarily, lens was unable to reflect seasonal changes, probably due to its composition and structural stability over time. The three neurosensory structures accumulated preferentially MeHg than iHg (MeHg was higher than 77% of tHg). Lens exhibited a higher retention capacity of MeHg (mean around 1 μg g(-1) at LAR), accumulating higher levels than the other two tissues. Interestingly, MeHg and iHg levels were significantly correlated for the brain and eye wall but poorly associated within the two analysed eye components. The high levels of MeHg found in the brain, eye wall and lens could compromise their functions and this needs further research.

  6. Nicotinic activation of laterodorsal tegmental neurons

    DEFF Research Database (Denmark)

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

    2009-01-01

    are unknown. We addressed this issue by examining the effects of nicotine on identified cholinergic and non-cholinergic LDT neurons using whole-cell patch clamp and Ca(2+)-imaging methods in brain slices from mice (P12-P45). Nicotine applied by puffer pipette or bath superfusion elicited membrane...... depolarization that often induced firing and TTX-resistant inward currents. Nicotine also enhanced sensitivity to injected current; and, baseline changes in intracellular calcium were elicited in the dendrites of some cholinergic LDT cells. In addition, activity-dependent calcium transients were increased......, suggesting that nicotine exposure sufficient to induce firing may lead to enhancement of levels of intracellular calcium. Nicotine also had strong actions on glutamate and GABA-releasing presynaptic terminals, as it greatly increased the frequency of miniature EPSCs and IPSCs to both cholinergic and non...

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

    Science.gov (United States)

    Davis, Tiffany J; de Fiebre, Christopher M

    2006-01-01

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

  8. Late-Onset Neurodegeneration with Brain Iron Accumulation with Diffusion Tensor Magnetic Resonance Imaging

    Directory of Open Access Journals (Sweden)

    Syed Omar Shah

    2012-12-01

    Full Text Available Introduction: Neuroferritinopathy is an autosomal dominant neurodegenerative disorder that includes a movement disorder, cognitive decline, and characteristic findings on brain magnetic resonance imaging (MRI due to abnormal iron deposition. Here, we present a late-onset case, along with diffusion tensor imaging (DTI. Case Presentation: We report the case of a 74-year-old Caucasian female with no significant past medical history who presented for evaluation of orofacial dyskinesia, suspected to be edentulous dyskinesia given her history of ill-fitting dentures. She had also developed slowly progressive dysarthria, dysphagia, visual hallucinations as well as stereotypic movements of her hands and feet. Results: The eye-of-the-tiger sign was demonstrated on T2 MRI. Increased fractional anisotropy and T2 hypointensity were observed in the periphery of the globus pallidus, putamen, substantia nigra, and dentate nucleus. T2 hyperintensity was present in the medial dentate nucleus and central globus pallidus. Discussion: The pallidal MRI findings were more typical of pantothenate kinase-associated neurodegeneration (PKAN, but given additional dentate and putamenal involvement, lack of retinopathy, and advanced age of onset, PKAN was less likely. Although the patient’s ferritin levels were within low normal range, her clinical and imaging features led to a diagnosis of neuroferritinopathy. Conclusion: Neurodegeneration with brain iron accumulation (NBIA is a rare cause of orofacial dyskinesia. DTI MRI can confirm abnormal iron deposition. The location of abnormal iron deposits helps in differentiating NBIA subtypes. Degeneration of the dentate and globus pallidus may occur via an analogous process given their similar T2 and DTI MRI appearance.

  9. 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.

  10. Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence

    Directory of Open Access Journals (Sweden)

    Lingjun Zuo

    2016-11-01

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

  11. Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2016-11-07

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Gajdosechova, Zuzana [Trace Element Speciation Laboratory, Department of Chemistry, Meston Walk, University of Aberdeen, Aberdeen AB24 3UE (United Kingdom); Brownlow, Andrew [SAC Wildlife Unit, Inverness (United Kingdom); Cottin, Nicolas T.; Fernandes, Mariana [Trace Element Speciation Laboratory, Department of Chemistry, Meston Walk, University of Aberdeen, Aberdeen AB24 3UE (United Kingdom); Read, Fiona L. [Oceanlab, University of Aberdeen, Main Street, Newburgh AB41 6AA (United Kingdom); Urgast, Dagmar S.; Raab, Andrea; Feldmann, Jörg; Krupp, Eva M. [Trace Element Speciation Laboratory, Department of Chemistry, Meston Walk, University of Aberdeen, Aberdeen AB24 3UE (United Kingdom)

    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 2.2 mg/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. - Highlights: • Trace elements were measured in a pod of 21 pilot whales stranded in Scotland. • Bioaccumulation of mercury and methyl mercury was found in all studied tissues. • Cadmium age related accumulation was observed in the liver and brain tissues. • Cadmium-selenium correlations suggest formation of cadmium-selenium complexes.

  14. Studies on accumulation of (14C)-mescaline in brain homogenates: effects of psychotropic and other agents.

    Science.gov (United States)

    Shah, N S; Gulati, O D

    1975-01-01

    Incubation of rat brain homogenates or 14,500 g pellet isolated from the homogenate with (14C)-mescaline was associated with accumulation of (14C)-mescaline in the pellet. 1.33 mumol/ml of chlorpromazine, trifluoperazine, fluphenazine, imipramine, desmethylimipramine, nortriptyline and amitriptyline inhibited the accumulation of mescaline. Lower concentrations (0.133-0.44 mumol/ml) of the psychotropic drugs were less effective. The tricyclic antidepressants were less potent than the tranquilizers. Although the trimethoxyphenylacetic acid (TMPA) levels of the pellet were also reduced by the psychotropic drugs, the TMPA:mescaline ratios were unchanged indicating that the drugs had no effect on the metabolism of mescaline. The inhibition of accumulation of mescaline by the high concentrations of tranquilizers may divert more of the hallucinogen to the receptor site. Thus, an explanation for the reported worsening of clinical syndrome of hallucinogenic poisoning by tranquilizers is provided.

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

    Science.gov (United States)

    Itasaka, Michio; Hironaka, Naoyuki; Miyata, Hisatsugu

    2015-06-01

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

  16. 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.

  17. Mercury accumulation and its distribution to metallothionein in mouse brain after sub-chronic pulse exposure to mercury vapor

    Energy Technology Data Exchange (ETDEWEB)

    Yasutake, A. [Biochemistry Section, National Institute for Minamata Disease, Minamata, Kumamoto 867-0008 (Japan); Sawada, M.; Shimada, A. [Department of Veterinary Pathology, Tottori University, 4-101 Koyamacho, Minami, Tottori 680-0945 (Japan); Satoh, M. [Department of Hygienics, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585 (Japan); Tohyama, C. [Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506 (Japan)

    2004-09-01

    Previously we found that exposure to mercury vapor effectively induced metallothionein (MT) biosynthesis in rat brain. Although the induction of not only MT-I/II but also MT-III was evident, the induction rate of the latter was much lower than that of the former. The brain of an MT-null mouse lacks MT-I/II, but has MT-III. Here we examined the effects of sub-chronic pulse exposure to mercury vapor on the brain MT in MT-null mice and their wild type controls. MT-null and wild type mice were preliminarily exposed to mercury vapor for 2 weeks at 0.1 mg Hg/m{sup 3} for 1 h/day for 3 days a week, and then exposed for 11 weeks at 4.1 mg Hg/m{sup 3} for 30 min/day for 3 days a week. This exposure caused no toxic signs such as abnormal behavior or loss of body weight gain in the mice of either strain throughout the experimental period. Twenty-four hours after the termination of the exposure, mice were sacrificed and brain samples were subjected to mercury analysis, MT assay, and pathological examination. The MT-null mice showed lower accumulation of mercury in the brain than the wild type mice. Mercury exposure resulted in a 70% increase of brain MT in the wild type mice, which was mostly accounted for by the increase in MT-I/II. On the other hand, the brain MT in the MT-null mice increased by 19%, suggesting less reactivity of the MT-III gene to mercury vapor. Although histochemical examination revealed silver-mercury grains in the cytoplasm of nerve cells and glial cells throughout the brains of both strains, no significant difference was observed between the two strains. (orig.)

  18. Relationship between brain accumulation of manganese and aberration of hippocampal adult neurogenesis after oral exposure to manganese chloride in mice.

    Science.gov (United States)

    Kikuchihara, Yoh; Abe, Hajime; Tanaka, Takeshi; Kato, Mizuho; Wang, Liyun; Ikarashi, Yoshiaki; Yoshida, Toshinori; Shibutani, Makoto

    2015-05-04

    We previously found persistent aberration of hippocampal adult neurogenesis, along with brain manganese (Mn) accumulation, in mouse offspring after developmental exposure to 800-ppm dietary Mn. Reduction of parvalbumin (Pvalb)(+) γ-aminobutyric acid (GABA)-ergic interneurons in the hilus of the dentate gyrus along with promoter region hypermethylation are thought to be responsible for this aberrant neurogenesis. The present study was conducted to examine the relationship between the induction of aberrant neurogenesis and brain Mn accumulation after oral Mn exposure as well as the responsible mechanism in young adult animals. We used two groups of mice with 28- or 56-day exposure periods to oral MnCl2·xH2O at 800 ppm as Mn, a dose sufficient to lead to aberrant neurogenesis after developmental exposure. A third group of mice received intravenous injections of Mn at 5-mg/kg body weight once weekly for 28 days. The 28-day oral Mn exposure did not cause aberrations in neurogenesis. In contrast, 56-day oral exposure caused aberrations in neurogenesis suggestive of reductions in type 2b and type 3 progenitor cells and immature granule cells in the dentate subgranular zone. Brain Mn accumulation in 56-day exposed cases, as well as in directly Mn-injected cases occurred in parallel with reduction of Pvalb(+) GABAergic interneurons in the dentate hilus, suggesting that this may be responsible for aberrant neurogenesis. For reduction of Pvalb(+) interneurons, suppression of brain-derived neurotrophic factor-mediated signaling of mature granule cells may occur via suppression of c-Fos-mediated neuronal plasticity due to direct Mn-toxicity rather than promoter region hypermethylation of Pvalb.

  19. CYP2A6 gene polymorphisms impact to nicotine metabolism

    Directory of Open Access Journals (Sweden)

    Dewi Muliaty

    2010-02-01

    Full Text Available Nicotine is a major addictive compound in tobacco cigarette smoke. After being absorbed by the lung nicotine is rapidly metabolized and mainly inactivated to cotinine by hepatic cytochrome P450 2A6 (CYP2A6 enzyme. Genetic polymorphisms in CYP2A6 may play a role in smoking behavior and nicotine dependence. CYP2A6*1A is the wild type of the CYP2A6 gene which is associated with normal or extensive nicotine metabolism. In the CYP2A6 gene, several polymorphic alleles have been reported such as CYP2A6*4, CYP2A6*7, CYP2A6*9, and CYP2A6*10 which are related to decreasing nicotine metabolism activity. The variation of nicotine metabolism activity could alter nicotine plasma levels. Smokers need a certain level of nicotine in their brain and must smoke regularly because of nicotine’s short half-life; this increases the number of smoked cigarettes in extensive metabolizers. Meanwhile, in slow metabolizers, nicotine plasma level may increase and results in nicotine toxicity. This will eventually lower the risk of dependence. (Med J Indones 2010; 19:46-51Keywords: cotinine, hepatic cytochrome P450 2A6, smoking behavior

  20. Pharmacological and immunochemical characterization of a2* nicotinic acetylcholine receptors (nAChRs) in mouse brain

    Institute of Scientific and Technical Information of China (English)

    Paul WHITEAKER; Jennifer A WILKING; Robert WB BROWN; Robert J BRENNAN; Allan C COLLINS; Jon M LINDSTROM; Jim BOULTER

    2009-01-01

    Aim: a2 nAChR subunit mRNA expression in mice is most intense in the olfactory bulbs and interpeduncular nucleus. We aimed to investigate the properties of a2* nAChRs in these mouse brain regions.Methods: a2 nAChR subunit-null mutant mice were engineered. Pharmacological and immunoprecipitation studies were used to determine the composition of a2 subunit-containing (a2*) nAChRs in these two regions.Results: [125I]Epibatidine (200 pmol/L) autoradiography and saturation binding demonstrated that al deletion reduces nAChR expression in both olfactory bulbs and interpeduncular nucleus (by 4.8±1.7 and 92卤26 fmol-mg"1 protein, respectively). Pharmacological characterization using the 02-selective drug A85380 to inhibit [125I]epibatidine binding proved inconclusive, so immunoprecipitation methods were used to further characterize a2* nAChRs. Protocols were established to immunoprecipitate 02 and 04 nAChRs. Immunoprecipitation specificity was ascertained using tissue from 02- and 04-null mutant mice, and efficacy was good (>90% of (32* and >80% of 04* nAChRs were routinely recovered). Conclusion: Immunoprecipitation experiments indicated that interpeduncular nucleus a2* nAChRs predominantly contain (32 subunits, while those in olfactory bulbs contain mainly 04 subunits. In addition, the immunoprecipitation evidence indicated that both nuclei, but especially the interpeduncular nucleus, express nAChR complexes containing both 02 and 04 subunits.

  1. Comparison of five different targeting ligands to enhance accumulation of liposomes into the brain.

    Science.gov (United States)

    van Rooy, Inge; Mastrobattista, Enrico; Storm, Gert; Hennink, Wim E; Schiffelers, Raymond M

    2011-02-28

    In many different studies nanocarriers modified with targeting ligands have been used to target to the brain. Many ligands have been successful, but it is difficult to compare results from different studies to determine which targeting ligand is the best. Therefore, we selected five targeting ligands (transferrin, RI7217, COG133, angiopep-2, and CRM197) and compared their ability to target liposomes to the brain in vitro and in vivo. In vitro, only CRM197-modified liposomes were able to bind to murine endothelial cells (bEnd.3). Both CRM197 and RI7217-modified liposomes associated with human endothelial cells (hCMEC/D3). In vivo, uptake of targeted liposomes was tested at 12h after iv injection. For some of the ligands, additional time points of 1 and 6h were tested. Only the RI7217 was able to significantly enhance brain uptake in vivo at all time points. Uptake in the brain capillaries was up to 10 times higher compared to untargeted liposomes, and uptake in the brain parenchyma was up to 4.3 times higher. Additionally, these results show that many targeting ligands that have been described for brain targeting, do not target to the brain in vivo when coupled to a liposomal delivery vehicle.

  2. Chronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer's disease.

    Science.gov (United States)

    Srivareerat, Marisa; Tran, Trinh T; Salim, Samina; Aleisa, Abdulaziz M; Alkadhi, Karim A

    2011-05-01

    Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by increased deposition of beta-amyloid (Aβ) peptides and progressive cholinergic dysfunction in regions of the brain involved in learning and memory processing. In AD, progressive accumulation of Aβ peptide impairs nicotinic acetylcholine receptor (nAChR) function by an unknown mechanism believed to involve α(7)- and α(4)β(2)-nAChR blockade. The three approaches of the current study evaluated the effects of chronic nicotine treatment in the prevention of Aβ-induced impairment of learning and short-term memory. Rat AD model was induced by 14-day i.c.v. osmotic pump infusion of a 1:1 mixture of 300 pmol/day Aβ(1-40)/Aβ(1-42) or Aβ(40-1) (inactive peptide, control). The effect of nicotine (2 mg/(kg day)) on Aβ-induced spatial learning and memory impairments was assessed by evaluation of performance in the radial arm water maze (RAWM), in vivo electrophysiological recordings of early-phase long-term potentiation (E-LTP) in urethane-anesthetized rats, and immunoblot analysis to determine changes in the levels of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), Aβ and memory-related proteins. The results indicate that 6 weeks of nicotine treatment reduced the levels of Aβ(1-40) and BACE1 peptides in hippocampal area CA1 and prevented Aβ-induced impairment of learning and short-term memory. Chronic nicotine also prevented the Aβ-induced inhibition of basal synaptic transmission and LTP in hippocampal area CA1. Furthermore, chronic nicotine treatment prevented the Aβ-induced reduction of α(7)- and α(4)-nAChR. These effects of nicotine may be due, at least in part, to upregulation of brain derived neurotropic factor (BDNF).

  3. Pyrilamine inhibits nicotine-induced catecholamine secretion.

    Science.gov (United States)

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

    2014-07-01

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

  4. Alcohol and nicotinic acetylcholine receptors

    Directory of Open Access Journals (Sweden)

    Jinsong Tang

    2013-05-01

    Full Text Available Background The frequent co-abuse of alcohol and tobacco may suggest that they share some common neurological mechanisms. For example, nicotine acts on Nicotinic acetylcholine receptors (nAChRs in the brain to release dopamine to sustain addiction. Might nAChRs be entwined with alcohol? Objectives This review summarizes recent studies on the relationship between alcohol and nAChRs, including the role of nAChRs in molecular biological studies, genetic studies and pharmacological studies on alcohol, which indicate that nAChRs have been potently modulated by alcohol. Methods We performed a cross-referenced literature search on biological, genetic and pharmacological studies of alcohol and nAChRs. Results Molecular biological and genetic studies indicated that nAChR (genes may be important in mediating alcohol intake, but we still lack substantial evidence about how it works. Pharmacological studies proved the correlation between nAChRs and alcohol intake, and the association between nicotine and alcohol at the nAChRs. The positive findings of varenicline (a partial agonist at the _4_2 nAChR, smoking-cessation pharmaceutical treatment for alcoholism, provides a new insight for treating co-abuse of these two substances. >Conclusions Molecular biological, genetic and pharmacological studies of alcohol at the nAChR level, provide a new sight for preventing and treating the co-abuse of alcohol and nicotine. Given the important role of nAChRs in nicotine dependence, the interaction between alcohol and nAChRs would provide a new insight in finding effective pharmacological treatments, in decreasing or stopping alcohol consumption and cigarette smoking concurrently.

  5. Glucose-6-phosphate Reduces Calcium Accumulation in Rat Brain Endoplasmic Reticulum

    Science.gov (United States)

    2012-04-01

    low millimolar range. Most Ca2+ is sequestered within organelles , including the endoplasmic reticulum (ER), Golgi, mitochondria , and nucleus (Carafoli...G6P and thapsigargin caused generalized reduction in Ca2+ accumulation in remarkably similar patterns with no apparent gray matter regional...with glucose-6-phosphate (10 mM) or thapsigargin (1 µM), revealed very similar pattern of generalized reduction in 45Ca2+ accumulation in gray and

  6. Locomotion induced by ventral tegmental microinjections of a nicotinic agonist.

    Science.gov (United States)

    Museo, E; Wise, R A

    1990-03-01

    Bilateral microinjections of the nicotinic agonist cytisine (0.1, 1 or 10 nanomoles per side) into the ventral tegmental area increased locomotor activity. This increase in locomotion was antagonized by mecamylamine (2 mg/kg, IP), a nicotinic antagonist that readily crosses the blood-brain barrier, and by pimozide (0.3 mg/kg, IP), a central dopaminergic antagonist. Hexamethonium (2 mg/kg, IP), a nicotinic antagonist that, unlike mecamylamine, does not cross the blood-brain barrier, had no effect; this suggests that mecamylamine's attenuation of cytisine-induced locomotor activity resulted from a blockade of central and not peripheral nicotinic receptors. The data support the notion that nicotinic and dopaminergic substrates interact at the level of the VTA to produce increases in locomotor activity.

  7. Submyelin potassium accumulation may functionally block subsets of local axons during deep brain stimulation: a modeling study

    Science.gov (United States)

    Bellinger, S. C.; Miyazawa, G.; Steinmetz, P. N.

    2008-09-01

    Deep brain stimulation has been used for over a decade to relieve the symptoms of Parkinson's disease, although its mechanism of action remains poorly understood. To better understand the direct effects of DBS on central neurons, a computational model of a myelinated axon has been constructed which includes the effects of K+ accumulation within the peri-axonal space. Using best estimates of anatomic and electrogenic model parameters for in vivo STN axons, the model predicts a functional block along the axon due to K+ accumulation in the submyelin space. The functional block occurs for a range of model parameters: high stimulation frequencies (>130 Hz); high extracellular K+ concentrations (>3 × 10-3 M); low maximum Na+/K+ ATPase current densities (stimulating frequency.

  8. Epidermal growth factor treatment of the adult brain subventricular zone leads to focal microglia/macrophage accumulation and angiogenesis.

    Science.gov (United States)

    Lindberg, Olle R; Brederlau, Anke; Kuhn, H Georg

    2014-04-01

    One of the major components of the subventricular zone (SVZ) neurogenic niche is the specialized vasculature. The SVZ vasculature is thought to be important in regulating progenitor cell proliferation and migration. Epidermal growth factor (EGF) is a mitogen with a wide range of effects. When stem and progenitor cells in the rat SVZ are treated with EGF, using intracerebroventricular infusion, dysplastic polyps are formed. Upon extended infusion, blood vessels are recruited into the polyps. In the current study we demonstrate how polyps develop through distinct stages leading up to angiogenesis. As polyps progress, microglia/macrophages accumulate in the polyp core concurrent with increasing cell death. Both microglia/macrophage accumulation and cell death peak during angiogenesis and subsequently decline following polyp vascularization. This model of inducible angiogenesis in the SVZ neurogenic niche suggests involvement of microglia/macrophages in acquired angiogenesis and can be used in detail to study angiogenesis in the adult brain.

  9. Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation.

    Science.gov (United States)

    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; Sanford, Lynn; Hamada, Jeffrey; Bettencourt, Conceição; Houlden, Henry; Chiapparini, Luisa; Zorzi, Giovanna; Kurian, Manju A; Nardocci, Nardo; Prokisch, Holger; Hayflick, Susan; Gout, Ivan; Tiranti, Valeria

    2014-01-02

    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 analysis. CoA synthase is a bifunctional enzyme catalyzing the final steps of CoA biosynthesis by coupling phosphopantetheine with ATP to form dephospho-CoA and its subsequent phosphorylation to generate CoA. We demonstrate alterations in RNA and protein expression levels of CoA synthase, as well as CoA amount, in fibroblasts derived from the two clinical cases and in yeast. This is the second inborn error of coenzyme A biosynthesis to be implicated in NBIA.

  10. 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...... 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 ...-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...

  11. The abnormal isoform of the prion protein accumulates in late-endosome-like organelles in scrapie-infected mouse brain.

    Science.gov (United States)

    Arnold, J E; Tipler, C; Laszlo, L; Hope, J; Landon, M; Mayer, R J

    1995-08-01

    The prion encephalopathies are characterized by accumulation in the brain of the abnormal form PrPsc of a normal host gene product PrPc. The mechanism and site of formation of PrPsc from PrPc are currently unknown. In this study, ME7 scrapie-infected mouse brain was used to show, both biochemically and by double-labelled immunogold electron microscopy, that proteinase K-resistant PrPsc is enriched in subcellular structures which contain the cation-independent mannose 6-phosphate receptor, ubiquitin-protein conjugates, beta-glucuronidase, and cathepsin B, termed late endosome-like organelles. The glycosylinositol phospholipid membrane-anchored PrPc will enter such compartment for normal degradation and the organelles may therefore act as chambers for the conversion of PrPc into infectious PrPsc in this murine model of scrapie.

  12. [The nucleolus of the cell is the site of iron accumulation in the substantia nigra neurons of the human brain].

    Science.gov (United States)

    Sukhorukova, Ye G; Grigoriev, I P; Kolos, Ye A; Korzhenevskiy, D E

    2012-01-01

    Distribution of iron in the substantia nigra of the human brain (10 men and women aged 27-78 years) was studied using Perls' histochemical method. Iron ions were demonstrated in the nigral neuropil and melanin-containing neurons. For the first time the nuclei of some neurons were found to contain iron accumulations. The intranuclear iron inclusions correspond to the nucleolus according to their sharp outline and sizes. Detection of iron in the neuronal nucleolus may contribute to the understanding of mechanisms of iron neurotoxicity for nigral dopaminergic neurons.

  13. Functional interaction between Lypd6 and nicotinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Arvaniti, Maria; Jensen, Majbrit M; Soni, Neeraj

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) affect multiple physiological functions in the brain and their functions are modulated by regulatory proteins of the Lynx family. Here, we report for the first time a direct interaction of the Lynx protein LY6/PLAUR domain-containing 6 (Lypd6) with n...... findings suggest that Lypd6 is a versatile inhibitor of cholinergic signaling in the brain, and that Lypd6 is dysregulated by nicotine exposure during early development. Regulatory proteins of the Lynx family modulate the function of nicotinic receptors (nAChRs). We report for the first time that the Lynx...

  14. Construction of a standard reference for PET studies of methionine accumulation using a computerised brain atlas

    Energy Technology Data Exchange (ETDEWEB)

    Romanowski, C.A.J. [Department of Neuroradiology, Royal Hallamshire Hospital, Sheffield S10 2JF (United Kingdom); Leslie, D.F. [Department of Clinical Neuroscience, Section of Neuroradiology, Karolinska Hospital, S-171 76 Stockholm (Sweden); Thurfjell, L. [Centre for Image Analysis, University of Uppsala (Sweden); Ericson, K. [Department of Clinical Neuroscience, Section of Neuroradiology, Karolinska Hospital, S-171 76 Stockholm (Sweden); Stone-Elander, S. [Karolinska Pharmacy, Karolinska Hospital, Stockholm (Sweden)

    1997-06-01

    Positron emission tomography (PET) is valuable for assessing the biochemistry and physiology of the human brain. A computerised brain atlas has been developed which allows demonstration of anatomical regions on PET images and manipulation of these images into a standardised anatomical space. Once the images are in this standardised three-dimensional space it is possible to make comparisons between individuals and groups of individuals. We describe the use of this atlas in the generation of a set of mean reference images using methionine PET images of normal volunteers. (orig.). With 5 figs.

  15. Pranlukast reduces neutrophil but not macrophage/microglial accumulation in brain after focal cerebral ischemia in mice

    Institute of Scientific and Technical Information of China (English)

    Li-sheng CHU; Er-qing WEI; Guo-liang YU; San-hua FANG; Yu ZHOU; Meng-ling WANG; Wei-ping ZHANG

    2006-01-01

    Aim:To determine whether pranlukast.a cysteinyl leukotriene receptor-1 antagonist,exerts an anti-inflammatory effect on focal cerebral ischemia in mice.Methods:Focal cerebral ischemia in mice was induced by permanent middle cerebral artery occlusion(MCAO).In addition to neurological deficits,infarct volume,degenerated neurons and endogenous IgG exudation,we detected accumulation of neutrophils and macrophage/microglia in the ischemic brain tissue 72 h after MCAO.Pranlukast was iP injected 30 min before and after MCAO.Results:Pranlukast significantly attenuated neurological deficits,infarct volume,neuron degeneration and IgG exudation.Importantly,pranlukast(0.01 and 0.1 mg/kg) inhibited myeloperoxidase-positive neutrophil,but not CDllb-positive macrophage/microglial accumulation in the ischemic cortical tissue.Conclusion:Pranlukast exerts an anti-inflammatory effect on focal cerebral ischemia in the subacute phase that is limited to neutrophil recruitment through the disrupted blood-brain barrier.

  16. C19orf12 and FA2H mutations are rare in Italian patients with neurodegeneration with brain iron accumulation.

    Science.gov (United States)

    Panteghini, Celeste; Zorzi, Giovanna; Venco, Paola; Dusi, Sabrina; Reale, Chiara; Brunetti, Dario; Chiapparini, Luisa; Zibordi, Federica; Siegel, Birgit; Siegel, Brigitte; Garavaglia, Barbara; Simonati, Alessandro; Bertini, Enrico; Nardocci, Nardo; Tiranti, Valeria

    2012-06-01

    Neurodegeneration with brain iron accumulation (NBIA) defines a wide spectrum of clinical entities characterized by iron accumulation in specific regions of the brain, predominantly in the basal ganglia. We evaluated the presence of FA2H and C19orf12 mutations in a cohort of 46 Italian patients with early onset NBIA, which were negative for mutations in the PANK2 and PLA2G6 genes. Follow-up molecular genetic and in vitro analyses were then performed. We did not find any mutations in the FA2H gene, although we identified 3 patients carrying novel mutations in the C19orf12 gene. The recent discovery of new genes responsible for NBIA extends the spectrum of the genetic investigation now available for these disorders and makes it possible to delineate a clearer clinical-genetic classification of different forms of this syndrome. A large fraction of patients still remain without a molecular genetics diagnosis, suggesting that additional NBIA genes are still to be discovered.

  17. Traffic jam at the blood-brain barrier promotes greater accumulation of Alzheimer's disease amyloid-β proteins in the cerebral vasculature.

    Science.gov (United States)

    Agyare, Edward K; Leonard, Sarah R; Curran, Geoffry L; Yu, Caroline C; Lowe, Val J; Paravastu, Anant K; Poduslo, Joseph F; Kandimalla, Karunya K

    2013-05-06

    Amyloid-β (Aβ) deposition in the brain vasculature results in cerebral amyloid angiopathy (CAA), which occurs in about 80% of Alzheimer's disease (AD) patients. While Aβ42 predominates parenchymal amyloid plaques in AD brain, Aβ40 is prevalent in the cerebrovascular amyloid. Dutch mutation of Aβ40 (E22Q) promotes aggressive cerebrovascular accumulation and leads to severe CAA in the mutation carriers; knowledge of how DutchAβ40 drives this process more efficiently than Aβ40 could reveal various pathophysiological events that promote CAA. In this study we have demonstrated that DutchAβ40 shows preferential accumulation in the blood-brain-barrier (BBB) endothelial cells due to its inefficient blood-to-brain transcytosis. Consequently, DutchAβ40 establishes a permeation barrier in the BBB endothelium, prevents its own clearance from the brain, and promotes the formation of amyloid deposits in the cerebral microvessels. The BBB endothelial accumulation of native Aβ40 is not robust enough to exercise such a significant impact on its brain clearance. Hence, the cerebrovascular accumulation of Aβ40 is slow and may require other copathologies to precipitate into CAA. In conclusion, the magnitude of Aβ accumulation in the BBB endothelial cells is a critical factor that promotes CAA; hence, clearing vascular endothelium of Aβ proteins may halt or even reverse CAA.

  18. Nicotine Elicits Convulsive Seizures by Activating Amygdalar Neurons

    Science.gov (United States)

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

    2017-01-01

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

  19. 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

    ethylenediaminetetraacetic acid (EDTA). The lower organic phases were isolated and evaporated to dryness under a stream of nitrogen and the lipids were redissolved in CDCl-CHOH-HO 100.0:29.9:5.2 (v/v/v) for NMR analysis. Increasing the period of post-decapitative ischemia resulted in an accumulation of two signals......-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 preparation of the NMR samples allowed the separation of the chemical shifts of N-acyl-ethanolamine phospholipids from those of the ethanolamine phospholipids. Moreover, the chemical shift of cardiolipin was moved from 0.15 ppm observed with Cs-EDTA to about 0.31 ppm with K-EDTA. The present study...

  20. 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.

  1. 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

  2. The accumulation of brain water-free sodium is associated with ischemic damage independent of the blood pressure in female rats.

    Science.gov (United States)

    Sumiyoshi, Manabu; Kitazato, Keiko T; Yagi, Kenji; Miyamoto, Takeshi; Kurashiki, Yoshitaka; Matsushita, Nobuhisa; Kinouchi, Tomoya; Kuwayama, Kazuyuki; Satomi, Junichiro; Nagahiro, Shinji

    2015-08-01

    Estrogen deficiency worsens ischemic stroke outcomes. In ovariectomized (OVX(+)) rats fed a high-salt diet (HSD), an increase in the body Na(+)/water ratio, which characterizes water-free Na(+) accumulation, was associated with detrimental vascular effects independent of the blood pressure (BP). We hypothesized that an increase in brain water-free Na(+) accumulation is associated with ischemic brain damage in OVX(+)/HSD rats. To test our hypothesis we divided female Wistar rats into 4 groups, OVX(+) and OVX(-) rats fed HSD or a normal diet (ND), and subjected them to transient cerebral ischemia. The brain Na(+)/water ratio was increased even in OVX(+)/ND rats and augmented in OVX(+)/HSD rats. The increase in the brain Na(+)/water ratio was positively correlated with expansion of the cortical infarct volume without affecting the BP. Interestingly, OVX(+) was associated with the decreased expression of ATP1α3, a subtype of the Na(+) efflux pump. HSD increased the expression of brain Na(+) influx-related molecules and the mineralocorticoid receptor (MR). The pretreatment of OVX(+)/HSD rats with the MR antagonist eplerenone reduced brain water-free Na(+) accumulation, up-regulated ATP1α3, down-regulated MR, and reduced the cortical infarct volume. Our findings show that the increase in the brain Na(+)/water ratio elicited by estrogen deficiency or HSD is associated with ischemic brain damage BP-independently, suggesting the importance of regulating the accumulation of brain water-free Na(+). The up-regulation of ATP1α3 and the down-regulation of MR may provide a promising therapeutic strategy to attenuate ischemic brain damage in postmenopausal women.

  3. 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.

  4. 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.

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

    Science.gov (United States)

    Uteshev, Victor V

    2014-03-15

    In the central nervous system, deficits in cholinergic neurotransmission correlate with decreased attention and cognitive impairment, while stimulation of neuronal nicotinic acetylcholine receptors improves attention, cognitive performance and neuronal resistance to injury as well as produces robust analgesic and anti-inflammatory effects. The rational basis for the therapeutic use of orthosteric agonists and positive allosteric modulators (PAMs) of nicotinic receptors arises from the finding that functional nicotinic receptors are ubiquitously expressed in neuronal and non-neuronal tissues including brain regions highly vulnerable to traumatic and ischemic types of injury (e.g., cortex and hippocampus). Moreover, functional nicotinic receptors do not vanish in age-, disease- and trauma-related neuropathologies, but their expression and/or activation levels decline in a subunit- and brain region-specific manner. Therefore, augmenting the endogenous cholinergic tone by nicotinic agents is possible and may offset neurological impairments associated with cholinergic hypofunction. Importantly, because neuronal damage elevates extracellular levels of choline (a selective agonist of α7 nicotinic acetylcholine receptors) near the site of injury, α7-PAM-based treatments may augment pathology-activated α7-dependent auto-therapies where and when they are most needed (i.e., in the penumbra, post-injury). Thus, nicotinic-PAM-based treatments are expected to augment the endogenous cholinergic tone in a spatially and temporally restricted manner creating the potential for differential efficacy and improved safety as compared to exogenous orthosteric nicotinic agonists that activate nicotinic receptors indiscriminately. In this review, I will summarize the existing trends in therapeutic applications of nicotinic PAMs.

  6. Century Tide Nicotine Patch

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Century Tide Nicotine Patch, a hi-tech smoking control therapy, is designed in accordance with the scientific principle of nicotine replacement. The therapy is promoted by the World Health Organization. Meanwhile, it also integrates traditional Chinese medical therapy and adopts advanced TTS technology.

  7. Developmental Neurotoxicity of Tobacco Smoke Directed Toward Cholinergic and Serotonergic Systems: More Than Just Nicotine.

    Science.gov (United States)

    Slotkin, Theodore A; Skavicus, Samantha; Card, Jennifer; Stadler, Ashley; Levin, Edward D; Seidler, Frederic J

    2015-09-01

    Tobacco smoke contains thousands of compounds in addition to nicotine, a known neuroteratogen. We evaluated the developmental neurotoxicity of tobacco smoke extract (TSE) administered to pregnant rats starting preconception and continued through the second postnatal week. We simulated nicotine concentrations encountered with second-hand smoke, an order of magnitude below those seen in active smokers, and compared TSE with an equivalent dose of nicotine alone, and to a 10-fold higher nicotine dose. We conducted longitudinal evaluations in multiple brain regions, starting in adolescence (postnatal day 30) and continued to full adulthood (day 150). TSE exposure impaired presynaptic cholinergic activity, exacerbated by a decrement in nicotinic cholinergic receptor concentrations. Although both nicotine doses produced presynaptic cholinergic deficits, these were partially compensated by hyperinnervation and receptor upregulation, effects that were absent with TSE. TSE also produced deficits in serotonin receptors in females that were not seen with nicotine. Regression analysis showed a profound sex difference in the degree to which nicotine could account for overall TSE effects: whereas the 2 nicotine doses accounted for 36%-46% of TSE effects in males, it accounted for only 7%-13% in females. Our results show that the adverse effects of TSE on neurodevelopment exceed those that can be attributed to just the nicotine present in the mixture, and further, that the sensitivity extends down to levels commensurate with second-hand smoke exposure. Because nicotine itself evoked deficits at low exposures, "harm reduction" nicotine products do not eliminate the potential for neurodevelopmental damage.

  8. Epidermal Growth Factor Treatment of the Adult Brain Subventricular Zone Leads to Focal Microglia/Macrophage Accumulation and Angiogenesis

    Directory of Open Access Journals (Sweden)

    Olle R. Lindberg

    2014-04-01

    Full Text Available One of the major components of the subventricular zone (SVZ neurogenic niche is the specialized vasculature. The SVZ vasculature is thought to be important in regulating progenitor cell proliferation and migration. Epidermal growth factor (EGF is a mitogen with a wide range of effects. When stem and progenitor cells in the rat SVZ are treated with EGF, using intracerebroventricular infusion, dysplastic polyps are formed. Upon extended infusion, blood vessels are recruited into the polyps. In the current study we demonstrate how polyps develop through distinct stages leading up to angiogenesis. As polyps progress, microglia/macrophages accumulate in the polyp core concurrent with increasing cell death. Both microglia/macrophage accumulation and cell death peak during angiogenesis and subsequently decline following polyp vascularization. This model of inducible angiogenesis in the SVZ neurogenic niche suggests involvement of microglia/macrophages in acquired angiogenesis and can be used in detail to study angiogenesis in the adult brain.

  9. Dementia means number of things - the overlap of neurodegeneration with brain iron accumulation (NBIA) and Alzheimer changes: an autopsy case.

    Science.gov (United States)

    Dziewulska, Dorota; Domitrz, Izabela; Domzał-Stryga, Anna

    2010-01-01

    In humans overlap between various neurodegenerative disorders is a well known phenomenon. We reported a case of a 77-year-old woman with parkinsonism, dystonia, psychiatric symptoms and progressing dementia misdiagnosed at the age of 51 years as Parkinson's disease. Histopathological examination of the patient's brain performed 26 years after the disease onset revealed numerous axonal spheroids and iron deposits in structures of the nigro-pallido-striatal system that enabled to diagnose neurodegeneration with brain iron accumulation (NBIA) (former Hallervorden-Spatz syndrome), and changes characteristic for Alzheimer's disease (AD). NBIA is a group of rare clinically and genetically heterogeneous diseases of the extrapyramidal system which common feature is abnormal iron storage in the basal ganglia. Disturbed iron metabolism is also one of the hypothetical patho-mechanisms of AD. A coexistence of morphological changes characteristic for AD and NBIA in our patient suggests that similar molecular mechanisms may be involved in pathogenesis of various neurodegenerative processes, especially in disorders with iron dyshomeostasis. This case contributes also to the increasing evidence of NBIA heterogeneity.

  10. 利用稳定同位素内标微透析技术进行尼古丁脑局部药动学研究%Study of pharmacokinetics of nicotine in local brain by using microdialysis and stable labeled isotope

    Institute of Scientific and Technical Information of China (English)

    吴秀君; 凌家俊; 付湘; 秦泽慧; 张英丰

    2011-01-01

    采用以稳定同位素为内标的微透析技术,研究清醒自由活动下大鼠脑局部药动学过程.健康SD大鼠为研究对象,以尼古T(nicotine)为模型药物,以氘代尼古丁(deuterium labeled nicotine,DL-nicotine)为微透析(microdialysis,MD)的内标物.样品采用LC-MS/MS法检测,同时测定透析液中尼古丁及DL-尼古丁的浓度.数据分析采用DAS2.0软件.经皮给予尼古丁后,大鼠脑局部尼古丁的吸收和分布过程符合二室模型,其中tin.为170.31 min,t1/2,6为263.30 min,AUC0-∞为2.75×105μg·L-1·min.DL-尼古丁可作为尼古丁的内标物进行探针回收率的校正;稳定同位素内标微透析技术可实现尼古丁在清醒状态大鼠脑局部药动学的研究,为戒烟方法的寻找及尼古丁经皮制剂的药动学一药效学相结合的研究提供了新思路.%The paper is to report the study of pharmacokinetics of transdermal administered nicotine in the brain of freely moving rat by using microdialysis with stable labeled isotope as internal standard. The pharmacokinetic behavior of nicotine in Sprague Dawley rat brain was investigated after intranasal administration (3.75 mg). Brain fluid samples were collected by intracerebral microdialysis with DL-nicotine as intemal standard. Concentrations of nicotine and DL-nicotine in the sample were measured by HPLC-MS/MS. Main pharmacokinetic parameters were calculated and analyzed by Das 2.0 pharmacokinetic software. The recovery of nicotine and the delivery of DL-nicotine were the same. The fate of absorption and distribution was two compartment model and the values of t1/2α was 170.31 min,t1/2β was 263.30 min and the AUC0-∞ was 2.75x105 μg·L-1.min separately. DL-nicotine can be used to calibrate the recovery of nicotine, and the new method of stable isotope microdialysis can be used to study the pharmacokinetics of freely moving rat. It will make sense for the treatment of addiction of tobacco and provide a new thought for the

  11. Activities of nicotinic acetylcholine receptors modulate neurotransmission and synaptic architecture

    Institute of Scientific and Technical Information of China (English)

    Akira Oda; Hidekazu Tanaka

    2014-01-01

    The cholinergic system is involved in a broad spectrum of brain function, and its failure has been implicated in Alzheimer’s disease. Acetylcholine transduces signals through muscarinic and nicotinic acetylcholine receptors, both of which inlfuence synaptic plasticity and cognition. However, the mechanisms that relate the rapid gating of nicotinic acetylcholine receptors to per-sistent changes in brain function have remained elusive. Recent evidence indicates that nicotinic acetylcholine receptors activities affect synaptic morphology and density, which result in per-sistent rearrangements of neural connectivity. Further investigations of the relationships between nicotinic acetylcholine receptors and rearrangements of neural circuitry in the central nervous system may help understand the pathogenesis of Alzheimer’s disease.

  12. 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.

  13. Functional interaction between Lypd6 and nicotinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Arvaniti, Maria; Jensen, Majbrit M; Soni, Neeraj;

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) affect multiple physiological functions in the brain and their functions are modulated by regulatory proteins of the Lynx family. Here, we report for the first time a direct interaction of the Lynx protein LY6/PLAUR domain-containing 6 (Lypd6) with n......AChRs in human brain extracts, identifying Lypd6 as a novel regulator of nAChR function. Using protein cross-linking and affinity purification from human temporal cortical extracts, we demonstrate that Lypd6 is a synaptically enriched membrane-bound protein that binds to multiple nAChR subtypes in the human...... brain. Additionally, soluble recombinant Lypd6 protein attenuates nicotine-induced hippocampal inward currents in rat brain slices and decreases nicotine-induced extracellular signal-regulated kinase phosphorylation in PC12 cells, suggesting that binding of Lypd6 is sufficient to inhibit n...

  14. Distribution of mercury in metallothionein-null mice after exposure to mercury vapor: amount of metallothionein isoform does not affect accumulation of mercury in the brain.

    Science.gov (United States)

    Yasutake, Akira; Yoshida, Minoru; Honda, Akiko; Watanabe, Chiho; Satoh, Masahiko

    2012-01-01

    To examine the contribution of metallothionein (MT) to mercury accumulation in mouse tissues, 129 strain female mice and MT null mice were exposed to metallic mercury vapor at a sub-toxic level, and Hg levels in the brain, kidney and liver were determined on 1, 3 and 7 days after the exposure. After exposure to mercury vapor, significant Hg accumulation was observed in the brains of wild-type and MT-I/II null and MT-III null mice, as well as in the liver and kidneys. No strain difference was observed in the tissue Hg accumulations 24 hr after the exposure except for the kidneys, where the highest accumulation was found in MT-III null mice. Although the brains of MT-III null mice showed slightly higher Hg accumulation than the other two strains, no significant difference was observed except in the cerebrum on Day 7. Gel chromatograms of cerebrum soluble fractions revealed that a significant amount of Hg existed as an MT-bound form in all the mouse strains. On the other hand, MT-bound Hg was found as a minor fraction in soluble fractions of the kidneys and livers in wild-type and MT-III null mice. Despite a significant strain difference in total MT levels in the cerebrum, there was no difference among the three strains in the amount of Hg accumulated in the cerebrum and its distribution rates in MT fractions. The present study demonstrated that brain uptake of Hg(0) and its accumulation as Hg(2+) did not depend on the amount of MT isoform in the tissue, at least in the early phase.

  15. 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.

  16. The role of nicotine in smoking: a dual-reinforcement model.

    Science.gov (United States)

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

    2009-01-01

    Models of intravenous nicotine self-administration in laboratory animals are being used to investigate the behavioral and neurobiological consequences of nicotine reinforcement, and to aid in the development of novel pharmacotherapies for smoking cessation. Central to these models is the principle of primary reinforcement, which posits that response-contingent presentation of a primary reinforcer, nicotine, engenders robust operant behavior, whereas response-independent drug delivery does not. This dictum of nicotine as a primary reinforcer has been widely used to explain why people smoke tobacco-smoking results in the rapid delivery of nicotine to the brain, setting up a cascade of neurobiological processes that strengthen subsequent smoking behavior. However, there is mounting evidence that the primary reinforcement model of nicotine self-administration fails to fully explain existing data from both the animal self-administration and human smoking literatures. We have recently proposed a "dual reinforcement" model to more fully capture the relationship between nicotine and self-administration, including smoking. Briefly, the "dual reinforcement" model posits that nicotine acts as both a primary reinforcer and a reinforcement enhancer. The latter action of nicotine had originally been uncovered by showing that a reinforcing VS, which accompanies nicotine delivery, synergizes with nicotine in the acquisition and maintenance of self-administration, and that this synergism can be reproduced by combining operant responding for the reinforcing stimulus with non-contingent (response-independent) nicotine. Thus, self-administration (and smoking) is sustained by three actions: (1) nicotine, acting as a primary reinforcer, can sustain behavior that leads to its delivery; (2) nicotine, acting as a primary reinforcer, can establish neutral environmental stimuli as conditioned reinforcers through Pavlovian associations; and (3) nicotine, acting as a reinforcement enhancer

  17. Effects of Menthol on Nicotine Pharmacokinetic, Pharmacology and Dependence in Mice.

    Directory of Open Access Journals (Sweden)

    Shakir D Alsharari

    Full Text Available Although menthol, a common flavoring additive to cigarettes, has been found to impact the addictive properties of nicotine cigarettes in smokers little is known about its pharmacological and molecular actions in the brain. Studies were undertaken to examine whether the systemic administration of menthol would modulate nicotine pharmacokinetics, acute pharmacological effects (antinociception and hypothermia and withdrawal in male ICR mice. In addition, we examined changes in the brain levels of nicotinic receptors of rodents exposed to nicotine and menthol. Administration of i.p. menthol significantly decreased nicotine's clearance (2-fold decrease and increased its AUC compared to i.p. vehicle treatment. In addition, menthol pretreatment prolonged the duration of nicotine-induced antinociception and hypothermia (2.5 mg/kg, s.c. for periods up to 180 min post-nicotine administration. Repeated administration of menthol with nicotine increased the intensity of mecamylamine-precipitated withdrawal signs in mice exposed chronically to nicotine. The potentiation of withdrawal intensity by menthol was accompanied by a significant increase in nicotine plasma levels in these mice. Western blot analyses of α4 and β2 nAChR subunit expression suggests that chronic menthol impacts the levels and distribution of these nicotinic subunits in various brain regions. In particular, co-administration of menthol and nicotine appears to promote significant increase in β2 and α4 nAChR subunit expression in the hippocampus, prefrontal cortex and striatum of mice. Surprisingly, chronic injections of menthol alone to mice caused an upregulation of β2 and α4 nAChR subunit levels in these brain regions. Because the addition of menthol to tobacco products has been suggested to augment their addictive potential, the current findings reveal several new pharmacological molecular adaptations that may contribute to its unique addictive profile.

  18. Effects of Menthol on Nicotine Pharmacokinetic, Pharmacology and Dependence in Mice.

    Science.gov (United States)

    Alsharari, Shakir D; King, Justin R; Nordman, Jacob C; Muldoon, Pretal P; Jackson, Asti; Zhu, Andy Z X; Tyndale, Rachel F; Kabbani, Nadine; Damaj, M Imad

    2015-01-01

    Although menthol, a common flavoring additive to cigarettes, has been found to impact the addictive properties of nicotine cigarettes in smokers little is known about its pharmacological and molecular actions in the brain. Studies were undertaken to examine whether the systemic administration of menthol would modulate nicotine pharmacokinetics, acute pharmacological effects (antinociception and hypothermia) and withdrawal in male ICR mice. In addition, we examined changes in the brain levels of nicotinic receptors of rodents exposed to nicotine and menthol. Administration of i.p. menthol significantly decreased nicotine's clearance (2-fold decrease) and increased its AUC compared to i.p. vehicle treatment. In addition, menthol pretreatment prolonged the duration of nicotine-induced antinociception and hypothermia (2.5 mg/kg, s.c.) for periods up to 180 min post-nicotine administration. Repeated administration of menthol with nicotine increased the intensity of mecamylamine-precipitated withdrawal signs in mice exposed chronically to nicotine. The potentiation of withdrawal intensity by menthol was accompanied by a significant increase in nicotine plasma levels in these mice. Western blot analyses of α4 and β2 nAChR subunit expression suggests that chronic menthol impacts the levels and distribution of these nicotinic subunits in various brain regions. In particular, co-administration of menthol and nicotine appears to promote significant increase in β2 and α4 nAChR subunit expression in the hippocampus, prefrontal cortex and striatum of mice. Surprisingly, chronic injections of menthol alone to mice caused an upregulation of β2 and α4 nAChR subunit levels in these brain regions. Because the addition of menthol to tobacco products has been suggested to augment their addictive potential, the current findings reveal several new pharmacological molecular adaptations that may contribute to its unique addictive profile.

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

    Science.gov (United States)

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

    2012-03-01

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

  20. 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.

  1. Nicotine inhibits memory CTL programming.

    Directory of Open Access Journals (Sweden)

    Zhifeng Sun

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

  2. Nicotine inhibits memory CTL programming.

    Science.gov (United States)

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

    2013-01-01

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

  3. Engineering of a hybrid nanoparticle-based nicotine nanovaccine as a next-generation immunotherapeutic strategy against nicotine addiction: A focus on hapten density.

    Science.gov (United States)

    Zhao, Zongmin; Powers, Kristen; Hu, Yun; Raleigh, Michael; Pentel, Paul; Zhang, Chenming

    2017-04-01

    Although vaccination is a promising way to combat nicotine addiction, most traditional hapten-protein conjugate nicotine vaccines only show limited efficacy due to their poor recognition and uptake by immune cells. This study aimed to develop a hybrid nanoparticle-based nicotine vaccine with improved efficacy. The focus was to study the impact of hapten density on the immunological efficacy of the proposed hybrid nanovaccine. It was shown that the nanovaccine nanoparticles were taken up by the dendritic cells more efficiently than the conjugate vaccine, regardless of the hapten density on the nanoparticles. At a similar hapten density, the nanovaccine induced a significantly stronger immune response against nicotine than the conjugate vaccine in mice. Moreover, the high- and medium-density nanovaccines resulted in significantly higher anti-nicotine antibody titers than their low-density counterpart. Specifically, the high-density nanovaccine exhibited better immunogenic efficacy, resulting in higher anti-nicotine antibody titers and lower anti-carrier protein antibody titers than the medium- and low-density versions. The high-density nanovaccine also had the best ability to retain nicotine in serum and to block nicotine from entering the brain. These results suggest that the hybrid nanoparticle-based nicotine vaccine can elicit strong immunogenicity by modulating the hapten density, thereby providing a promising next-generation immunotherapeutic strategy against nicotine addiction.

  4. Nicotine addiction and withdrawal

    Science.gov (United States)

    ... Hg Possibly cause sweating, nausea, and diarrhea Stimulate memory and alertness; people who use tobacco often depend on it to help them accomplish certain tasks and perform well Symptoms of nicotine withdrawal appear within 2 to 3 hours after ...

  5. Nicotine and health.

    Science.gov (United States)

    2014-07-01

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

  6. Synthesis and biodistribution of radioiodinated nicotine analogs

    Energy Technology Data Exchange (ETDEWEB)

    Chan, S.M.; Basmadjian, G.P.; Marten, D.F.; Sadek, S.; Magarian, R.A.; Grunder, J.R.; Ice, R.D.

    1984-01-01

    The authors reported previously on the synthesis and biodistribution of radioiodinated 5-iodonicotine. In their continuous effort to search for a potential brain as well as adrenal medulla imaging agent, the authors synthesized four radioiodinated nicotine analogs. The labeled compounds were prepared by brominating nicotinic acid, and reacting the acylated product with the appropriate amines to give the respective amides which were then reduced with diborane to the amines. I-125 labeling was done by halogen exchange. Biodistribution studies performed in female Sprague-Dawley rats showed that all these compounds were taken up rapidly by the brain and the adrenal. The highest uptake of all these compounds in both organs occurred at 2 minutes after tail vein injections. The organ:blood ratios at 2 minutes and the T/sub 1/3/ (min.) of radioactivity in these organs were compared.

  7. Comparison of mercury accumulation among the brain, liver, kidney, and the brain regions of rats administered methylmercury in various phases of postnatal development

    Energy Technology Data Exchange (ETDEWEB)

    Sakamoto, M.; Nakano, A. [National Institute for Minamata Disease, Kumamoto (Japan)

    1995-10-01

    Several animal studies have indicated that a developing organism in its prenatal and early postnatal stage may be at higher risk in toxic metal exposure than in adult stage. Many infants were congenitally affected by methylmercury in the epidemics in Japan and Iraq. The infants reported from Minamata, Japan, had severe cerebral palsy, whereas their mothers had mild or no manifestations of poisoning. Some of the high susceptibility in infants may resulted from the specific features of the methylmercury metabolism in the developing organisms. Prenatal or postnatal development is characterized by functional immaturity of organs, which may affect the mercury (Hg) accumulation among organs. It seems possible that the Hg distribution might, in fact, reflect the toxic effects of methylmercury during a given developing phase. Thus, its distribution deserves closer examination. In our previous study, when a toxic level of methylmercury was administered, the Hg distribution and its effects on body weight gain and neurological disorders were found to be different among the rat postnatal developing phases. In the present study the Hg distribution among organs and brain regions was investigated during the several development phases with a nontoxic level of methylmercury treatment. 24 refs., 1 fig., 2 tabs.

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

    Science.gov (United States)

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

    2009-11-01

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

  9. Defective lipid metabolism in neurodegeneration with brain iron accumulation (NBIA) syndromes: not only a matter of iron.

    Science.gov (United States)

    Colombelli, Cristina; Aoun, Manar; Tiranti, Valeria

    2015-01-01

    Neurodegeneration with brain iron accumulation (NBIA) is a group of devastating and life threatening rare diseases. Adult and early-onset NBIA syndromes are inherited as X-chromosomal, autosomal dominant or recessive traits and several genes have been identified as responsible for these disorders. Among the identified disease genes, only two code for proteins directly involved in iron metabolism while the remaining NBIA genes encode proteins with a wide variety of functions ranging from fatty acid metabolism and autophagy to still unknown activities. It is becoming increasingly evident that many neurodegenerative diseases are associated with metabolic dysfunction that often involves altered lipid metabolism. This is not surprising since neurons have a peculiar and heterogeneous lipid composition critical for the development and correct functioning of the nervous system. This review will focus on specific NBIA forms, namely PKAN, CoPAN, PLAN, FAHN and MPAN, which display an interesting link between neurodegeneration and alteration of phospholipids and sphingolipids metabolism, mitochondrial morphology and membrane remodelling.

  10. Nicotine increases GABAergic input on rat dorsal raphe serotonergic neurons through alpha7 nicotinic acetylcholine receptor.

    Science.gov (United States)

    Hernández-Vázquez, F; Chavarría, K; Garduño, J; Hernández-López, S; Mihailescu, S P

    2014-12-15

    The dorsal raphe nucleus (DRN) contains large populations of serotonergic (5-HT) neurons. This nucleus receives GABAergic inhibitory afferents from many brain areas and from DRN interneurons. Both GABAergic and 5-HT DRN neurons express functional nicotinic acetylcholine receptors (nAChRs). Previous studies have demonstrated that nicotine increases 5-HT release and 5-HT DRN neuron discharge rate by stimulating postsynaptic nAChRs and by increasing glutamate and norepinephrine release inside DRN. However, the influence of nicotine on the GABAergic input to 5-HT DRN neurons was poorly investigated. Therefore, the aim of this work was to determine the effect of nicotine on GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) of 5-HT DRN neurons and the subtype of nAChR(s) involved in this response. Experiments were performed in coronal slices obtained from young Wistar rats. GABAergic sIPSCs were recorded from post hoc-identified 5-HT DRN neurons with the whole cell voltage patch-clamp technique. Administration of nicotine (1 μM) increased sIPSC frequency in 72% of identified 5-HT DRN neurons. This effect was not reproduced by the α4β2 nAChR agonist RJR-2403 and was not influenced by TTX (1 μM). It was mimicked by the selective agonist for α7 nAChR, PNU-282987, and exacerbated by the positive allosteric modulator of the same receptor, PNU-120596. The nicotine-induced increase in sIPSC frequency was independent on voltage-gated calcium channels and dependent on Ca(2+)-induced Ca(2+) release (CICR). These results demonstrate that nicotine increases the GABAergic input to most 5-HT DRN neurons, by activating α7 nAChRs and producing CICR in DRN GABAergic terminals.

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

    Directory of Open Access Journals (Sweden)

    Linzy M. Hendrickson

    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.

  12. 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…

  13. Prenatal nicotine alters vigilance states and AchR gene expression in the neonatal rat: implications for SIDS.

    Science.gov (United States)

    Frank, M G; Srere, H; Ledezma, C; O'Hara, B; Heller, H C

    2001-04-01

    Maternal smoking is a major risk factor for sudden infant death syndrome (SIDS). The mechanisms by which cigarette smoke predisposes infants to SIDS are not known. We examined the effects of prenatal nicotine exposure on sleep/wake ontogenesis and central cholinergic receptor gene expression in the neonatal rat. Prenatal nicotine exposure transiently increased sleep continuity and accelerated sleep/wake ontogeny in the neonatal rat. Prenatal nicotine also upregulated nicotinic and muscarinic cholinergic receptor mRNAs in brain regions involved in regulating vigilance states. These findings suggest that the nicotine contained in cigarette smoke may predispose human infants to SIDS by interfering with the normal maturation of sleep and wake.

  14. Thermochemical Properties of Nicotine Salts

    Directory of Open Access Journals (Sweden)

    Riggs DM

    2014-12-01

    Full Text Available The thermal gravimetric analysis (TGA and differential scanning calorimetry (DSC results presented in this report clearly show that the thermal stability and the endothermic peak nicotine release temperatures are different for different nicotine salts and these temperatures appear to be linked to the general microstructural details of the salt itself. In addition, the peak nicotine release temperatures are highly dependent upon the sample size used. The heat of vaporization for neat (non-protonated nicotine is also sample-size dependent. The TGA data showed that the least stable of the salts tested at elevated temperatures was the liquid salt nicotine triacetate followed by the crystalline materials (e.g., nicotine gallate and finally, the amorphous salts (e.g., nicotine alginate. The DSC results revealed that the liquid and crystalline salts exhibit nicotine release endotherms that are strongly related to the sample weight being tested. The amorphous salts show nicotine endotherm peak temperatures that are nearly independent of the sample weight. The range of peak nicotine release temperatures varied depending upon the specific salts and the sample size from 83 oC to well over 200 oC. Based on these results, the evolution of nicotine from the nicotine salt should be expected to vary based on the composition of the salt, the details of its microstructure, and the amount of nicotine salt tested.

  15. Nicotine Inhibits Memory CTL Programming

    OpenAIRE

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

    2013-01-01

    Nicotine is the main tobacco component responsible for tobacco addiction and is used extensively in smoking and smoking cessation therapies. However, little is known about its effects on the immune system. We confirmed that multiple nicotinic receptors are expressed on mouse and human cytotoxic T lymphocytes (CTLs) and demonstrated that nicotinic receptors on mouse CTLs are regulated during activation. Acute nicotine presence during activation increases primary CTL expansion in vitro, but imp...

  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. Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-gp/ABCB1) transport afatinib and restrict its oral availability and brain accumulation.

    Science.gov (United States)

    van Hoppe, Stéphanie; Sparidans, Rolf W; Wagenaar, Els; Beijnen, Jos H; Schinkel, Alfred H

    2017-03-10

    Afatinib is a highly selective, irreversible inhibitor of EGFR and (HER)-2. It is orally administered for the treatment of patients with EGFR mutation-positive types of metastatic NSCLC. We investigated whether afatinib is a substrate for the multidrug efflux transporters ABCB1 and ABCG2 and whether these transporters influence oral availability and brain and other tissue accumulation of afatinib. We used in vitro transport assays to assess human (h)ABCB1-, hABCG2- or murine (m)Abcg2-mediated transport of afatinib. To study the single and combined roles of Abcg2 and Abcb1a/1b in oral afatinib disposition, we used appropriate knockout mouse strains. Afatinib was transported well by hABCB1, hABCG2 and mAbcg2 in vitro. Upon oral administration of afatinib, Abcg2(-/-), Abcb1a/1b(-/-) and Abcb1a/1b(-/-);Abcg2(-/-) mice displayed a 4.2-, 2.4- and 7-fold increased afatinib plasma AUC0-24 compared with wild-type mice. Abcg2-deficient strains also displayed decreased afatinib plasma clearance. At 2h, relative brain accumulation of afatinib was not significantly altered in the single knockout strains, but 23.8-fold increased in Abcb1a/1b(-/-);Abcg2(-/-) mice compared to wild-type mice. Abcg2 and Abcb1a/1b restrict oral availability and brain accumulation of afatinib. Inhibition of these transporters may therefore be of clinical importance for patients with brain (micro)metastases positioned behind an intact blood-brain barrier.

  18. Reinforcer devaluation as a consequence of acute nicotine exposure and withdrawal

    Science.gov (United States)

    Kirshenbaum, Ari; Green, John; Fay, Michael; Parks, Angelique; Phillips, Jesse; Stone, Jason; Roy, Tessa

    2014-01-01

    RATIONALE Nicotine discontinuation produces behaviors in rats that are congruent with anhedonia, and these symptoms may be related to the devaluation of non-nicotine reinforcers. OBJECTIVE Four separate experiments were performed to explore the parameters surrounding nicotine-induced reinforcer devaluation. METHODS In Experiments 1 and 2, nicotine (0.1 or 0.3 mg/kg) or 0.3 mg/kg nicotine plus 1.0 mg/kg mecamylamine was delivered to rats prior to progressive ratio (PR) schedule sessions in which sucrose was used as a reinforcer. In order to (a) evaluate reinforcer enhancement by nicotine, and (b) reinforcer devaluation in the absence of nicotine, all rats experienced two PR schedule sessions per day for 10 days. Experiment 3 involved nicotine (0.3 mg/kg) and a visual stimulus in place of sucrose reinforcement. In Experiment 4, rats received nicotine (0.3 mg/kg) either before or after a single PR-schedule session for 10 days. RESULTS Experiments 1 and 2 demonstrate that reinforcer devaluation is related to the occupation of nicotinic-acetylcholine receptors. Results from Experiment 3 provide some evidence that devaluation occurs with either sucrose or visual-stimulus reinforcement. Experiment 4 demonstrates that a necessary condition for reinforcer devaluation to occur is the concurrent exposure to the reinforcer and nicotine. CONCLUSIONS Reinforcer devaluation in rats emerges rapidly in a progressive, orderly fashion that coincides with accumulated exposure to nicotine. These results suggest that reinforcer devaluation may be a feature of nicotine that contributes to the abuse liability of tobacco products. PMID:25401169

  19. Effects of ganglion blocking agents on nicotine extensor convulsions and lethality in mice

    Science.gov (United States)

    Aceto, M. D.; Bentley, H. C.; Dembinski, J. R.

    1969-01-01

    1. The ganglion blocking agents, chlorisondamine, pentamethonium, mecamylamine, decamethonium and hexamethonium all block nicotine extensor convulsions when administered intraventricularly in mice. Tetraethylammonium was inactive. 2. For the intraventricular route, there is a relationship between ganglionic blocking potency and blocking of nicotine extensor convulsions. Indirect evidence suggests that the site(s) of action of nicotine extensor convulsions and lethality is central in origin and associated with brain areas near the ventricles. 3. When ganglion blocking agents are given orally, subcutaneously or intravenously varying degrees of protection can be observed probably depending on factors such as whether or not the drugs cross the blood-brain barrier, absorption, etc., and the effectiveness in protecting mice from nicotine is not related to ganglionic blocking potency. 4. Atropine and morphine given intraventricularly or subcutaneously did not protect mice from the LD95 of nicotine. Chlorpromazine gave very erratic results and phenobarbitone was effective subcutaneously and to a lesser extent intraventricularly. PMID:4390479

  20. Nicotine: the Desirable Drug

    Institute of Scientific and Technical Information of China (English)

    瞿桂林

    2001-01-01

    Pure Nicotine,just three drops can kill an adult Yet every day,millions ofpeople take it into their lungs. 纯尼古丁,三滴就可以毒死一个成年人。但每天仍有数以百万的人将它吸入肺中。

  1. 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.)

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

    Science.gov (United States)

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

    2014-11-01

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

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

    Science.gov (United States)

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

    2017-02-01

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

  4. Vitamin E Nicotinate.

    Science.gov (United States)

    Duncan, Kimbell R; Suzuki, Yuichiro J

    2017-03-13

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

  5. Nicotine impact on melanogenesis and antioxidant defense system in HEMn-DP melanocytes.

    Science.gov (United States)

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

    2014-10-01

    Nicotine is a compound of tobacco plants and is responsible for addictive properties of tobacco which is used by about one billion of smokers all over the world. Recently, nicotine has drawn even more attention due to its presumed neuroprotective and antioxidant features as far as common use in various forms of smoking cessation therapies. It is suggested that nicotine may be accumulated in human tissues containing melanin. This may in turn influence biochemical processes in human cells producing melanin. The aim of this study was to examine the impact of nicotine on melanogenesis and antioxidant defense system in cultured normal human melanocytes (HEMn-DP). Nicotine induced concentration-dependent loss in melanocytes viability. The value of EC50 was determined to be 2.52 mM. Nicotine modulated melanin biosynthesis in normal human melanocytes. Significant changes in hydrogen peroxide content and cellular antioxidant enzymes: SOD, CAT, and GPx activities were stated in melanocytes exposed to nicotine, which indicates alterations of antioxidant defense system. The results obtained in vitro may explain a potential influence of nicotine on biochemical processes in melanocytes in vivo during long-term exposition to nicotine.

  6. Nicotinic Acetylcholine Receptors in the Pathophysiology of Alzheimer's Disease

    DEFF Research Database (Denmark)

    Thomsen, Morten Skøtt; Andreasen T., Jesper; Arvaniti, Maria

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) have been pursued for decades as potential molecular targets to treat cognitive dysfunction in Alzheimer's disease (AD) due to their positioning within regions of the brain critical in learning and memory, such as the prefrontal cortex and hippocampus...

  7. Functional interaction between Lypd6 and nicotinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Arvaniti, Maria; Jensen, Majbrit M; Soni, Neeraj;

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) affect multiple physiological functions in the brain and their functions are modulated by regulatory proteins of the Lynx family. Here, we report for the first time a direct interaction of the Lynx protein LY6/PLAUR domain-containing 6 (Lypd6) with n...

  8. Measuring brain manganese and iron accumulation in rats following 14 weeks of low-dose manganese treatment using atomic absorption spectroscopy and magnetic resonance imaging.

    Science.gov (United States)

    Fitsanakis, Vanessa A; Zhang, Na; Anderson, Joel G; Erikson, Keith M; Avison, Malcolm J; Gore, John C; Aschner, Michael

    2008-05-01

    Chronic exposure to manganese (Mn) may lead to a movement disorder due to preferential Mn accumulation in the globus pallidus and other basal ganglia nuclei. Iron (Fe) deficiency also results in increased brain Mn levels, as well as dysregulation of other trace metals. The relationship between Mn and Fe transport has been attributed to the fact that both metals can be transported via the same molecular mechanisms. It is not known, however, whether brain Mn distribution patterns due to increased Mn exposure vs. Fe deficiency are the same, or whether Fe supplementation would reverse or inhibit Mn deposition. To address these questions, we utilized four distinct experimental populations. Three separate groups of male Sprague-Dawley rats on different diets (control diet [MnT], Fe deficient [FeD], or Fe supplemented [FeS]) were given weekly intravenous Mn injections (3 mg Mn/kg body mass) for 14 weeks, whereas control (CN) rats were fed the control diet and received sterile saline injections. At the conclusion of the study, both blood and brain Mn and Fe levels were determined by atomic absorption spectroscopy and magnetic resonance imaging. The data indicate that changes in dietary Fe levels (either increased or decreased) result in regionally specific increases in brain Mn levels compared with CN or MnT animals. Furthermore, there was no difference in either Fe or Mn accumulation between FeS or FeD animals. These data suggest that dietary Fe manipulation, whether increased or decreased, may contribute to brain Mn deposition in populations vulnerable to increased Mn exposure.

  9. Developmental sex differences in nicotinic currents of prefrontal layer VI neurons in mice and rats.

    Directory of Open Access Journals (Sweden)

    Nyresa C Alves

    Full Text Available BACKGROUND: There is a large sex difference in the prevalence of attention deficit disorder; yet, relatively little is known about sex differences in the development of prefrontal attention circuitry. In male rats, nicotinic acetylcholine receptors excite corticothalamic neurons in layer VI, which are thought to play an important role in attention by gating the sensitivity of thalamic neurons to incoming stimuli. These nicotinic currents in male rats are significantly larger during the first postnatal month when prefrontal circuitry is maturing. The present study was undertaken to investigate whether there are sex differences in the nicotinic currents in prefrontal layer VI neurons during development. METHODOLOGY/PRINCIPAL FINDINGS: Using whole cell recording in prefrontal brain slice, we examined the inward currents elicited by nicotinic stimulation in male and female rats and two strains of mice. We found a prominent sex difference in the currents during the first postnatal month when males had significantly greater nicotinic currents in layer VI neurons compared to females. These differences were apparent with three agonists: acetylcholine, carbachol, and nicotine. Furthermore, the developmental sex difference in nicotinic currents occurred despite male and female rodents displaying a similar pattern and proportion of layer VI neurons possessing a key nicotinic receptor subunit. CONCLUSIONS/SIGNIFICANCE: This is the first illustration at a cellular level that prefrontal attention circuitry is differently affected by nicotinic receptor stimulation in males and females during development. This transient sex difference may help to define the cellular and circuit mechanisms that underlie vulnerability to attention deficit disorder.

  10. Effect of repeated nicotine exposure on high-affinity nicotinic acetylcholine receptor density in spontaneously hypertensive rats.

    Science.gov (United States)

    Hohnadel, Elizabeth J; Hernandez, Caterina M; Gearhart, Debra A; Terry, Alvin V

    Spontaneously hypertensive rats (SHRs) are often used as a model of attention deficit hyperactivity disorder (ADHD) and to investigate the effects of hypertension on cognitive function. Further, they appear to have reduced numbers of central nicotinic acetylcholine receptors (nAChRs) and, therefore, may be useful to model certain aspects of Alzheimer's disease (AD) and other forms of dementia given that a decrease in nAChRs is thought to contribute to cognitive decline in these disorders. In the present study, based on reports that chronic nicotine exposure increases nAChRs in several mammalian models, we tested the hypothesis that repeated exposures to a relatively low dose of the alkaloid would ameliorate the receptor deficits in SHR. Thus, young-adult SHRs and age-matched Wistar-Kyoto (WKY) control rats were treated with either saline or nicotine twice a day for 14 days (total daily dose = 0.7 mg/kg nicotine base) and then sacrificed. Quantitative receptor autoradiography with [125I]-IPH, an epibatidine analog, revealed: (1) that high-affinity nAChRs were higher in saline-treated WKY (control) rats compared to saline-treated SHRs in 18 of the 19 brain region measured, although statistically different only in the mediodorsal thalamic nuclei, (2) that nicotine significantly increased nAChR binding in WKY rats in six brain areas including cortical regions and the anterior thalamic nucleus, (3) that there were no cases where nicotine significantly increased nAChR binding in SHRs. These results indicate that subjects deficient in nAChRs may be less sensitive to nAChR upregulation with nicotine than normal subjects and require higher doses or longer periods of exposure.

  11. Beta2-containing nicotinic acetylcholine receptors mediate calcium/calmodulin-dependent protein kinase-II and synapsin I protein levels in the nucleus accumbens after nicotine withdrawal in mice.

    Science.gov (United States)

    Jackson, Kia J; Imad Damaj, M

    2013-02-15

    Nicotinic acetylcholine receptors are calcium-permeable and the initial targets for nicotine. Studies suggest that calcium-dependent mechanisms mediate some behavioral responses to nicotine; however, the post-receptor calcium-dependent mechanisms associated with chronic nicotine and nicotine withdrawal remain unclear. The proteins calcium/calmodulin-dependent protein kinase II (CaMKII) and synapsin I are essential for neurotransmitter release and were shown to be involved in drug dependence. In the current study, using pharmacological techniques, we sought to (a) complement previously published behavioral findings from our lab indicating a role for calcium-dependent signaling in nicotine dependence and (b) expand on previously published acute biochemical and pharmacological findings indicating the relevance of calcium-dependent mechanisms in acute nicotine responses by evaluating the function of CaMKII and synapsin I after chronic nicotine and withdrawal in the nucleus accumbens, a brain region implicated in drug dependence. Male mice were chronically infused with nicotine for 14 days, and treated with the β2-selective antagonist dihydro-β-erythroidine (DHβE), or the α7 antagonist, methyllycaconitine citrate (MLA) 20min prior to dissection of the nucleus accumbens. Results show that phosphorylated and total CaMKII and synapsin I protein levels were significantly increased in the nucleus accumbens after chronic nicotine infusion, and reduced after treatment with DHβE, but not MLA. A spontaneous nicotine withdrawal assessment also revealed significant reductions in phosphorylated CaMKII and synapsin I levels 24h after cessation of nicotine treatment. Our findings suggest that post-receptor calcium-dependent mechanisms associated with nicotine withdrawal are mediated through β2-containing nicotinic receptors.

  12. Nicotinic receptors, memory, and hippocampus.

    Science.gov (United States)

    Kutlu, Munir Gunes; Gould, Thomas J

    2015-01-01

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

  13. Nicotine and inflammatory neurological disorders

    Institute of Scientific and Technical Information of China (English)

    Wen-Hua PIAO; Denise CAMPAGNOLO; Carlos DAYAO; Ronald J LUKAS; Jie WU; Fu-Dong SHI

    2009-01-01

    Cigarette smoke is a major health risk factor which significantly increases the incidence of diseases including lung cancer and respiratory infections. However, there is increasing evidence that smokers have a lower incidence of some inflamma- tory and neurodegenerative diseases. Nicotine is the main immunosuppressive constituent of cigarette smoke, which inhib-its both the innate and adaptive immune responses. Unlike cigarette smoke, nicotine is not yet considered to be a carcino-gen and may, in fact, have therapeutic potential as a neuroprotective and anti-inflammatory agent. This review provides a synopsis summarizing the effects of nicotine on the immune system and its (nicotine) influences on various neurological diseases.

  14. Nicotine and periodontal tissues

    Directory of Open Access Journals (Sweden)

    Malhotra Ranjan

    2010-01-01

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

  15. 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.

  16. Nicotinic systems in central nervous systems disease: degenerative disorders and beyond.

    Science.gov (United States)

    Newhouse, P A; Kelton, M

    2000-03-01

    Advances in the understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors has provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realization that such receptors are changed in degenerative neurologic diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Ongoing investigations of the molecular substructure of CNS nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioral, motor, and sensory functioning. Clues from careful studies of human cognition and behavior are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Modulation of these receptors with the ultimate goal of producing therapeutic benefits is the goal of these investigations and drug development. This paper will review studies from our laboratory and others that point to the importance of CNS nicotinic mechanisms in normal human cognitive and behavioral functioning as well as their role in disease states. In addition, this paper will examine potential clinical applications of nicotine and/or nicotinic agonists in a variety of CNS disorders with particular emphasis on structural brain disease including: movement disorders such as Parkinson's disease and Tourette's syndrome, cognitive/behavioral disorders such as Alzheimer's disease, attention deficit/hyperactivity disorder, and schizophrenia, and other more speculative applications. Important results from early therapeutic studies of nicotine and/or nicotinic agonists in these disease states are presented. For example, recent studies with nicotine and novel nicotinic agonists such as ABT-418 by our group

  17. Drugs, Brains, and Behavior: The Science of Addiction

    Science.gov (United States)

    ... Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine Other Drugs Related Topics Addiction Science Adolescent Brain Comorbidity College-Age & Young Adults ...

  18. Local neutrophil influx following lateral fluid-percussion brain injury in rats is associated with accumulation of complement activation fragments of the third component (C3) of the complement system.

    Science.gov (United States)

    Keeling, K L; Hicks, R R; Mahesh, J; Billings, B B; Kotwal, G J

    2000-06-01

    Traumatic brain injury can lead to locally destructive secondary events mediated by several inflammatory components. Following lateral fluid-percussion (FP) brain injury in rats, we examined cortical and hippocampal sections for neutrophil infiltration and accumulation of complement component C3. Neutrophil influx into the brain after injury was detected by an improved myeloperoxidase (MPO) microassay and manual cell counting, while C3 accumulation was detected using immunocytochemistry. MPO levels were elevated in the injured cortical tissue, whereas C3 immunoreactivity was increased in both injured cortical and ipsilateral hippocampal sections. These results show that the FP model of head injury leads to an intense local inflammatory reaction and subsequent tissue destruction.

  19. Inorganic mercury accumulation in brain following waterborne exposure elicits a deficit on the number of brain cells and impairs swimming behavior in fish (white seabream-Diplodus sargus).

    Science.gov (United States)

    Pereira, Patrícia; Puga, Sónia; Cardoso, Vera; Pinto-Ribeiro, Filipa; Raimundo, Joana; Barata, Marisa; Pousão-Ferreira, Pedro; Pacheco, Mário; Almeida, Armando

    2016-01-01

    The current study contributes to fill the knowledge gap on the neurotoxicity of inorganic mercury (iHg) in fish through the implementation of a combined evaluation of brain morphometric alterations (volume and total number of neurons plus glial cells in specific regions of the brain) and swimming behavior (endpoints related with the motor activity and mood/anxiety-like status). White seabream (Diplodus sargus) was exposed to realistic levels of iHg in water (2μgL(-1)) during 7 (E7) and 14 days (E14). After that, fish were allowed to recover for 28 days (PE28) in order to evaluate brain regeneration and reversibility of behavioral syndromes. A significant reduction in the number of cells in hypothalamus, optic tectum and cerebellum was found at E7, accompanied by relevant changes on swimming behavior. Moreover, the decrease in the number of neurons and glia in the molecular layer of the cerebellum was followed by a contraction of its volume. This is the first time that a deficit on the number of cells is reported in fish brain after iHg exposure. Interestingly, a recovery of hypothalamus and cerebellum occurred at E14, as evidenced by the identical number of cells found in exposed and control fish, and volume of cerebellum, which might be associated with an adaptive phenomenon. After 28 days post-exposure, the optic tectum continued to show a decrease in the number of cells, pointing out a higher vulnerability of this region. These morphometric alterations coincided with numerous changes on swimming behavior, related both with fish motor function and mood/anxiety-like status. Overall, current data pointed out the iHg potential to induce brain morphometric alterations, emphasizing a long-lasting neurobehavioral hazard.

  20. The Mammalian "Obesogen" Tributyltin Targets Hepatic Triglyceride Accumulation and the Transcriptional Regulation of Lipid Metabolism in the Liver and Brain of Zebrafish.

    Directory of Open Access Journals (Sweden)

    Angeliki Lyssimachou

    Full Text Available Recent findings indicate that different Endocrine Disrupting Chemicals (EDCs interfere with lipid metabolic pathways in mammals and promote fat accumulation, a previously unknown site of action for these compounds. The antifoulant and environmental pollutant tributyltin (TBT, which causes imposex in gastropod snails, induces an "obesogenic" phenotype in mammals, through the activation of the nuclear receptors retinoid X receptor (RXR and peroxisome proliferator-activated receptor gamma (PPARγ. In teleosts, the effects of TBT on the lipid metabolism are poorly understood, particularly following exposure to low, environmental concentrations. In this context, the present work shows that exposure of zebrafish to 10 and 50 ng/L of TBT (as Sn from pre-hatch to 9 months of age alters the body weight, condition factor, hepatosomatic index and hepatic triglycerides in a gender and dose related manner. Furthermore, TBT modulated the transcription of key lipid regulating factors and enzymes involved in adipogenesis, lipogenesis, glucocorticoid metabolism, growth and development in the brain and liver of exposed fish, revealing sexual dimorphic effects in the latter. Overall, the present study shows that the model mammalian obesogen TBT interferes with triglyceride accumulation and the transcriptional regulation of lipid metabolism in zebrafish and indentifies the brain lipogenic transcription profile of fish as a new target of this compound.

  1. Data on amyloid precursor protein accumulation, spontaneous physical activity, and motor learning after traumatic brain injury in the triple-transgenic mouse model of Alzheimer׳s disease.

    Science.gov (United States)

    Kishimoto, Yasushi; Shishido, Hajime; Sawanishi, Mayumi; Toyota, Yasunori; Ueno, Masaki; Kubota, Takashi; Kirino, Yutaka; Tamiya, Takashi; Kawai, Nobuyuki

    2016-12-01

    This data article contains supporting information regarding the research article entitled "Traumatic brain injury accelerates amyloid-β deposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer׳s disease" (H. Shishido, Y. Kishimoto, N. Kawai, Y. Toyota, M. Ueno, T. Kubota, Y. Kirino, T. Tamiya, 2016) [1]. Triple-transgenic (3×Tg)-Alzheimer׳s disease (AD) model mice exhibited significantly poorer spatial learning than sham-treated 3×Tg-AD mice 28 days after traumatic brain injury (TBI). Correspondingly, amyloid-β (Aβ) deposition within the hippocampus was significantly greater in 3×Tg-AD mice 28 days after TBI. However, data regarding the short-term and long-term influences of TBI on amyloid precursor protein (APP) accumulation in AD model mice remain limited. Furthermore, there is little data showing whether physical activity and motor learning are affected by TBI in AD model mice. Here, we provide immunocytochemistry data confirming that TBI induces significant increases in APP accumulation in 3×Tg-AD mice at both 7 days and 28 days after TBI. Furthermore, 3×Tg-AD model mice exhibit a reduced ability to acquire conditioned responses (CRs) during delay eyeblink conditioning compared to sham-treated 3×Tg-AD model mice 28 days after TBI. However, physical activity and motor performance are not significantly changed in TBI-treated 3×Tg-AD model mice.

  2. 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.

  3. If the data contradict the theory, throw out the data: Nicotine addiction in the 2010 report of the Surgeon General

    Directory of Open Access Journals (Sweden)

    Frenk Hanan

    2011-05-01

    Full Text Available Abstract The reports of US Surgeon General on smoking are considered the authoritative statement on the scientific state of the art in this field. The previous report on nicotine addiction published in 1988 is one of the most cited references in scientific articles on smoking and often the only citation provided for specific statements of facts regarding nicotine addiction. In this commentary we review the chapter on nicotine addiction presented in the recent report of the Surgeon General. We show that the nicotine addiction model presented in this chapter, which closely resembles its 22 years old predecessor, could only be sustained by systematically ignoring all contradictory evidence. As a result, the present SG's chapter on nicotine addiction, which purportedly "documents how nicotine compares with heroin and cocaine in its hold on users and its effects on the brain," is remarkably biased and misleading.

  4. If the data contradict the theory, throw out the data: Nicotine addiction in the 2010 report of the Surgeon General.

    Science.gov (United States)

    Frenk, Hanan; Dar, Reuven

    2011-05-19

    The reports of US Surgeon General on smoking are considered the authoritative statement on the scientific state of the art in this field. The previous report on nicotine addiction published in 1988 is one of the most cited references in scientific articles on smoking and often the only citation provided for specific statements of facts regarding nicotine addiction. In this commentary we review the chapter on nicotine addiction presented in the recent report of the Surgeon General. We show that the nicotine addiction model presented in this chapter, which closely resembles its 22 years old predecessor, could only be sustained by systematically ignoring all contradictory evidence. As a result, the present SG's chapter on nicotine addiction, which purportedly "documents how nicotine compares with heroin and cocaine in its hold on users and its effects on the brain," is remarkably biased and misleading.

  5. 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.

  6. Acute nicotine administration in Alzheimer's disease: an exploratory EEG study.

    Science.gov (United States)

    Knott, V; Engeland, C; Mohr, E; Mahoney, C; Ilivitsky, V

    2000-01-01

    Previous findings of cognitive deficits and EEG slowing in Alzheimer's patients, together with independent reports of the performance enhancing and electrocortical activating properties of nicotine in normal adults, stimulated this study to examine the acute effects of nicotine on spectrum-analyzed EEG in patients with dementia of the Alzheimer type (DAT). Thirteen patients, 6 currently receiving cholinesterase inhibitor treatment and the remaining being medication free, were administered 2 mg of nicotine polacrilex under randomized, placebo-controlled conditions. Compared to age-regressed EEG norms, the pretreatment EEG spectrums of patients in general were characterized by excessive slow (delta and theta)-wave power, diminished fast (alpha and beta)-wave power and slow mean alpha and total band frequencies. Although postnicotine EEG indices remained within the abnormal range, nicotine, compared to placebo, significantly shifted EEG towards normal values by reducing slow wave (relative delta and theta) power and augmenting fast (relative alpha-1, alpha-2, beta-1) wave power. No differences were observed between treated and nontreated patients in response to nicotine. The results are discussed in relation to cholinergic and brain arousal systems and their relationship to cognitive processes.

  7. Delayed hyperoxic ventilation attenuates oxygen-induced free radical accumulation during early reperfusion after global brain ischemia.

    Science.gov (United States)

    Wang, Yan; Yuan, Li; Liu, Ping; Zhao, Min

    2015-02-11

    To compare the effect of immediate and delayed administration of oxygen on the accumulation of free radicals in ischemia-reperfusion animal models. Thirty-two adult male Mongolian gerbils with microdialysis probes implanted in the right hippocampal CA1 were divided randomly into four groups (eight each). One group was sham-operated (Sham group) whereas the other three groups were subjected to 10 min bilateral carotid artery occlusion (BCAO). BCAO-treated animals were then subjected to the following: (a) immediate 30% O2 (near normoxia, NO group), (b) immediate 100% O2 (hyperoxia, HO group), and (c) 30% O2 for 60 min, followed by 100% O2 for 60 min (delayed hyperoxia, DHO group). Hippocampal accumulation of hydroxyl radicals (•OH) during reperfusion was estimated by measuring 2,3-dihydroxybenzoic acid (DHBA) and 2,5-DHBA in microdialysis perfusate. Hippocampi were removed 2 h after perfusion to measure malondialdehyde, pyruvate dehydrogenase activity, indices of lipid peroxidation, and cellular respiration. At 24 h after BCAO, the histology of hippocampi was analyzed to rate the injury. Immediately after the onset of reperfusion, all groups showed markedly elevated DHBA, which returned to baseline over 1-2 h. Compared with the NO group, the HO group showed significantly higher peak DHBA and slower recovery. In contrast, the DHO group was not significantly different from the NO group in terms of the DHBA level. DHO animals also showed significantly lower hippocampal malondialdehyde accumulation and higher pyruvate dehydrogenase activity at 2 h after reperfusion versus the HO group. Histology analysis also showed animals in the DHO group with ameliorated injury compared with the HO group. Hydroxyl radical accumulation was more sensitive to O2 during early reperfusion. Delayed hyperoxia may re-establish oxidative metabolism while minimizing oxidative stress after CA.

  8. Using growth models to relate acquisition of nicotine self-administration to break point and nicotinic receptor binding.

    Science.gov (United States)

    Donny, Eric C; Lanza, Stephanie T; Balster, Robert L; Collins, Linda M; Caggiula, Anthony; Rowell, Peter P

    2004-07-15

    Growth modeling can be used to characterize individual and mean acquisition trajectories for drug self-administration. Individual characteristics can also be incorporated into the growth model, providing a powerful tool for investigating the relationship between acquisition and other behavioral and biological measures. We illustrate the utility of this method by examining the relationship between acquisition of nicotine self-administration and (1) break point on a progressive ratio schedule of reinforcement, and (2) the density of brain nicotinic receptors (B(max)). Daily infusion rates from male and female Sprague-Dawley rats were modeled with break point or B(max) as time-invariant covariates. Use of this model led to two novel findings regarding individual differences in acquisition. First, greater rates of change in infusions early in acquisition were related to higher break points; this relationship was mediated by a similar effect of increasing the number of responses required to obtain nicotine. Second, animals displaying more resistance to increases in the response requirement during acquisition, as indicated by a smaller drop in the rate of nicotine self-administration, generally had fewer nicotinic receptors at the end of the experiment. The relationships revealed demonstrate the usefulness of growth models in the quantitative analysis of individual differences in drug self-administration behavior.

  9. Neuronal nicotinic receptors in dementia with Lewy bodies and schizophrenia: alpha-bungarotoxin and nicotine binding in the thalamus.

    Science.gov (United States)

    Court, J; Spurden, D; Lloyd, S; McKeith, I; Ballard, C; Cairns, N; Kerwin, R; Perry, R; Perry, E

    1999-10-01

    Neuronal nicotinic receptors have been implicated in schizophrenia on the basis of the high incidence of tobacco smoking in patients, abnormalities in cytisine and alpha-bungarotoxin (alphaBGT) binding in the hippocampus, and linkage between auditory P50 deficits and the region of chromosome 15 coding the alpha7 subunit. In another disease associated with psychosis, dementia with Lewy bodies (DLB), in which visual hallucinations predominate, reductions in nicotine binding have been identified in various cortical and subcortical regions. We investigated both alphaBGT and nicotine binding autoradiographically in different thalamic nuclei in autopsy brain tissue from patients with schizophrenia and DLB. AlphaBGT binding in the reticular nucleus was moderately reduced (25%) in schizophrenia and more extensively reduced (50%) in DLB. There were no significant alterations in nicotine binding in schizophrenia, and in DLB, a trend towards moderate reductions in most nuclei reached significance in the lateral dorsal nucleus. It is concluded that widespread abnormalities of thalamic nicotine are not implicated in schizophrenia or DLB, but that reticular alphaBGT binding may be involved to a lesser and greater extent in the pathophysiology or psychopathology of both disorders.

  10. 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.

  11. Mephedrone and nicotine: oxidative stress and behavioral interactions in animal models.

    Science.gov (United States)

    Budzynska, Barbara; Boguszewska-Czubara, Anna; Kruk-Slomka, Marta; Kurzepa, Jacek; Biala, Grazyna

    2015-05-01

    The purpose of our experiment was to examine the influence of co-administration of nicotine and mephedrone on anxiety-like behaviors, cognitive processes and the nicotine-induced behavioral sensitization as well as processes connected with induction of oxidative stress in the brain of male Swiss mice. The results revealed that co-administration of subthreshold doses of mephedrone and nicotine (0.05 mg/kg each) exerted marked anxiogenic profile in the elevated plus maze and displayed pro-cognitive action in the passive avoidance paradigm (nicotine 0.05 mg/kg and mephedrone 2.5 mg/kg). Furthermore, one of the main findings of the present study was that mephedrone, administered alone at the dose not affecting locomotor activity of mice (1 mg/kg), enhanced the expression of nicotine-induced locomotor sensitization. Moreover, mephedrone administered with nicotine decreased general antioxidant status and catalase activity as well as antioxidant enzymes activity in the hippocampus and prefrontal cortex and increased concentration of malondialdehyde, an indicator of lipid peroxidation processes. Considering the likelihood that mephedrone is taken as a part of polydrug combination with nicotine, the effects of this combination on mammalian organisms have been confirmed in our study. Understanding the consequences of co-administration of psychoactive substances on the central nervous system and oxidative processes in the brain provide the important toxicological significance, and may be useful in polydrug intoxication treatment.

  12. 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.

  13. Belief about nicotine Modulates subjective craving and insula activity in Deprived smokers

    DEFF Research Database (Denmark)

    Gu, X. S.; Lohrenz, Terry; Salas, Ramiro

    2016-01-01

    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......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...

  14. Effects of cannabinoid receptor 1 (brain) on lipid accumulation by transcriptional control of CPT1A and CPT1B.

    Science.gov (United States)

    Zhang, Y-F; Yuan, Z-Q; Song, D-G; Zhou, X-H; Wang, Y-Z

    2014-02-01

    CB1 (also known as CNR1), a main receptor for cannabinoids acting at PPARs, can enhance fat deposition. Carnitine palmitoyltransferase-1 (CPT1), an enzyme responsible for the transport of long-chain fatty acids for β-oxidation, is closely related to fat deposition. Whether CB1 can regulate intramuscular adipocytes lipid accumulation through regulation of CPT1 is unclear. Based on the investigation of tissue- and breed-specific CPT1A and CPT1B mRNA expression levels in Jinhua and Landrace pigs, we studied the effects of CB1 on lipid accumulation and CPT1B expression by treating porcine intramuscular adipocytes with CB1 antagonist Δ9-THC and antagonist SR141716. Results showed that muscle CPT1 mRNA was expressed at higher levels in the longissimus dorsi and subcutaneous fat. Liver CPT1A mRNA expression levels were higher in the pancreas, duodenum and liver. Compared with Landrace pigs, CPT1A and CPT1B in the longissimus dorsi of Jinhua pigs were significantly higher and positively correlated with intramuscular fat content. However, for subcutaneous fat, CPT1 levels were significantly lower and negatively correlated with body fat percentage. Δ9-THC significantly increased CB1 mRNA levels and lipid accumulation but decreased CPT1A and CPT1B mRNA levels. Conversely, SR141716 reduced CB1 mRNA levels but increased CPT1A and CPT1B mRNA levels, resulting in decreased lipid accumulation. The CPT1 antagonist etomoxir did not affect CB1 expression, suggesting that CB1 is likely upstream of CPT1A and CPT1B. Meanwhile, PPARA expression was greatly decreased when CPT1A and CPT1B were inhibited and enhanced when CPT1A and CPT1B were activated. Taken together, these data indicate that CB1 can affect intramuscular fat deposition by regulating both CPT1A and CPT1B mRNA expression, with the PPARA signal pathway likely playing a major role in this process.

  15. Accumulation of mercury, selenium and PCBs in domestic duck brain, liver and egg from a contaminated area with an investigation of their redox responses.

    Science.gov (United States)

    Cheng, Jinping; Zhao, Wenchang; Wang, Qian; Liu, Xiaojie; Wang, Wenhua

    2013-05-01

    PCBs and methylmercury (MeHg) are two of the most ubiquitous contaminants in the Qingzhen (QZ) area of Guizhou province. The estimated tolerable daily intakes (TDIs) of total mercury (T-Hg), MeHg, PCBs and Se from contaminated rice, eggs and fish by Chinese people in QZ showed that both MeHg and PCBs exceeded the corresponding safety limits. Pearson's correlation analyses of mercury and Se in all duck tissues showed that there were high correlations with T-Hg or MeHg and Se in QZ samples. However, the molar ratio between T-Hg and Se in brain tissues was close to 1, suggesting that Se is antagonistic to mercury toxicity only in brain tissues. Biochemical analyses showed that both superoxide dismutase and glutathione peroxidase increased in the brain, whereas in the liver and egg these enzymes decreased. However, lipid peroxidation and H2O2 generation in liver and egg tissues showed contrary responses, where significant increases in these tissues were seen relative to controls. Mercury and PCBs co-accumulation in liver and egg tissues gave rise to large numbers of free radicals as well as aggravated alkyl free radicals, superoxide radical and nitric oxide, thereby resulting in oxidative stress in these tissues. It can be concluded that an adaptive response of the redox defense system is present in brain tissues, as opposed to a general break down of the redox defense system in liver and egg. The results obtained in this study will provide basic information on exposure and risk assessment in local residents.

  16. A method based on Monte Carlo simulations and voxelized anatomical atlases to evaluate and correct uncertainties on radiotracer accumulation quantitation in beta microprobe studies in the rat brain

    Science.gov (United States)

    Pain, F.; Dhenain, M.; Gurden, H.; Routier, A. L.; Lefebvre, F.; Mastrippolito, R.; Lanièce, P.

    2008-10-01

    The β-microprobe is a simple and versatile technique complementary to small animal positron emission tomography (PET). It relies on local measurements of the concentration of positron-labeled molecules. So far, it has been successfully used in anesthetized rats for pharmacokinetics experiments and for the study of brain energetic metabolism. However, the ability of the technique to provide accurate quantitative measurements using 18F, 11C and 15O tracers is likely to suffer from the contribution of 511 keV gamma rays background to the signal and from the contribution of positrons from brain loci surrounding the locus of interest. The aim of the present paper is to provide a method of evaluating several parameters, which are supposed to affect the quantification of recordings performed in vivo with this methodology. We have developed realistic voxelized phantoms of the rat whole body and brain, and used them as input geometries for Monte Carlo simulations of previous β-microprobe reports. In the context of realistic experiments (binding of 11C-Raclopride to D2 dopaminergic receptors in the striatum; local glucose metabolic rate measurement with 18F-FDG and H2O15 blood flow measurements in the somatosensory cortex), we have calculated the detection efficiencies and corresponding contribution of 511 keV gammas from peripheral organs accumulation. We confirmed that the 511 keV gammas background does not impair quantification. To evaluate the contribution of positrons from adjacent structures, we have developed β-Assistant, a program based on a rat brain voxelized atlas and matrices of local detection efficiencies calculated by Monte Carlo simulations for several probe geometries. This program was used to calculate the 'apparent sensitivity' of the probe for each brain structure included in the detection volume. For a given localization of a probe within the brain, this allows us to quantify the different sources of beta signal. Finally, since stereotaxic accuracy is

  17. Repeated administration of alpha7 nicotinic acetylcholine receptor (nAChR) agonists, but not positive allosteric modulators, increases alpha7 nAChR levels in the brain

    DEFF Research Database (Denmark)

    Christensen, Ditte Z; Mikkelsen, Jens D; Hansen, Henrik H;

    2010-01-01

    The alpha7 nicotinic acetylcholine receptor (nAChR) is an important target for treatment of cognitive deficits in schizophrenia and Alzheimer's disease. However, the receptor desensitizes rapidly in vitro, which has led to concern regarding its applicability as a clinically relevant drug target...

  18. Structurally distinct nicotine immunogens elicit antibodies with non-overlapping specificities

    Science.gov (United States)

    Pravetoni, M; Keyler, DE; Pidaparthi, RR; Carroll, FI; Runyon, SP; Murtaugh, MP; Earley, CA; Pentel, PR

    2011-01-01

    Nicotine conjugate vaccine efficacy is limited by the concentration of nicotine-specific antibodies that can be reliably generated in serum. Previous studies suggest that the concurrent use of 2 structurally distinct nicotine immunogens in rats can generate additive antibody responses by stimulating distinct B cell populations. In the current study we investigated whether it is possible to identify a third immunologically distinct nicotine immunogen. The new 1′-SNic immunogen (2S)-N,N′-(disulfanediyldiethane-2,1-diyl)bis[4-(2-pyridin-3-ylpyrrolidin-1-yl)butanamide] conjugated to keyhole limpet hemocyanin (KLH) differed from the existing immunogens 3′-AmNic-rEPA and 6-CMUNic-BSA in linker position, linker composition, conjugation chemistry, and carrier protein. Vaccination of rats with 1′-SNic-KLH elicited high concentrations of high affinity nicotine-specific antibodies. The antibodies produced in response to 1′-SNic-KLH did not appreciably cross-react in ELISA with either 3′-AmNic-rEPA or 6-CMUNic-BSA or vice-versa, showing that the B cell populations activated by each of these nicotine immunogens were non-overlapping and distinct. Nicotine retention in serum was increased and nicotine distribution to brain substantially reduced in rats vaccinated with 1′-SNic-KLH compared to controls. Effects of 1′-SNic-KLH on nicotine distribution were comparable to those of 3′-AmNic-rEPA which has progressed to late stage clinical trials as an adjunct to smoking cessation. These data show that it is possible to design multiple immunogens from a small molecule such as nicotine which elicit independent immune responses. This approach could be applicable to other addiction vaccines or small molecule targets as well. PMID:22100986

  19. Acute nicotine administration effects on fractional anisotropy of cerebral white matter and associated attention performance

    Directory of Open Access Journals (Sweden)

    Peter eKochunov

    2013-09-01

    Full Text Available Introduction.Nicotinic acetylcholine receptors are present in the cerebral white matter (WM. We hypothesized that WM response to nicotine can be detected by diffusion tensor imaging (DTI; and that such responses may be associated with nicotine-led cognitive enhancement in sustained attention. MethodsA randomized, nicotine-placebo patch, crossover, double-blind clinical trial in two non-overlapping cohorts of smokers was used to test the hypothesis. The discovery cohort consisted of 39 subjects (N=20/19 controls/schizophrenic patients, age=36.8±10.1years and the replication cohorts consisted of 38 healthy smokers (31.7±10.5years. WM integrity was measured by fractional anisotropy (FA values for the whole brain and nine preselected WM tracts using tract-based-spatial-statistics. Results.Nicotine significantly enhanced FA values for the genu of corpus callosum compared with placebo (FAgenu (p=0.01 in smokers with low recent smoking exposure as measured by low average cotinine level. This finding was replicated in the second cohort (p=0.02. FAgenu values explained 22% of variance in performance of a sustained attention task during the nicotine session (p=0.006. However, this effect was limited to schizophrenia patients (r= 0.62 and 0.09; p=0.003 and 0.7 for patients and controls, respectively.Conclusion. Acute pharmacological influence of nicotine patch on WM integrity appeared present, but was dependent on nicotine intake from recent smoking. Change in the WM integrity in the genu of corpus callosum was assocatied with a significant proportion of variability of nicotine-led changes in sustained attention/working memory of the smokers. Further studies will be necessary to understand biophysical underpinning of the nicotine-related changes in FA.

  20. [Adult-onset case of idiopathic neurodegeneration with brain iron accumulation without mutations in the PANK2 and PLA2G6 genes].

    Science.gov (United States)

    Saiki, Shinji; Sekine, Takeshi; Ueno, Yuji; Yoshino, Hiroyo; Takahashi, Junko; Tani, Yoshihiko; Kambe, Yasunori; Motoi, Yumiko; Hattori, Nobutaka

    2009-08-01

    A 47-year-old man with a 15-year history of bipolar disorder treated with anti-depressants, lithium carbonate or neuroleptics was admitted because of marked difficulty in gait and speech. At the age 45, he was unable to walk without bilateral assists and became a wheel-chair state. There was no family history and his mother, father and younger sister were neurologically free. General physical examinations revealed no abnormalities. Neurologically, he was moderately demented (mini mental state examination: 18/30) and showed bilateral horizontal gaze nystagmus, parkinsonism, cerebellar ataxia, dysarthria and moderate spastic paraparesis. No involuntary movements were noted. Wet blood smear showed acanthocytes, while blood chemistries revealed no abnormalities including levels of serum creatine kinase, hepatic enzymes and blood beta-lipoprotein. Kell antigen expressions of the red blood cells were within normal limit. Western blot analysis with anti-chorein antibody detected normal chorein expression levels of the red blood cells. Cranial MRI showed severe symmetric atrophy of the frontotemporal lobes, caudate nuclei, putamen, and brainstem. Also, MRI-gradient echo showed symmetric iron accumulation in the medial portion of the globus pallidus without surrounding high intensity areas, so called "eye-of-the-tiger sign". Genetic analyses revealed no mutations in the PANK2 and PLA2G6 genes. Therefore, he was diagnosed as idiopathic neurodegeneration with brain iron accumulation (NBIA). These findings suggest that NBIA is heterogeneous and other additional genes remain to be found.

  1. Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.

    Science.gov (United States)

    Hartig, Monika B; Iuso, Arcangela; Haack, Tobias; Kmiec, Tomasz; Jurkiewicz, Elzbieta; Heim, Katharina; Roeber, Sigrun; Tarabin, Victoria; Dusi, Sabrina; Krajewska-Walasek, Malgorzata; Jozwiak, Sergiusz; Hempel, Maja; Winkelmann, Juliane; Elstner, Matthias; Oexle, Konrad; Klopstock, Thomas; Mueller-Felber, Wolfgang; Gasser, Thomas; Trenkwalder, Claudia; Tiranti, Valeria; Kretzschmar, Hans; Schmitz, Gerd; Strom, Tim M; Meitinger, Thomas; Prokisch, Holger

    2011-10-07

    The disease classification neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of progressive neurodegenerative disorders characterized by brain iron deposits in the basal ganglia. For about half of the cases, the molecular basis is currently unknown. We used homozygosity mapping followed by candidate gene sequencing to identify a homozygous 11 bp deletion in the orphan gene C19orf12. Mutation screening of 23 ideopathic NBIA index cases revealed two mutated alleles in 18 of them, and one loss-of-function mutation is the most prevalent. We also identified compound heterozygous missense mutations in a case initially diagnosed with Parkinson disease at age 49. Psychiatric signs, optic atrophy, and motor axonal neuropathy were common findings. Compared to the most prevalent NBIA subtype, pantothenate kinase associated neurodegeneration (PKAN), individuals with two C19orf12 mutations were older at age of onset and the disease progressed more slowly. A polyclonal antibody against the predicted membrane spanning protein showed a mitochondrial localization. A histopathological examination in a single autopsy case detected Lewy bodies, tangles, spheroids, and tau pathology. The mitochondrial localization together with the immunohistopathological findings suggests a pathomechanistic overlap with common forms of neurodegenerative disorders.

  2. Evidence that the major metabolites accumulating in medium-chain acyl-CoA dehydrogenase deficiency disturb mitochondrial energy homeostasis in rat brain.

    Science.gov (United States)

    Schuck, Patrícia Fernanda; Ferreira, Gustavo da Costa; Tonin, Anelise Miotti; Viegas, Carolina Maso; Busanello, Estela Natacha Brandt; Moura, Alana Pimentel; Zanatta, Angela; Klamt, Fábio; Wajner, Moacir

    2009-11-03

    Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an inherited metabolic disorder of fatty acid oxidation in which the affected patients predominantly present high levels of octanoic (OA) and decanoic (DA) acids and their glycine and carnitine by-products in tissues and body fluids. It is clinically characterized by episodic encephalopathic crises with coma and seizures, as well as by progressive neurological involvement, whose pathophysiology is poorly known. In the present work, we investigated the in vitro effects of OA and DA on various parameters of energy homeostasis in mitochondrial preparations from brain of young rats. We found that OA and DA markedly increased state 4 respiration and diminished state 3 respiration as well as the respiratory control ratio, the mitochondrial membrane potential and the matrix NAD(P)H levels. In addition, DA-elicited increase in oxygen consumption in state 4 respiration was partially prevented by atractyloside, indicating the involvement of the adenine nucleotide translocator. OA and DA also reduced ADP/O ratio, CCCP-stimulated respiration and the activities of respiratory chain complexes. The data indicate that the major accumulating fatty acids in MCADD act as uncouplers of oxidative phosphorylation and as metabolic inhibitors. Furthermore, DA, but not OA, provoked a marked mitochondrial swelling and cytochrome c release from mitochondria, reflecting a permeabilization of the inner mitochondrial membrane. Taken together, these data suggest that OA and DA impair brain mitochondrial energy homeostasis that could underlie at least in part the neuropathology of MCADD.

  3. Nicotine stimulates adhesion molecular expression via calcium influx and mitogen-activated protein kinases in human endothelial cells.

    Science.gov (United States)

    Wang, Yajing; Wang, Zhaoxia; Zhou, Ying; Liu, Liming; Zhao, Yangxing; Yao, Chenjiang; Wang, Lianyun; Qiao, Zhongdong

    2006-02-01

    To evaluate the effect of nicotine on endothelium dysfunction and development of vascular diseases, we investigated the influence on adhesion molecular expression mediated by nicotine and the mechanism of this effect in human umbilical vein endothelial cells (HUVECs). The result showed that nicotine could induce surface/soluble vascular cell adhesion molecule (VCAM-1) and endothelial selectin (E-selectin) expression in a time-response decline manner and the peak appeared at 15 min. This action could be mediated by mitogen-activated protein kinase/extracellular signal regulated kinase 1/2 (MAPK/ERK1/2) and MAPK/p38 because their activation could be distinctly blocked by MAPK inhibitors, PD098059 or SB203580. Mecamylamine (non-selective nicotinic receptor inhibitor), alpha-bungarotoxin (alpha7 nicotinic receptor inhibitor) could block Ca2+ accumulation, and then, prevented the phosphorylation on ERK1/2 and p38. They also inhibited the surface/soluble VCAM-1, E-selectin production of HUVECs modulated by nicotine. Therefore, we concluded that: (i) nicotine obviously up-regulates VCAM-1 and E-selectin expression at 15 min in HUVECs, (ii) nicotine activates HUVECs triggered by the ERK1/2 and p38 phosphorylation with an involvement of intracellular calcium mobilization chiefly mediated by alpha7 nicotinic receptor, (iii) intracellular Ca2+ activates a sequential pathway from alpha7 nicotinic receptor to the phosphorylation of ERK1/2, p38. These elucidate that nicotine activates HUVECs through fast signal transduction pathway and arguments their capacity of adhesion molecular production. Further more nicotine may contribute its influence to the progression of vascular disease such as atherosclerotic lesion.

  4. Behavioral and neural substrates of habit formation in rats intravenously self-administering nicotine.

    Science.gov (United States)

    Clemens, Kelly J; Castino, Matthew R; Cornish, Jennifer L; Goodchild, Ann K; Holmes, Nathan M

    2014-10-01

    Tobacco addiction involves a transition from occasional, voluntary smoking towards habitual behavior that becomes increasingly resistant to quitting. The development of smoking habits may reflect a loss of behavioral control that can be modeled in rats. This study investigated the behavioral and neural substrates of habit formation in rats exposed to either brief (10 days) or extended (47 days) intravenous (IV) nicotine self-administration training. Following training, the first cohort of rats were exposed to a nicotine devaluation treatment, which involved repeated pairings of IV nicotine with lithium injection. They were then tested for sensitivity of responding to nicotine devaluation under extinction and reinstatement conditions. The second cohort of rats received equivalent self-administration training followed by processing of brain tissue for c-Fos immunohistochemistry. After brief training, devaluation suppressed nicotine-seeking during tests of extinction and reinstatement, confirming that responding is initially sensitive to current nicotine value, and therefore, goal directed. In contrast, after extended training, devaluation had no effect on extinction or reinstatement of responding, indicating that responding had become habitual. Complementary neuroanalysis revealed that extended nicotine self-administration was associated with increased c-Fos expression in brain regions implicated in habitual control of reward seeking, including activation of the dorsolateral striatum and substantia nigra pars compacta. These findings provide evidence of direct devaluation of an IV drug reward, that nicotine self-administration is initially goal-directed but becomes habitual with extended training, and that this behavioral transition involves activation of brain areas associated with the nigrostriatal system.

  5. Nitrosamines as nicotinic receptor ligands

    OpenAIRE

    Schuller, Hildegard M

    2007-01-01

    Nitrosamines are carcinogens formed in the mammalian organism from amine precursors contained in food, beverages, cosmetics and drugs. The potent carcinogen, NNK, and the weaker carcinogen, NNN, are nitrosamines formed from nicotine. Metabolites of the nitrosamines react with DNA to form adducts responsible for genotoxic effects. We have identified NNK as a high affinity agonist for the alpha7 nicotinic acetylcholine receptor (α7nAChR) whereas NNN bound with high affinity to epibatidine-sensi...

  6. C3-halogenation of cytisine generates potent and efficacious nicotinic receptor agonists.

    Science.gov (United States)

    Abin-Carriquiry, J Andrés; Voutilainen, Merja H; Barik, Jacques; Cassels, Bruce K; Iturriaga-Vásquez, Patricio; Bermudez, Isabel; Durand, Claudia; Dajas, Federico; Wonnacott, Susan

    2006-04-24

    Neuronal nicotinic acetylcholine receptors subserve predominantly modulatory roles in the brain, making them attractive therapeutic targets. Natural products provide key leads in the quest for nicotinic receptor subtype-selective compounds. Cytisine, found in Leguminosae spp., binds with high affinity to alpha4beta2* nicotinic receptors. We have compared the effect of C3 and C5 halogenation of cytisine and methylcytisine (MCy) on their interaction with native rat nicotinic receptors. 3-Bromocytisine (3-BrCy) and 3-iodocytisine (3-ICy) exhibited increased binding affinity (especially at alpha7 nicotinic receptors; Ki approximately 0.1 microM) and functional potency, whereas C5-halogenation was detrimental. 3-BrCy and 3-ICy were more potent than cytisine at evoking [3H]dopamine release from striatal slices (EC50 approximately 11 nM), [3H]noradrenaline release from hippocampal slices (EC50 approximately 250 nM), increases in intracellular Ca2+ in PC12 cells and inward currents in Xenopus oocytes expressing human alpha3beta4 nicotinic receptor (EC50 approximately 2 microM). These compounds were also more efficacious than cytisine. C3-halogenation of cytisine is proposed to stabilize the open conformation of the nicotinic receptor but does not enhance subtype selectivity.

  7. An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior

    Science.gov (United States)

    Jung, Yonwoo; Hsieh, Lawrence S.; Lee, Angela M.; Zhou, Zhifeng; Coman, Daniel; Heath, Christopher J.; Hyder, Fahmeed; Mineur, Yann S.; Yuan, Qiaoping; Goldman, David; Bordey, Angelique; Picciotto, Marina R.

    2016-01-01

    Developmental nicotine exposure causes persistent changes in cortical neuron morphology and in behavior. We used microarray screening to identify master transcriptional or epigenetic regulators mediating these effects of nicotine and discovered increases in Ash2l, a component of a histone methyltransferase complex. We therefore examined genome-wide changes in H3K4 tri-methylation, a mark induced by the Ash2l complex associated with increased gene transcription. A significant number of regulated promoter sites were involved in synapse maintenance. We found that Mef2c interacts with Ash2l and mediates changes in H3K4 tri-methylation. Knockdown of Ash2l or Mef2c abolishes nicotine-mediated alterations of dendritic complexity in vitro and in vivo, and attenuates nicotine-dependent changes in passive avoidance behavior. In contrast, overexpression mimics nicotine-mediated alterations of neuronal structure and passive avoidance behavior. These studies identify Ash2l as a novel target induced by nicotinic stimulation that couples developmental nicotine exposure to changes in brain epigenetic marks, neuronal structure and behavior. PMID:27239938

  8. 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

  9. Evaluating the immunogenicity of an intranasal vaccine against nicotine in mice using the Adjuvant Finlay Proteoliposome (AFPL1).

    Science.gov (United States)

    Fraleigh, Nya L; Boudreau, Justin; Bhardwaj, Nitin; Eng, Nelson F; Murad, Yanal; Lafrenie, Robert; Acevedo, Reinaldo; Oliva, Reynaldo; Diaz-Mitoma, Francisco; Le, Hoang-Thanh

    2016-08-01

    Tobacco smoking is recognized as a global pandemic resulting in 6 million deaths per year. Despite a variety of anti-smoking products available to aid with tobacco cessation, the majority of people who attempt to quit smoking relapse within 6 months due to the addictive nature of nicotine. An immunotherapy approach could offer a promising treatment option by inducing a potent selective antibody response against nicotine in order to block its distribution to the brain and its addictive effects in the central nervous system. Our nicotine vaccine candidate was administered intranasally using the Neisseria meningitidis serogroup B Adjuvant Finlay Proteoliposome 1 (AFPL1) as a part of the delivery system. This system was designed to generate a robust immune response by stimulating IL-1β production through Toll-like receptor 4 (TLR4), a potent mechanism for mucosal immunity. The vaccine induced high antibody titers in mice sera in addition to inducing mucosal antibodies. The efficacy of our vaccine was demonstrated using in vivo challenge experiments with radioactive [(3)H]-nicotine, followed by an analysis of nicotine distribution in the lung, liver, blood and brain. Our results were encouraging as the nicotine concentration in the brain tissue of mice vaccinated with our candidate vaccine was four times lower than in non-vaccinated controls; suggesting that the anti-nicotine antibodies were able to block nicotine from crossing the blood brain barrier. In summary, we have developed a novel nicotine vaccine for the treatment of tobacco addiction by intranasal administration and also demonstrated that the AFPL1 can be used as a potential adjuvant for this vaccine design.

  10. 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. W...

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

    Directory of Open Access Journals (Sweden)

    George E. eBarreto

    2015-01-01

    Full Text Available 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.

  12. 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.

  13. 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...

  14. 21 CFR 172.310 - Aluminum nicotinate.

    Science.gov (United States)

    2010-04-01

    ... Special Dietary and Nutritional Additives § 172.310 Aluminum nicotinate. Aluminum nicotinate may be safely... additive, expressed as niacin, shall appear on the label of the food additive container or on that of...

  15. Brain accumulation of the EML4-ALK inhibitor ceritinib is restricted by P-glycoprotein (P-GP/ABCB1) and breast cancer resistance protein (BCRP/ABCG2)

    NARCIS (Netherlands)

    Kort, Anita; Sparidans, Rolf; Wagenaar, Els; Beijnen, Jacob; Schinkel, Alfred H.

    2015-01-01

    We aimed to clarify the roles of the multidrug transporters ABCB1 and ABCG2 in oral availability and brain accumulation of ceritinib, an oral anaplastic lymphoma kinase (ALK) inhibitor used to treat metastatic non-small cell lung cancer (NSCLC) after progression on crizotinib. Importantly, NSCLC is

  16. Nicotinic Receptor Activity Alters Synaptic Plasticity

    Directory of Open Access Journals (Sweden)

    John A. Dani

    2001-01-01

    Full Text Available Studies using specific agonists, antagonists, and lesions have shown that nicotinic cholinergic systems participate in attention, learning, and memory[1,2]. The nicotinic manipulations usually have the greatest influence on difficult tasks or on cognitively impaired subjects[2]. For example, Alzheimer's disease is characterized by a loss of cholinergic projections and nicotinic acetylcholine receptors (nAChRs in the cortex and hippocampus[3]. Nicotine skin patches can improve learning rates and attention in Alzheimer's patients[4].

  17. Impulsive behavior and nicotinic acetylcholine receptors.

    Science.gov (United States)

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

    2012-01-01

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

  18. N-CAM dysfunction and unexpected accumulation of PSA-NCAM in brain of adult-onset autosomal-dominant leukodystrophy.

    Science.gov (United States)

    Piccinini, Marco; Buccinnà, Barbara; De Marco, Giovanni; Lupino, Elisa; Ramondetti, Cristina; Grifoni, Silvia; Votta, Barbara; Giordana, Maria Teresa; Rinaudo, Maria Teresa

    2010-03-01

    Previously, myelin from cerebral white matter (CWM) of two subjects of a family with orthochromatic adult-onset autosomal-dominant leukodystrophy (ADLD) was disclosed to exhibit defective large isoform of myelin-associated glycoprotein (L-MAG) and patchy distribution only in the elder subject. L-MAG and neural cell adhesion molecule (N-CAM) (N-CAM 180, 140, and 120) are structurally related and concur to myelin/axon interaction. In early developmental stages, in neurons and glia N-CAM is converted into polysialylated (PSA)-NCAM by two sialyltransferases sialyltransferase-X (STX) and polysialyltransferase-1 (PST). Notably, PSA-NCAM disrupts N-CAM adhesive properties and is nearly absent in the adult brain. Here, CWM extracts and myelin of the two subjects were searched for the expression pattern of the N-CAM isoforms and PSA-NCAM, and their CWM was evaluated for N-CAM, STX and PST gene copy number and gene expression as mRNA. Biochemically, we disclosed that in CWM extracts and myelin from both subjects, PSA-NCAM accumulates, N-CAM 180 considerably increases, N-CAM 140 is modestly modified and N-CAM 120 remarkably decreases; duplication of genes encoding N-CAM, STX and PST was not revealed, whereas PST mRNA was clearly increased. Immunohistochemically, in CWM of both subjects, we found an unusually diffuse accumulation of PSA-NCAM without inflammation markers. PSA-NCAM persistence, up-regulated PST mRNA and previously uncovered defective L-MAG may be early pathogenetic events in this ADLD form.

  19. Age-related decline in nicotinic receptor availability with [123I]5-IA-85380 SPECT

    OpenAIRE

    2008-01-01

    Human postmortem studies have reported decreases with age in high affinity nicotine binding in brain. We investigated the effect of age on β2-containing nicotinic acetylcholine receptor (β2-nAChR) availability in eight brain regions of living human subjects using the ligand [123I]5-IA-85380 ([123I]5-IA) and single photon emission computed tomography (SPECT). Healthy, nonsmokers (N=47) ranging in age from 18-85 were administered [123I]5-IA using a bolus plus constant infusion paradigm and imag...

  20. In vivo human buccal permeability of nicotine

    DEFF Research Database (Denmark)

    Adrian, Charlotte L; Olin, Helle B D; Dalhoff, Kim;

    2006-01-01

    The aim was to examine the in vivo buccal pH-dependent permeability of nicotine in humans and furthermore compare the in vivo permeability of nicotine to previous in vitro permeability data. The buccal permeability of nicotine was examined in a three-way cross-over study in eight healthy non-smok...

  1. Nicotine's defensive function in nature.

    Directory of Open Access Journals (Sweden)

    Anke Steppuhn

    2004-08-01

    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 D(4-nicotinic acid (NA, we demonstrate that silencing pmt inhibits nicotine production, while the excess NA dimerizes to form anatabine. Larvae of the nicotine-adapted herbivore Manduca sexta (tobacco hornworm grew faster and, like the beetle Diabrotica undecimpunctata, preferred IRpmt plants in choice tests. When planted in their native habitat, IRpmt plants were attacked more frequently and, compared to wild-type plants, lost 3-fold more leaf area from a variety of native herbivores, of which the beet armyworm, Spodoptera exigua, and Trimerotropis spp. grasshoppers caused the most damage. These results provide strong evidence that nicotine functions as an efficient defense in nature and highlights the value of transgenic techniques for ecological research.

  2. Pre-clinical properties of the alpha 4 beta 2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence

    NARCIS (Netherlands)

    Rollema, H.; Shrikhande, A.; Ward, K. M.; Tingley, F. D.; Coe, J. W.; O'Neill, B. T.; Tseng, E.; Wang, E. Q.; Mather, R. J.; Hurst, R. S.; Williams, K. E.; de Vries, M.; Cremers, T.; Bertrand, S.; Bertrand, D.

    2010-01-01

    Background and purpose: Smoking cessation trials with three high-affinity partial agonists of alpha 4 beta 2 neuronal nicotinic acetylcholine receptors (nAChRs) have demonstrated differences in their clinical efficacy. This work examines the origin of the differences by taking into account brain exp

  3. High Temperature Induces Expression of Tobacco Transcription Factor NtMYC2a to Regulate Nicotine and JA Biosynthesis

    Directory of Open Access Journals (Sweden)

    Liming Yang

    2016-10-01

    Full Text Available Environmental stress elevates the level of jasmonic acid (JA and activates the biosynthesis of nicotine and related pyridine alkaloids in tobacco (Nicotiana tabacum L. by up-regulating the expression of putrescine N-methyltransferase 1 (NtPMT1, which encodes a putrescine N-methyl transferase that catalyzes nicotine formation. The JA signal suppressor JASMONATE ZIM DOMAIN 1 (NtJAZ1 and its target protein, NtMYC2a, also regulate nicotine biosynthesis; however, how these proteins interact to regulate abiotic-induced nicotine biosynthesis is poorly understood. In this study, we found that high-temperature (HT treatment activated transcription of NtMYC2a, which subsequently stimulated the transcription of genes associated with JA biosynthesis, including Lipoxygenase (LOX, Allene oxide synthase (AOS, Allene oxide cyclase (AOC, and 12-oxophytodienodate reductase (OPR. Overexpression of NtMYC2a increased nicotine biosynthesis by enhancing its binding to the promoter of NtPMT1. Overexpression of either NtJAZ1 or proteasome-resistant NtJAZ1∆C suppressed nicotine production under normal conditions, but overexpression only of the former resulted in low levels of nicotine under HT treatment. These data suggest that HT induces NtMYC2a accumulation through increased transcription to activate nicotine synthesis; meanwhile, HT-induced NtMYC2a can activate JA synthesis to promote additional NtMYC2a activity by degrading NtJAZ1 at the post-transcriptional level.

  4. Varenicline and cytisine diminish the dysphoric-like state associated with spontaneous nicotine withdrawal in rats.

    Science.gov (United States)

    Igari, Moe; Alexander, Jon C; Ji, Yue; Qi, Xiaoli; Papke, Roger L; Bruijnzeel, Adrie W

    2014-01-01

    Tobacco addiction is characterized by a negative mood state upon smoking cessation and relapse after periods of abstinence. Clinical studies indicate that negative mood states lead to craving and relapse. The partial α4/α6/β2* nicotinic acetylcholine receptor (nAChR) agonists varenicline and cytisine are widely used as smoking cessation treatments. Varenicline has been approved in the United States for smoking cessation and cytisine is used in Eastern European countries. Despite the widespread use of these compounds, very little is known about their effects on mood states. These studies investigated the effects of varenicline, cytisine, and the cytisine-derivative 3-(pyridin-3'-yl)-cytisine (3-pyr-Cyt) on brain reward function in nicotine-naive and nicotine-withdrawing rats. The cytisine-derivative 3-pyr-Cyt is a very weak α4β2* nAChR partial agonist and like cytisine and varenicline has antidepressant-like effects in animal models. The intracranial self-stimulation (ICSS) procedure was used to investigate the effects of these compounds on brain reward function. Elevations in ICSS thresholds reflect a dysphoric state and a lowering of thresholds is indicative of a potentiation of brain reward function. It was shown that acute administration of nicotine and varenicline lowered ICSS thresholds. Acute administration of cytisine or 3-pyr-Cyt did not affect ICSS thresholds. Discontinuation of chronic, 14 days, nicotine administration led to elevations in ICSS thresholds that lasted for about 2 days. Varenicline and cytisine, but not 3-pyr-Cyt, diminished the nicotine withdrawal-induced elevations in ICSS thresholds. In conclusion, these studies indicate that varenicline and cytisine diminish the dysphoric-like state associated with nicotine withdrawal and may thereby prevent relapse to smoking in humans.

  5. Synthesis and biodistribution of radioiodinated nicotine analogs

    Energy Technology Data Exchange (ETDEWEB)

    Chan, S.M.; Basmadjian, G.P.; Sadek, S.A.; Magarian, R.A.; Grunder, J.R.; Marten, D.F.

    1986-06-01

    Four /sup 125/I-labelled nicotine analogs were synthesized: 3-(methylpropylaminomethyl)-, 3-(diethylaminomethyl)-, 3-(isopropylaminomethyl)-, and 3-(diisopropylaminomethyl)-5-(/sup 125/I)-iodopyridines. 5-Bromonicotinic acid was acylated with thionyl chloride and then reacted with the appropriate primary and secondary amines to give the corresponding amides which were reduced with diborane to the desirable amines. Radioiodination was done by halogen exchange. Biodistribution studies in rats, showed that all four labelled compounds were rapidly taken up by the brain and the adrenal gland. This was followed by rapid washout of the compounds from these organs. The most promising of these compounds, 3-(diisopropylaminomethyl)-5-(/sup 125/I)-iodopyridine, showed a brain-to-blood ratio of 6.0:1 and an adrenal-to-blood ratio of 35.9:1 at 2 minutes post administration. In vitro correlation studies showed that brain uptake of these compounds depends on both protein binding and lipophilicity, whereas adrenal uptake depends only on lipophilicity.

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

    Science.gov (United States)

    Kayir, Hakan; Semenova, Svetlana; Markou, Athina

    2014-01-03

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

  7. Neurodegeneration with Brain Iron Accumulation

    Science.gov (United States)

    ... of dystonia and spasticity, including oral medications, intrathecal baclofen pump (in which a small pump is implanted ... of dystonia and spasticity, including oral medications, intrathecal baclofen pump (in which a small pump is implanted ...

  8. Blockade of CRF1 receptors in the central nucleus of the amygdala attenuates the dysphoria associated with nicotine withdrawal in rats.

    Science.gov (United States)

    Bruijnzeel, Adrie W; Ford, Jenna; Rogers, Jessica A; Scheick, Stacey; Ji, Yue; Bishnoi, Mahendra; Alexander, Jon C

    2012-03-01

    The majority of smokers relapse during the acute withdrawal phase when withdrawal symptoms are most severe. The goal of the present studies was to investigate the role of corticotropin-releasing factor (CRF) and noradrenergic transmission in the central nucleus of the amygdala (CeA) in the dysphoria associated with smoking cessation. It was investigated if blockade of CRF1 receptors, blockade of α1-adrenergic receptors, or stimulation of α2-adrenergic receptors in the CeA diminishes the deficit in brain reward function associated with nicotine withdrawal in rats. Nicotine dependence was induced by implanting minipumps that delivered a nicotine solution. Withdrawal was precipitated with the nicotinic acetylcholine receptor antagonist mecamylamine. A discrete-trial intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In all the experiments, mecamylamine elevated the brain reward thresholds of the rats chronically treated with nicotine and did not affect the brain reward thresholds of the saline-treated control rats. Intra-CeA administration of the CRF1 receptor antagonist R278995/CRA0450 completely prevented the mecamylamine-induced elevations in brain reward thresholds in the nicotine-treated rats and did not affect the brain reward thresholds of the saline-treated control rats. R278995/CRA0450 has also been shown to block sigma-1 receptors but there is no evidence that this could affect negative mood states. Intra-CeA administration of the α1-adrenergic receptor antagonist prazosin or the α2-adrenergic receptor agonist clonidine did not affect the brain reward thresholds of the nicotine or saline-treated rats. These studies suggest that CRF1 receptor antagonists may diminish the dysphoria associated with smoking cessation by blocking CRF1 receptors in the CeA.

  9. Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement.

    Science.gov (United States)

    Tolu, S; Eddine, R; Marti, F; David, V; Graupner, M; Pons, S; Baudonnat, M; Husson, M; Besson, M; Reperant, C; Zemdegs, J; Pagès, C; Hay, Y A H; Lambolez, B; Caboche, J; Gutkin, B; Gardier, A M; Changeux, J-P; Faure, P; Maskos, U

    2013-03-01

    Smoking is the most important preventable cause of mortality and morbidity worldwide. This nicotine addiction is mediated through the nicotinic acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within the ventral tegmental area (VTA), the key brain area responsible for the reinforcing properties of all drugs of abuse, nicotine acts on several different cell types and afferents. Identifying the precise action of nicotine on this microcircuit, in vivo, is important to understand reinforcement, and finally to develop efficient smoking cessation treatments. We used a novel lentiviral system to re-express exclusively high-affinity nAChRs on either dopaminergic (DAergic) or γ-aminobutyric acid-releasing (GABAergic) neurons, or both, in the VTA. Using in vivo electrophysiology, we show that, contrary to widely accepted models, the activation of GABA neurons in the VTA plays a crucial role in the control of nicotine-elicited DAergic activity. Our results demonstrate that both positive and negative motivational values are transmitted through the dopamine (DA) neuron, but that the concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons. This work identifies the GABAergic interneuron as a potential target for smoking cessation drug development.

  10. Effects of nicotine and depressive traits on affective priming of lateralized emotional word identification.

    Science.gov (United States)

    Gilbert, David G; Carlson, Joshua M; Riise, Hege; Rabinovich, Norka E; Sugai, Chihiro; Froeliger, Brett

    2008-08-01

    Based on evidence suggesting that depressive traits, emotional information processing, and the effects of nicotine may be mediated by lateralized brain mechanisms, analyses assessed the influence of depressive traits and nicotine patch on emotional priming of lateralized emotional word identification in 61 habitual smokers. Consistent with hypotheses, nicotine as compared to placebo patch enhanced right visual field (RVF) emotional word identification while decreasing performance of emotional word identification in the left visual field (LVF). Nicotine also enhanced positive affect and decreased negative affect. Consistent with the Heller model of depression, scoring high in depressive traits was associated with a general decrease in LVF emotional word identification. Additionally, this general LVF deficit was especially pronounced for positive word identification in individuals scoring high in trait depression. Positive primes facilitated positive target identification in the RVF and negative primes facilitated negative target identification in the LVF. Thus, nicotine promoted a LVF word-identification deficit similar to that observed in those with depressive traits. However, nicotine also enhanced RVF processing and reduced negative affect, whereas it enhanced positive affect.

  11. "Effect of the drug transporters ABCB1, ABCC2, and ABCG2 on the disposition and brain accumulation of the taxane analog BMS-275,183".

    Science.gov (United States)

    Marchetti, Serena; Pluim, Dick; Beijnen, Jos H; Mazzanti, Roberto; van Tellingen, Olaf; Schellens, Jan H M

    2014-12-01

    BMS-275,183 is a novel oral C-4 methyl carbonate analogue of paclitaxel. Recently, a drug-drug interaction between BMS-275,183 and benzimidazole proton pump inhibitors (PPIs) was suggested in clinical trials resulting in elevated drug exposure and toxicity. We explored whether the interaction takes place at the level of P-glycoprotein (Pgp, MDR1, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2) and MRP2 (ABCC2) using in vitro and in vivo models. In vitro cell survival, drug accumulation, efflux and transport studies with BMS-275,183 were performed employing MDCKII (wild-type, MDR1, BCRP, MRP2) and LLCPK (wild-type and MDR1) cells. In vivo the pharmacokinetics and tissue distribution of BMS-275,183 after p.o. and i.v. administration were explored in Mdr1a/1b(-/-) and wild-type mice, in presence or absence of the PPI pantoprazole. Results In vitro, BMS-275,183 was found to be a good substrate for MDR1, a moderate substrate for MRP2 and not a substrate for BCRP. In vivo, oral bioavailability, plasma AUC0-6h and brain concentrations were significantly 1.5-, 4-, and 2-fold increased, respectively, in Mdr1a/1b(-/-) compared with wild-type mice (p < 0.001). However, oral co-administration of pantoprazole (40 mg/kg) did not alter the pharmacokinetics of BMS-275,183 in wild-type mice. Conclusions BMS-275,183 is efficiently transported by Pgp and to a lesser extent by MRP2 in vitro. Genetic deletion of Pgp significantly altered the pharmacokinetics and brain distribution of p.o. and i.v. administered BMS-275,183 in Mdr1a/1b-/- compared to wild-type mice. Oral co-administration of BMS-275,183 with pantoprazole did not affect the pharmacokinetics of BMS-275,183 in wild-type mice, suggesting no interaction with PPI at the dose employed.

  12. The long-term effects of prenatal nicotine exposure on response inhibition: an fMRI study of young adults.

    Science.gov (United States)

    Longo, Carmelinda A; Fried, Peter A; Cameron, Ian; Smith, Andra M

    2013-01-01

    The long-term effects of prenatal nicotine exposure on response inhibition were investigated in young adults using functional magnetic resonance imaging (fMRI). Participants were members of the Ottawa Prenatal Prospective Study, a longitudinal study that collected a unique body of information on participants from infancy to young adulthood, which allowed for the measurement of an unprecedented number of potentially confounding drug exposure variables including: prenatal marijuana and alcohol exposure and current marijuana, nicotine and alcohol use. Twelve young adults with prenatal nicotine exposure and 13 non-exposed controls performed a Go/No-Go task while fMRI blood oxygen level-dependent responses were examined. Despite similar task performance, participants prenatally exposed to nicotine demonstrated significantly greater activity in several regions of the brain that typically subserve response inhibition including the inferior frontal gyrus, the inferior parietal lobe, the thalamus and the basal ganglia. In addition, prenatally exposed participants showed greater activity in relatively large posterior regions of the cerebellum. These results suggest that prenatal nicotine exposure leads to altered neural functioning during response inhibition that continues into adulthood. This alteration is compensated for by recruitment of greater neural resources within regions of the brain that subserve response inhibition and the recruitment of additional brain regions to successfully perform the task. Response inhibition is an important executive functioning skill and impairments can impede functioning in much of everyday life. Thus, awareness of the continued long-term neural physiological effects of prenatal nicotine exposure is critical.

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

    DEFF Research Database (Denmark)

    Lindell, G; Bukhave, Klaus; Lilja, I;

    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...

  14. 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.

  15. Astrocytic and neuronal accumulation of elevated extracellular K+ with a 2/3 K+/Na+ flux ratio - consequences for energy metabolism, osmolarity and higher brain function

    Directory of Open Access Journals (Sweden)

    Leif eHertz

    2013-08-01

    Full Text Available Brain excitation increases neuronal Na+ concentration by 2 major mechanisms: i Na+influx caused by glutamatergic synaptic activity; and ii action-potential-mediateddepolarization by Na+ influx followed by repolarizating K+ efflux, increasingextracellular K+ concentration. This review deals mainly with the latter and it concludesthat clearance of extracellular K+ is initially mainly effectuated by Na+,K+-ATPasemediatedK+ uptake into astrocytes, at K+ concentrations above ~10 mM aided by uptakeof Na+, K+ and 2 Cl- by the cotransporter NKCC1. Since operation of the astrocytic Na+,K+-ATPase requires K+-dependent glycogenolysis for stimulation of the intracellularATPase site, it ceases after normalization of extracellular K+ concentration. This allowsK+ release via the inward rectifying K+ channel Kir1.4, perhaps after trans-astrocyticconnexin- and/or pannexin-mediated K+ transfer, which would be a key candidate fordetermination by synchronization-based computational analysis and may have signalingeffects. Spatially dispersed K+ release would have little effect on extracellular K+concentration and allow K+ accumulation by the less powerful neuronal Na+,K+-ATPase,which is not stimulated by increases in extracellular K+. Since the Na+,K+-ATPaseexchanges 3 Na+ with 2 K+, it creates extracellular hypertonicity and cell shrinkage.Hypertonicity also stimulates NKCC1, which, aided by -adrenergic stimulation of theNa+,K+-ATPase, causes regulatory volume increase, furosemide-inhibited undershoot in[K+]e and perhaps facilitation of the termination of slow neuronal hyperpolarization(sAHP, with behavioral consequences. The ion transport processes involved minimizeionic disequilibria caused by the asymmetric Na+,K+-ATPase fluxes.

  16. 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.

  17. 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.

  18. Functional distribution of nicotinic receptors in CA3 region of the hippocampus.

    Science.gov (United States)

    Grybko, Michael; Sharma, Geeta; Vijayaraghavan, Sukumar

    2010-01-01

    Nicotinic acetylcholine receptor (nAChR) modulation of a number of parameters of synaptic signaling in the brain has been demonstrated. It is likely that effects of nicotine are due to its ability to modulate network excitability as a whole. A pre-requisite to understanding the effects of nicotine on network properties is the elucidation of functional receptors. We have examined the distribution of functional nAChRs in the dentate gyrus granule cells and the CA3 region of the mammalian hippocampus using calcium imaging from acute slices. Our results demonstrate the presence of functional nAChRs containing the alpha7 subunit (alpha7-nAChRs) on mossy fiber boutons, CA3 pyramidal cells, and on astrocytes. In addition, both CA3 interneurons and granule cells show nicotinic signals. Our study suggests that functional nicotinic receptors are widespread in their distribution and that calcium imaging might be an effective technique to examine locations of these receptors in the mammalian brain.

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

    Science.gov (United States)

    López-Hidalgo, Mónica; Salgado-Puga, Karla; Alvarado-Martínez, Reynaldo; Medina, Andrea Cristina; Prado-Alcalá, Roberto A; García-Colunga, Jesús

    2012-01-01

    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.

  20. Association Between Smoking, Nicotine Dependence, and BDNF Val(66)Met Polymorphism with BDNF Concentrations in Serum

    NARCIS (Netherlands)

    Jamal, Mumtaz; Van der Does, Willem; Elzinga, Bernet M.; Molendijk, Marc L.; Penninx, Brenda W. J. H.

    2015-01-01

    Introduction: Nicotine use is associated with the upregulation of brain-derived neurotrophic factor (BDNF) in serum. An association between smoking and the BDNF Val(66)Met polymorphism has also been found. The aim of this study is to examine the levels of serum BDNF in never-smokers, former smokers,

  1. Frequency-Dependent Modulation of Dopamine Release by Nicotine and Dopamine D1 Receptor Ligands: An In Vitro Fast Cyclic Voltammetry Study in Rat Striatum.

    Science.gov (United States)

    Goutier, W; Lowry, J P; McCreary, A C; O'Connor, J J

    2016-05-01

    Nicotine is a highly addictive drug and exerts this effect partially through the modulation of dopamine release and increasing extracellular dopamine in regions such as the brain reward systems. Nicotine acts in these regions on nicotinic acetylcholine receptors. The effect of nicotine on the frequency dependent modulation of dopamine release is well established and the purpose of this study was to investigate whether dopamine D1 receptor (D1R) ligands have an influence on this. Using fast cyclic voltammetry and rat corticostriatal slices, we show that D1R ligands are able to modulate the effect of nicotine on dopamine release. Nicotine (500 nM) induced a decrease in dopamine efflux at low frequency (single pulse or five pulses at 10 Hz) and an increase at high frequency (100 Hz) electrical field stimulation. The D1R agonist SKF-38393, whilst having no effect on dopamine release on its own or on the effect of nicotine upon multiple pulse evoked dopamine release, did significantly prevent and reverse the effect of nicotine on single pulse dopamine release. Interestingly similar results were obtained with the D1R antagonist SCH-23390. In this study we have demonstrated that the modulation of dopamine release by nicotine can be altered by D1R ligands, but only when evoked by single pulse stimulation, and are likely working via cholinergic interneuron driven dopamine release.

  2. 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.

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

    Science.gov (United States)

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

    2004-01-01

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

  4. Nicotine Effects on the Impact of Stress

    Science.gov (United States)

    2016-03-01

    have abnormally reduced responses to environments previously associated with the stressor, which we term “context-potentiated startle (CPS)”, but no...a missed dose of nicotine) have abnormally persistent CPS, but no differences in FPS. Projected to warfighters, this suggests that nicotine...cognitive function that can enhance aversive or traumatic memories. It is currently unknown if nicotine use increases or decreases vulnerability to the

  5. Nicotine Effects on the Impact of Stress

    Science.gov (United States)

    2015-09-01

    Betty Diamond 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: bcarlezon@mclean.harvard.edu 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S...We now report that we have examined other permutations of our experimental design, including those in which access to nicotine is sustained for...nicotine access, rats that received fear conditioning during nicotine withdrawal showed sustained elevation of %CPS but reduced %FPS as well as enhanced

  6. The effects of erdosteine, N-acetylcysteine, and vitamin E on nicotine-induced apoptosis of hippocampal neural cells.

    Science.gov (United States)

    Demiralay, Rezan; Gürsan, Nesrin; Erdem, Havva

    2008-08-01

    This study investigated the frequency of apoptosis in rat hippocampal neural cells after intraperitoneal nicotine injection, examining the roles of the inflammatory markers myeloperoxidase (MPO) and tumor necrosis factor alpha (TNF-alpha) in nicotine-induced brain damage and the protective effects of three known antioxidant agents, N-acetylcysteine (NAC), erdosteine, and vitamin E. Female Wistar rats were divided into seven groups, each composed of nine rats: 2 negative control groups, 2 positive control groups, one erdosteine-treated group (500 mg/kg), one NAC-treated group (500 mg/kg), and one vitamin E-treated group (500 mg/kg). Nicotine was intraperitoneally injected at a dosage of 0.6 mg/kg for 21 days. Following nicotine injection, the antioxidants were administered orally; treatment was continued until the rats were killed. Apoptosis level in hippocampal neural cells was determined by using TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick endlabeling) method. Staining of cytoplasmic TNF-alpha in hippocampal neural cells and hippocampus MPO activity were evaluated by immunohistochemistry. Nicotine administration had no effect on local TNF-alpha production, or hippocampal MPO activity. The treatments with erdosteine, NAC and vitamin E significantly reduced the rate of nicotine-induced hippocampal neural cell apoptosis. This findings suggest that erdosteine and NAC can be as effective as vitamin E in protecting against nicotine-induced hippocampal neural cell apoptosis.

  7. 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.

  8. Cytisine-based nicotinic partial agonists as novel antidepressant compounds.

    Science.gov (United States)

    Mineur, Yann S; Eibl, Christoph; Young, Grace; Kochevar, Christopher; Papke, Roger L; Gündisch, Daniela; Picciotto, Marina R

    2009-04-01

    Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like properties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) including those containing the beta2 subunit (beta2(*)), results in antidepressant-like effects. Previous studies have shown that cytisine, a partial agonist at alpha4/beta2(*) nAChRs, and a full agonist at alpha3/beta4(*) and alpha7 nAChRs, has antidepressant-like properties in several rodent models of antidepressant efficacy; however, it is not clear whether more selective partial agonists will also be effective in these models. We tested cytisine and two derivatives, 5-bromo-cytisine (5-Br-Cyt) and 3-(pyridin-3'-yl)-cytisine (3-pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests. 3-pyr-Cyt was a partial agonist with very low efficacy at alpha4/beta2(*) nAChRS but had no agonist effects at other nAChRs normally targeted by cytisine, and it was effective in mouse models of antidepressant efficacy. Animals showed dose-dependent antidepressant-like effects in all three behavioral paradigms. 5-Br-Cyt was not effective in behavioral tests when administered peripherally, probably because of its inability to penetrate the blood-brain barrier, because it efficiently reduced immobility in the tail suspension test when administered intraventricularly. These results suggest that novel nicotinic partial agonists may provide new possibilities for development of drugs to treat mood disorders.

  9. Nicotinic Acetylcholine Receptors in the Pathophysiology of Alzheimer's Disease

    DEFF Research Database (Denmark)

    Thomsen, Morten Skøtt; Andreasen, Jesper Tobias; Arvaniti, Maria;

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) have been pursued for decades as potential molecular targets to treat cognitive dysfunction in Alzheimer's disease (AD) due to their positioning within regions of the brain critical in learning and memory, such as the prefrontal cortex and hippocampus......, and their demonstrated role in processes underlying cognition such as synaptic facilitation, and theta and gamma wave activity. Historically, activity at these receptors is facilitated in AD by use of drugs that increase the levels of their endogenous agonist acetylcholine, and more recently nAChR selective ligands have...

  10. Combined effects of marijuana and nicotine on memory performance and hippocampal volume.

    Science.gov (United States)

    Filbey, Francesca M; McQueeny, Tim; Kadamangudi, Shrinath; Bice, Collette; Ketcherside, Ariel

    2015-10-15

    Combined use of marijuana (MJ) and tobacco is highly prevalent in today's population. Individual use of either substance is linked to structural brain changes and altered cognitive function, especially with consistent reports of hippocampal volume deficits and poorer memory performance. However, the combined effects of MJ and tobacco on hippocampal structure and on learning and memory processes remain unknown. In this study, we examined both the individual and combined effects of MJ and tobacco on hippocampal volumes and memory performance in four groups of adults taken from two larger studies: MJ-only users (n=36), nicotine-only (Nic-only, n=19), combined marijuana and nicotine users (MJ+Nic, n=19) and non-using healthy controls (n=16). Total bilateral hippocampal volumes and memory performance (WMS-III logical memory) were compared across groups controlling for total brain size and recent alcohol use. Results found MJ and MJ+Nic groups had smaller total hippocampal volumes compared to Nic-only and controls. No significant difference between groups was found between immediate and delayed story recall. However, the controls showed a trend for larger hippocampal volumes being associated with better memory scores, while MJ+Nic users showed a unique inversion, whereby smaller hippocampal volume was associated with better memory. Overall, results suggest abnormalities in the brain-behavior relationships underlying memory processes with combined use of marijuana and nicotine use. Further research will need to address these complex interactions between MJ and nicotine.

  11. 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.

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

    Science.gov (United States)

    Ring, Avi; Strom, Bjorn Oddvar; Turner, Simon R; Timperley, Christopher M; Bird, Michael; Green, A Christopher; Chad, John E; Worek, Franz; Tattersall, John E H

    2015-01-01

    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.

  13. Cross-regulation between colocalized nicotinic acetylcholine and 5-HT3 serotonin receptors on presynaptic nerve terminals

    Institute of Scientific and Technical Information of China (English)

    John J DOUGHERTY; Robert A NICHOLS

    2009-01-01

    Aim: Substantial colocalization of functionally independent a4 nicotinic acetylcholine receptors and 5-HT3 serotonin receptors on presynaptic terminals has been observed in brain. The present study was aimed at addressing whether nicotinic acetylcholine receptors and 5-HT3 serotonin receptors interact on the same presynaptic terminal, suggesting a convergence of cholinergic and serotonergic regulation.Methods: Ca2+ responses in individual, isolated nerve endings purified from rat striatum were measured using confocal imaging.Results: Application of 500 nmol/L nicotine following sustained stimulation with the highly selective 5-HT3 receptor agonist m-chlorophenylbiguanide at 100 nmol/L resulted in markedly reduced Ca2* responses (28% of control) in only those striatal nerve endings that originally responded to m-chlorophenylbiguanide. The cross-regulation developed over several minutes. Presynaptic nerve endings that had not responded to m-chlorophenylbiguanide, indicating that 5-HT3 receptors were not present, displayed typical responses to nicotine. Application of m-chlorophenylbiguanide following sustained stimulation with nicotine resulted in partially attenuated Ca2* responses (49% of control). Application of m-chlorophenylbiguanide following sustained stimulation with m-chlorophenylbiguanide also resulted in a strong attenuation of Ca2+ responses (12% of control), whereas nicotine-induced Ca2t responses following sustained stimulation with nicotine were not significantly different from control.Conclusion: These results indicate that the presynaptic Ca2+ increases evoked by either 5-HT, receptor or nicotinic acetylcholine receptor activation regulate subsequent responses to 5-HT3 receptor activation, but that only 5-HT3 receptors cross-regulate subsequent nicotinic acetylcholine receptor-mediated responses. The findings suggest a specific interaction between the two receptor systems in the same striatal nerve terminal, likely involving Ca2+-dependent

  14. Effects of acute nicotine administration on behavioral and neural (EEG) correlates of working memory in non-smokers.

    Science.gov (United States)

    Fisher, Derek J; Daniels, Richelle; Jaworska, Natalia; Knobelsdorf, Amy; Knott, Verner J

    2012-01-06

    Enhancements in working memory (WM) performance have been previously reported following acute smoking/nicotine. Neuroimaging and behavioral assessments of nicotine's effects on WM have yielded inconsistent findings. Few studies, however, have examined the effects of nicotine on WM-related neural activity in non-smokers. The present study examined the effect of acute nicotine gum administration (6 mg) on electroencephalographic (EEG) activity (alpha(1), alpha(2) and theta bands) and performance on the parametrically manipulated N-back task of WM in 20 non-smoking adults. EEG activity varied with WM load (e.g. alpha(1) decreasing and theta increasing). Performance on the N-back was also load-sensitive, with slower reaction times and decreased accuracy associated with increasing memory load. Neither response speed nor accuracy measures were affected by nicotine but EEG was, with the effects varying by load and brain region. Nicotine-induced increases in alpha(2) and theta were observed under lower (0-, 1-back) memory load conditions Additionally, nicotine significantly reduced signal detection sensitivity values and altered response bias toward being more conservative at all levels of the N-back. Taken together, these findings suggest that while nicotine may boost WM neural processes at lower levels of WM load in non-smokers, it also may activate concurrent behavioral inhibition networks that negate any effects on behavioral performance. Additionally, nicotine appears to have no impact, or perhaps a negative impact, on these processes under more demanding (2-back, 3-back) conditions in non-smokers.

  15. 人胰淀素受体和烟碱乙酰胆碱受体在大鼠大脑神经元上的功能偶联作用%Functional coupling reactions of human amylin receptor and nicotinic acetylcholine receptors in rat brain neurons

    Institute of Scientific and Technical Information of China (English)

    李宗明; 李秀凤

    2012-01-01

    人胰淀素(hAmylin)是由分泌胰岛素的胰岛B细胞释放,作用于靶组织,维持细胞的兴奋性和葡萄糖在体内的稳态.hAmylin分泌异常会引起人类的疾病,特别是阿尔茨海默氏病(Alzheimer's disease,AD).目前对于hAmylin通过激活什么样的受体从而产生脑神经元的神经毒性仍然不清楚.已知烟碱乙酰胆碱受体(nicotinic acetylcholine receptors,nAChRs)是引发多种神经性疾病的关键因素.本研究通过记录hAmylin和烟碱对基底前脑神经元的全细胞电流和膜电位的影响,来确定hAmylin受体和烟碱受体两者之间的相互作用.在酶解分离的基底前脑Broca区(diagonal band of Broca,DBB)胆碱能神经元上进行全细胞膜片钳记录,结果显示,hAmylin或烟碱单独应用,均引起剂量(1 nmol/L~20 μmol/L)依赖性膜电位的去极化和DBB神经元放电频率增加.hAmylin受体拮抗剂AC253,不仅阻断hAmylin的兴奋作用,而且也阻断烟碱对神经元的兴奋作用;同样,使用nAChR竞争性拮抗剂二氢-β-刺桐啶碱(dihydro-β-erythroidine,DHβE),可以阻断烟碱和hAmylin对DBB神经元的兴奋作用.以上结果提示,hAmylin受体和nAChRs受体在DBB神经元可能是功能偶联的,协同影响DBB神经元的兴奋性.%Human amylin (hAmylin) is co-released with insulin from pancreatic B-cells and the actions of this peptide on its target tissues maintain the cell excitability and glucose homeostasis.Inappropriate control of hAmylin secretion may result in human disease,particularly Alzheimer's disease (AD).It's unknown that which kind of receptor is activated by human amylin,leading to the neurotoxicity in neurons of brain.Nicotinic acetylcholine receptors (nAChRs) are known to play a critical role in a variety of nervous diseases.In the present study,we sought to determine the inter-relationships between these two receptors by examining the actions of hAmylin and nicotine on whole-cell currents and membrane potential in basal

  16. 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.

  17. Serotonin transporter genotype and depressive symptoms moderate effects of nicotine on spatial working memory.

    Science.gov (United States)

    Carlson, Joshua M; Gilbert, David G; Riise, Hege; Rabinovich, Norka E; Sugai, Chihiro; Froeliger, Brett

    2009-06-01

    Smokers may use nicotine to self-medicate for situation-specific or person-specific cognitive or affective deficits. Although evidence suggests that nicotine replacement therapy (NRT), relative to placebo, enhances spatial working memory (SWM) in smoking-abstinent smokers with schizophrenia, the extent to which NRT may be helpful in attenuating abstinence-related SWM in other groups with deficits in SWM is unknown. Depressive symptoms are associated with both tobacco smoking and deficits in SWM. Previous studies have found that smoking abstinence increases depressive affect and depression-related hemispheric asymmetries in brain activation. Although the serotonin neurotransmitter system is closely associated with depression and the effects of nicotine, the authors are not aware of any studies that have evaluated the possible role of individual differences in serotonin transporter (5-HTT) genotype and depressive symptoms as moderators of the effects of NRT on SWM. Thus, the current study assessed the effects of NRT (nicotine patch) on SWM in relation to: (1) depressive traits and (2) 5-HTT genotype. Smoking-deprived habitual smokers (N = 64) completed the dot recall test of SWM during counterbalanced and double-blind nicotine and placebo testing sessions. There was a marginal overall effect of NRT on SWM. More importantly, NRT enhanced SWM in 5-HTT short allele carriers, relative to those with two long alleles, and this enhancement in short-allele carriers was greater for individuals with higher levels of depressive symptoms.

  18. Nicotinic modulation of hippocampal cell signaling and associated effects on learning and memory.

    Science.gov (United States)

    Kutlu, Munir Gunes; Gould, Thomas J

    2016-03-01

    The hippocampus is a key brain structure involved in synaptic plasticity associated with long-term declarative memory formation. Importantly, nicotine and activation of nicotinic acetylcholine receptors (nAChRs) can alter hippocampal plasticity and these changes may occur through modulation of hippocampal kinases and transcription factors. Hippocampal kinases such as cAMP-dependent protein kinase (PKA), calcium/calmodulin-dependent protein kinases (CAMKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-jun N-terminal kinase 1 (JNK1), and the transcription factor cAMP-response element-binding protein (CREB) that are activated either directly or indirectly by nicotine may modulate hippocampal plasticity and in parallel hippocampus-dependent learning and memory. Evidence suggests that nicotine may alter hippocampus-dependent learning by changing the time and magnitude of activation of kinases and transcription factors normally involved in learning and by recruiting additional cell signaling molecules. Understanding how nicotine alters learning and memory will advance basic understanding of the neural substrates of learning and aid in understanding mental disorders that involve cognitive and learning deficits.

  19. 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.

  20. Functional proteins involved in regulation of intracellular Ca(2+) for drug development: chronic nicotine treatment upregulates L-type high voltage-gated calcium channels.

    Science.gov (United States)

    Katsura, Masashi; Ohkuma, Seitaro

    2005-03-01

    Neurochemical mechanisms underlying drug dependence and withdrawal syndrome remain unclear. In this review, we discuss how chronic nicotine exposure to neurons affects expression of diazepam binding inhibitor (DBI), an endogenous anxiogenic neuropeptide supposed to be a common substance participating drug dependence, and function of L-type high voltage-gated Ca(2+) channels (HVCCs). We also discuss the functional interaction between DBI and L-type HVCCs in nicotine dependence. Both DBI levels and [(45)Ca(2+)] influx significantly increased in the brain from mice treated with nicotine for long term, which was further enhanced after abrupt cessation of nicotine and was abolished by nicotinic acetylcholine receptor (nAChR) antagonists. Similar responses of DBI expression and L-type HVCC function were observed in cerebral cortical neurons after sustained exposure to nicotine. In addition, increased DBI expression was inhibited by antagonists of nAChR and L-type HVCCs. Sustained exposure of neurons to nicotine significantly enhanced expression of alpha(1) and alpha(2)/delta(1) subunits for L-type HVCCs and caused an increase in the B(max) value of [(3)H]verapamil binding to the particulate fractions. Therefore, it is concluded that the alterations in DBI expression is mediated via increased influx of Ca(2+) through upregulated L-type HVCCs and these neurochemical changes have a close relationship with development of nicotine dependence and/or its withdrawal syndrome.

  1. Spectral confocal imaging of fluorescently tagged nicotinic receptors in knock-in mice with chronic nicotine administration.

    Science.gov (United States)

    Renda, Anthony; Nashmi, Raad

    2012-02-10

    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 brain. Chronic nicotine exposure in both rodents and humans results in increased numbers of nicotinic acetylcholine receptors (nAChRs) in brain tissue. Similarly, alterations in the glutamatergic GluN1 or GluA1 channels have been implicated in triggering sensitization to other addictive drugs such as cocaine, amphetamines and opiates. Consequently, the ability to map and quantify distribution and expression patterns of specific ion channels is critically important to understanding the mechanisms of addiction. The study of brain region-specific effects of individual drugs was advanced by the advent of techniques such as radioactive ligands. However, the low spatial resolution of radioactive ligand binding prevents the ability to quantify ligand-gated ion channels in specific subtypes of neurons. Genetically encoded fluorescent reporters, such as green fluorescent protein (GFP) and its many color variants, have revolutionized the field of biology. By genetically tagging a fluorescent reporter to an endogenous protein one can visualize proteins in vivo. One advantage of fluorescently tagging proteins with a probe is the elimination of antibody use, which have issues of nonspecificity and accessibility to the target protein. We have used this strategy to fluorescently label nAChRs, which enabled the study of receptor assembly using Förster Resonance Energy Transfer (FRET) in transfected cultured cells. More recently, we have used the knock-in approach to engineer mice with yellow fluorescent protein tagged α4 nAChR subunits (α4YFP), enabling precise quantification of the receptor ex vivo at submicrometer resolution in CNS

  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. International Brain Drain and China’ s Human Capital Accumulation:Based on the Perspective of Study Abroad%跨国人才外流与中国人力资本积累--基于出国留学的视角

    Institute of Scientific and Technical Information of China (English)

    许家云; 李平; 王永进

    2016-01-01

    人才的跨国外流,究竟是促进了本国的人力资本积累,还是导致了本国人力资本的净损失?回答该问题,对中国在开放经济条件下实施合理的人才开放政策以推动经济增长具有重要意义。本文在开放经济框架内,将人才外流引入人力资本积累的内生决定模型,从理论上探讨了人才外流与本国人力资本积累的关系。在理论分析的基础上,本文进一步使用世界上60个国家和地区2000-2010年的面板数据进行了计量估计。实证结果表明:人才外流与中低收入国家和地区的人力资本积累呈倒“U”型关系,但与高收入国家和地区的人力资本积累线性负相关;人才外流对本国人力资本积累的影响受到本国技能劳动占比和其所生产产品替代弹性的影响。进一步鼓励和合理引导人才尤其是高层次人才的国际流动对提升中国的人力资本水平意义重大。%Whether brain outflow is beneficial to the home countries’ human capital accumulation, or is adverse to its human capital accumulation? Answering this question is of great importance for China to implement reasonable talent policy. This paper analyses the relationship between brain drain and home countries ’ human capital accumulation by taking the brain drain into the endogenously determined model of human capital accumulation in an open economy framework. Furthermore, we test the effects of the brain outflow on home countries’ human capital accumulation by using panel data of 60 countries or regions in the world from 2000-2010 . The results show that:There is an inverted “U” ⁃shaped relationship between brain outflow and the level of human capital for low and middle income countries or regions, but it shows a negative linear relationship with the human capital level in the high income countries or regions; The impact of brain drain on home countries’ human capital accumulation can be

  4. Disconnection between activation and desensitization of autonomic nicotinic receptors by nicotine and cotinine.

    Science.gov (United States)

    Buccafusco, Jerry J; Shuster, Laura C; Terry, Alvin V

    2007-02-08

    Cotinine is the major metabolite of nicotine in humans, and the substance greatly outlasts the presence of nicotine in the body. Recently, cotinine has been shown to exert pharmacological properties of its own that include potential cognition enhancement, anti-psychotic activity, and cytoprotection. Since the metabolite is generally less potent than nicotine in vivo, we considered whether part of cotinine's efficacy could be related to a reduced ability to desensitize nicotinic receptors as compared with nicotine. Rats freely moving in their home cages were instrumented to allow ongoing measurement of mean arterial blood pressure (MAP). The ganglionic stimulant dimethylphenylpiperazinium (DMPP) maximally increased MAP by 25mmHg. Slow (20min) i.v. infusion of nicotine (0.25-1micromol) produced no change in resting MAP, but the pressor response to subsequent injection of DMPP was significantly attenuated in a dose-dependent manner by up to 51%. Pre-infusion of equivalent doses of cotinine produced the same maximal degree of inhibition of the response to DMPP. Discrete i.v. injections of nicotine also produced a dose dependent increase in MAP of up to 43mmHg after the highest tolerated dose. In contrast, injection of cotinine produced no significant change in MAP up to 13 times the highest dose of nicotine. These results illustrate the disconnection between nicotinic receptor activation and receptor desensitization, and they suggest that cotinine's pharmacological actions are either mediated through partial desensitization, or through non-ganglionic subtypes of nicotinic receptors.

  5. Nicotine Increases Alcohol Intake in Adolescent Male Rats

    Science.gov (United States)

    Lárraga, Armando; Belluzzi, James D.; Leslie, Frances M.

    2017-01-01

    self-administration in adolescent males also increased subsequent oral EtOH intake. These findings suggest that brain mechanisms underlying the reinforcing effects of EtOH and nicotine are both age- and sex-dependent, and that tobacco or e-cigarette use may increase the vulnerability of teenage boys to alcohol abuse. PMID:28275339

  6. 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 ...

  7. Assessment of nicotine dependence in subjects with vascular dementia

    OpenAIRE

    2015-01-01

    Background: Nicotine Dependence is an important public health issue. Nicotine Dependence is a risk factor for vascular diseases like Myocardial Infarction and Vascular dementia. The rate of nicotine dependence in Indian subjects with Vascular Dementia is not known. Hence we decided to assess Nicotine Dependence in subjects with Vascular Dementia Methods: Nicotine Dependence in subjects with Vascular Dementia was assessed among subjects presenting to Memory Clinic of a tertiary car...

  8. An experimental study on (131I-CHIBA-1001: a radioligand for α7 nicotinic acetylcholine receptors.

    Directory of Open Access Journals (Sweden)

    Lei Yin

    Full Text Available OBJECTIVE: The α7 nicotinic acetylcholine receptors (nAChRs play a vital role in the pathophysiology of neuropsychiatric diseases such as Alzheimer's disease and depression. However, there is currently no suitable positron emission tomography (PET or Single-Photon Emission Computed Tomography (SPECT radioligands for imaging α7 nAChRs in brain. Here our aim is to radiosynthesize a novel SPECT radioligand (131I-CHIBA-1001 for whole body biodistribution study and in vivo imaging of α7 nAChRs in brain. METHOD: (131I-CHIBA-1001 was radiosynthesized by chloramine-T method. Different conditions of reaction time and temperature were tested to get a better radiolabeling yield. Radiolabeling yield and radiochemical purities of (131I-CHIBA-1001 were analyzed by thin layer chromatography (TLC and high-performance liquid chromatography (HPLC system. Whole body biodistribution study was performed at different time points post injection of (131I-CHIBA-1001 in KM mice. Monkey subject was used for in vivo SPECT imaging in brain. RESULT: The radiolabeling yield of (131I-CHIBA-1001 reached 96% within 1.5∼2.0 h at 90∼95°C. The radiochemical purity reached more than 99% after HPLC purification. (131I-CHIBA-1001 was highly stable in saline and fresh human serum in room temperature and 37°C separately. The biodistribution data of brain at 15, 30, and 60 min were 11.05±1.04%ID/g, 8.8±0.04%ID/g and 6.28±1.13%ID/g, respectively. In experimental SPECT imaging, the distribution of radioactivity in the brain regions was paralleled with the distribution of α7 nAChRs in the monkey brain. Moreover, in the blocking SPECT imaging study, the selective α7 nAChR agonist SSR180711 blocked the radioactive uptake in the brain successfully. CONCLUSION: The CHIBA-1001 can be successfully radiolabeled with (131I using the chloramine-T method. (131I-CHIBA-1001 can successfully accumulate in the monkey brain and image the α7 acetylcholine receptors. (131I-CHIBA-1001 can be a

  9. Nicotinic receptors in aging and dementia.

    Science.gov (United States)

    Picciotto, Marina R; Zoli, Michele

    2002-12-01

    Activation of neuronal nicotinic acetylcholine receptors (nAChRs) has been shown to maintain cognitive function following aging or the development of dementia. Nicotine and nicotinic agonists have been shown to improve cognitive function in aged or impaired subjects. Smoking has also been shown in some epidemiological studies to be protective against the development of neurodegenerative diseases. This is supported by animal studies that have shown nicotine to be neuroprotective both in vivo and in vitro. Treatment with nicotinic agonists may therefore be useful in both slowing the progression of neurodegenerative illnesses, and improving function in patients with the disease. While increased nicotinic function has been shown to be beneficial, loss of cholinergic markers is often seen in patients with dementia, suggesting that decreased cholinergic function could contribute to both the cognitive deficits, and perhaps the neuronal degeneration, associated with dementia. In this article we will review the literature on each of these areas. We will also present hypotheses that might address the mechanisms underlying the ability of nAChR function to protect against neurodegeneration or improve cognition, two potentially distinct actions of nicotine.

  10. Multiple Kinases Involved in the Nicotinic Modulation of Gamma Oscillations in the Rat Hippocampal CA3 Area

    Science.gov (United States)

    Wang, JianGang; He, XiaoLong; Guo, Fangli; Cheng, XiangLin; Wang, Yali; Wang, XiaoFang; Feng, ZhiWei; Vreugdenhil, Martin; Lu, ChengBiao

    2017-01-01

    Neuronal synchronization at gamma band frequency (20–80 Hz, γ oscillations) is closely associated with higher brain function, such as learning, memory and attention. Nicotinic acetylcholine receptors (nAChRs) are highly expressed in the hippocampus, and modulate hippocampal γ oscillations, but the intracellular mechanism underlying such modulation remains elusive. We explored multiple kinases by which nicotine can modulate γ oscillations induced by kainate in rat hippocampal area CA3 in vitro. We found that inhibitors of cyclic AMP dependent kinase (protein kinase A, PKA), protein kinase C (PKC), N-methyl-D-aspartate receptor (NMDA) receptors, Phosphoinositide 3-kinase (PI3K) and extracellular signal-related kinases (ERK), each individually could prevent the γ oscillation-enhancing effect of 1 μM nicotine, whereas none of them affected baseline γ oscillation strength. Inhibition of the serine/threonine kinase Akt increased baseline γ oscillations and partially blocked its nicotinic enhancement. We propose that the PKA-NMDAR-PI3K-ERK pathway modifies cellular properties required for the nicotinic enhancement of γ oscillations, dependent on a PKC-ERK mediated pathway. These signaling pathways provide clues for restoring γ oscillations in pathological conditions affecting cognition. The suppression of γ oscillations at 100 μM nicotine was only dependent on PKA-NMDAR activation and may be due to very high intracellular calcium levels.

  11. Nicotine, auditory sensory memory and attention in a human ketamine model of schizophrenia: moderating influence of a hallucinatory trait

    Directory of Open Access Journals (Sweden)

    Verner eKnott

    2012-09-01

    Full Text Available Background: The procognitive actions of the nicotinic acetylcholine receptor (nAChR agonist nicotine are believed, in part, to motivate the excessive cigarette smoking in schizophrenia, a disorder associated with deficits in multiple cognitive domains, including low level auditory sensory processes and higher order attention-dependent operations. Objectives: As N-methyl-D-aspartate receptor (NMDAR hypofunction has been shown to contribute to these cognitive impairments, the primary aims of this healthy volunteer study were to: a to shed light on the separate and interactive roles of nAChR and NMDAR systems in the modulation of auditory sensory memory (and sustained attention, as indexed by the auditory event-related brain potential (ERP – mismatch negativity (MMN, and b to examine how these effects are moderated by a predisposition to auditory hallucinations/delusions (HD. Methods: In a randomized, double-blind, placebo controlled design involving a low intravenous dose of ketamine (.04 mg/kg and a 4 mg dose of nicotine gum, MMN and performance on a rapid visual information processing (RVIP task of sustained attention were examined in 24 healthy controls psychometrically stratified as being lower (L-HD, n = 12 or higher (H-HD for HD propensity. Results: Ketamine significantly slowed MMN, and reduced MMN in H-HD, with amplitude attenuation being blocked by the co-administration of nicotine. Nicotine significantly enhanced response speed (reaction time and accuracy (increased % hits and d΄ and reduced false alarms on the RIVIP, with improved performance accuracy being prevented when nicotine was administered with ketamine. Both % hits and d΄, as well as reaction time were poorer in H-HD (vs. L-HD and while hit rate and d΄ was increased by nicotine in H-HD, reaction time was slowed by ketamine in L-HD. Conclusions: Nicotine alleviated ketamine-induced sensory memory impairments and improved attention, particularly in individuals prone to HD.

  12. Use of Monoclonal Antibodies to Study the Structural Basis of the Function of Nicotinic Acetylcholine Receptors on Electric Organ and Muscle and to Determine the Structure of Nicotinic Acetylcholine Receptors on Neurons

    Science.gov (United States)

    1989-09-30

    of chicken neurona .4receptor subunits. Sequences of al and a2 are from Net .Ot al. -l Sequences of a3 and a4 were determintl from clones described...Sucrose gradient analysis of neurona & nicotinic receptors was conducted as follows. Chicken ind rat brain receptors were extracted from crude

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

    Science.gov (United States)

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

    2015-01-01

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

  14. Affective temperaments in nicotine-dependent and non-nicotine-dependent individuals

    Directory of Open Access Journals (Sweden)

    Włodzimierz Oniszczenko

    2016-07-01

    Full Text Available Background One of the smoking risk factors influencing nicotine dependency may be human personality; however, few studies have examined the association between Akiskal’s affective temperaments and smoking in adults. Our study aims to evaluate the associations between nicotine dependence and affective temperaments using the TEMPS-A. Participants and procedure The sample in this study consisted of 678 healthy Caucasian adults aged from 17 to 69 years, including 134 self-declared nicotine-dependent subjects (89 females and 45 males and 544 self-declared non-nicotine-dependent subjects (352 females and 192 males. The Polish version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A was used to assess affective temperaments (depressive, cyclothymic, hyperthymic, irritable and anxious. Results Nicotine-dependent individuals scored higher on cyclothymic, irritable and anxious temperaments than non-nicotine-dependents (no significant differences with regard to depressive and hyperthymic temperaments. Among the nicotine-dependent individuals, females scored higher on anxious temperaments than males (no differences with regard to the other affective temperaments, and among the non-nicotine-dependent individuals, females exhibited more depressive, cyclothymic and anxious temperaments than males, while males exhibited more hyperthymic temperaments than females. Conclusions The results suggest that affective, cyclothymic and irritable temperaments in both genders and anxious temperaments in females may be predictors of nicotine dependence in adults.

  15. 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;

    2015-01-01

    ), acetylcholinesterase (AChE) and glutamine synthetase (GS)) and receptor density (dopamine-2 (D2), muscarinic cholinergic (mAChR) and gamma-butyric acid type A (GABA-A)) along with PFSA and PFCA concentrations. Average brain ∑PFSA concentration was 25ng/g ww where PFOS accounted for 91%. Average ∑PFCA concentration...

  16. Pyridine salvage and nicotinic acid conjugate synthesis in leaves of mangrove species.

    Science.gov (United States)

    Ashihara, Hiroshi; Yin, Yuling; Deng, Wei-Wei; Watanabe, Shin

    2010-01-01

    The metabolic fate of [carbonyl-14C]nicotinamide was surveyed in leaf disks of seven mangrove species, Bruguiera gymnorrhiza, Rhizophora stylosa, Kandeliaobovata, Sonneratia alba, Pemphis acidula, Lumnitzera racemosa and Avicennia marina, with and without 250 mM NaCl. Uptake of [14C]nicotinamide by leaf disks was stimulated by 250 mM NaCl in K. candel, R. stylosa, A. marina and L. racemosa. [Carbonyl-14C]nicotinamide was converted to nicotinic acid and was utilised for the synthesis of nucleotides and nicotinic acid conjugates. Formation of nicotinic acid by the deaminase reaction was rapid; there was little accumulation of nicotinamide in the disks 3h after administration. Radioactivity from [carbonyl-14C]nicotinamide was incorporated into pyridine nucleotides (mainly NAD and NADP) in all mangrove leaves, and the rates varied from 2% (in L. racemosa) to 15% (S. alba) of the total radioactivity taken up. NaCl generally reduced nicotinic acid salvage for NAD and NADP. In all mangrove leaf disks, the most heavily labelled compounds (up to 70% of total radioactivity) were trigonelline (N-methylnicotinic acid) and/or nicotinic acid N-glucoside. Trigonelline was formed in all mangrove plants, but N-glucoside synthesis was found only in leaves of A. marina and K. obovata. In A. marina, incorporation of radioactivity into N-glucoside (51%) was much greater than incorporation into trigonelline (2%). In general, NaCl stimulates the synthesis of these pyridine conjugates. The rate of decarboxylation of nicotinic acid in roots of A. marina seedlings was much greater than for the corresponding reaction observed in leaves.

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

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    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.

  18. The quantitative evaluation of cholinergic markers in spatial memory improvement induced by nicotine-bucladesine combination in rats.

    Science.gov (United States)

    Azami, Kian; Etminani, Maryam; Tabrizian, Kaveh; Salar, Fatemeh; Belaran, Maryam; Hosseini, Asieh; Hosseini-Sharifabad, Ali; Sharifzadeh, Mohammad

    2010-06-25

    We previously showed that post-training intra-hippocampal infusion of nicotine-bucladesine combination enhanced spatial memory retention in the Morris water maze. Here we investigated the role of cholinergic markers in nicotine-bucladesine combination-induced memory improvement. We assessed the expression of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) in CA1 region of the hippocampus and medial septal area (MSA) of the brain. Post-training bilateral infusion of a low concentration of either nicotine or bucladesine into the CA1 region of the hippocampus did not affect spatial memory significantly. Quantitative immunostaining analysis of optical density in CA1 regions and evaluation of immunopositive neurons in medial septal area of brain sections from all combination groups revealed a significant increase (Pnicotine and in a concentration dependent manner. Also, increase in the optical density and amount of ChAT and VAChT immunostaining correlated with the decrease in escape latency and traveled distance in rats treated with nicotine and low dose of bucladesine. Taken together, these results suggest that significant increases of ChAT and VAChT protein expressions in the CA1 region and medial septal area are the possible mechanisms of spatial memory improvement induced by nicotine-bucladesine combination.

  19. Synthesis and evaluation of new imaging agent for central nicotinic acetylcholine receptor {alpha}{sub 7} subtype

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, Mikako [Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu (Japan); Nishiyama, Shingo; Tsukada, Hideo [PET Center, Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu (Japan); Hatano, Kentaro [National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu (Japan); Fuchigami, Takeshi [Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu (Japan); Yamaguchi, Hiroshi [National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu (Japan); Molecular Imaging Frontier Research Center, Hamamatsu University School of Medicine, Hamamatsu (Japan); Matsushima, Yoshitaka [Department of Chemistry, Hamamatsu University School of Medicine, Hamamatsu (Japan); Ito, Kengo [National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu (Japan); Magata, Yasuhiro [Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu (Japan); Molecular Imaging Frontier Research Center, Hamamatsu University School of Medicine, Hamamatsu (Japan)], E-mail: magata@hama-med.ac.jp

    2010-04-15

    Introduction: The nicotinic acetylcholine receptor (nAChR) {alpha}7 subtype ({alpha}{sub 7} nAChR) is one of the major nAChR subtypes in the brain. We synthesized C-11 labeled {alpha}{sub 7} nAChR ligands, (R)-2-[{sup 11}C]methylamino-benzoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester ([{sup 11}C](R)-MeQAA) and its isomer (S)-[{sup 11}C]MeQAA, for in vivo investigation with positron emission tomography (PET). Then, the potential of (R)- and (S)-[{sup 11}C]MeQAA for in vivo imaging of {alpha}{sub 7} nAChR in the brain was evaluated in mice and monkeys. Methods: The binding affinity for {alpha}{sub 7} 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 {alpha}{sub 7} nAChR was 41 and 182 nM for (R)- and (S)-MeQAA, respectively. The initial uptake in the mouse brain was high ([{sup 11}C](R)-MeQAA: 7.68 and [{sup 11}C](S)-MeQAA: 6.65 %dose/g at 5 min). The clearance of [{sup 11}C](R)-MeQAA was slow in the hippocampus ({alpha}{sub 7} nAChR-rich region) but was rapid in the cerebellum ({alpha}{sub 7} nAChR-poor region). On the other hand, the clearance was fast for [{sup 11}C](S)-MeQAA in all regions. The brain uptake of [{sup 11}C](R)-MeQAA was decreased by methyllycaconitine ({alpha}{sub 7} nAChR antagonist) treatment. In monkeys, {alpha}{sub 7} 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 [{sup 11}C](R)-MeQAA, while the uptake was rather homogeneous for [{sup 11}C](S)-MeQAA. Conclusions: [{sup 11}C](R)-MeQAA was successfully synthesized and showed high uptake to the brain. However, since the in vivo selectivity for {alpha}{sub 7} nAChR was not enough, further PET kinetic analysis or structure optimization is needed for specific visualization of brain {alpha}{sub 7} nAChRs in vivo.

  20. Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment.

    Science.gov (United States)

    Lombardo, Sylvia; Maskos, Uwe

    2015-09-01

    Alzheimer's Disease (AD) is the major form of senile dementia, characterized by neuronal loss, extracellular deposits, and neurofibrillary tangles. It is accompanied by a loss of cholinergic tone, and acetylcholine (ACh) levels in the brain, which were hypothesized to be responsible for the cognitive decline observed in AD. Current medication is restricted to enhancing cholinergic signalling for symptomatic treatment of AD patients. The nicotinic acetylcholine receptor family (nAChR) and the muscarinic acetylcholine receptor family (mAChR) are the target of ACh in the brain. Both families of receptors are affected in AD. It was demonstrated that amyloid beta (Aβ) interacts with nAChRs. Here we discuss how Aβ activates or inhibits nAChRs, and how this interaction contributes to AD pathology. We will discuss the potential role of nAChRs as therapeutic targets. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

  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.

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

    Science.gov (United States)

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

    2015-11-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

  4. Impact of repeated nicotine and alcohol coexposure on in vitro and in vivo chlorpyrifos dosimetry and cholinesterase inhibition.

    Science.gov (United States)

    Lee, S; Poet, T S; Smith, J N; Hjerpe, A L; Gunawan, R; Timchalk, C

    2011-01-01

    Chlorpyrifos (CPF) is an organophosphorus insecticide, and neurotoxicity results from inhibition of acetylcholinesterase (AChE) by its metabolite, chlorpyrifos-oxon. Routine consumption of alcohol and tobacco modifies metabolic and physiological processes impacting the metabolism and pharmacokinetics of other xenobiotics, including pesticides. This study evaluated the influence of repeated ethanol and nicotine coexposure on in vivo CPF dosimetry and cholinesterase (ChE) response (ChE- includes AChE and/or butyrylcholinesterase (BuChE)). Hepatic microsomes were prepared from groups of naive, ethanol-only (1 g/kg/d, 7 d, po), and ethanol + nicotine (1 mg/kg/d 7 d, sc)-treated rats, and the in vitro metabolism of CPF was evaluated. For in vivo studies, rats were treated with saline or ethanol (1 g/kg/d, po) + nicotine (1 mg/kg/d, sc) in addition to CPF (1 or 5 mg/kg/d, po) for 7 d. The major CPF metabolite, 3,5,6-trichloro-2-pyridinol (TCPy), in blood and urine and the plasma ChE and brain acetylcholinesterase (AChE) activities were measured in rats. There were differences in pharmacokinetics, with higher TCPy peak concentrations and increased blood TCPy AUC in ethanol + nicotine groups compared to CPF only (approximately 1.8- and 3.8-fold at 1 and 5 mg CPF doses, respectively). Brain AChE activities after ethanol + nicotine treatments showed significantly less inhibition following repeated 5 mg CPF/kg dosing compared to CPF only (96 ± 13 and 66 ± 7% of naive at 4 h post last CPF dosing, respectively). Although brain AChE activity was minimal inhibited for the 1-mg CPF/kg/d groups, the ethanol + nicotine pretreatment resulted in a similar trend (i.e., slightly less inhibition). No marked differences were observed in plasma ChE activities due to the alcohol + nicotine treatments. In vitro, CPF metabolism was not markedly affected by repeated ethanol or both ethanol + nicotine exposures. Compared with a previous study of nicotine and CPF exposure, there were no

  5. Effect of Nicotine on Gallbladder Bile

    Directory of Open Access Journals (Sweden)

    Anglo-Dutch Nicotine Intestinal Study Group

    1994-01-01

    Full Text Available Several studies have shown that symptomatic gallstones are largely a disease of nonsmokers, which raises the possibility that nicotine may protect against the formation of gallstones. To examine the effect of nicotine on the gallbladder, 32 rabbits were allocated to four groups: controls and three treatment groups in which nicotine tartarate at low, medium and high doses was administered subcutaneously via an osmotic minipump. After 14 days’ treatment the gallbladder was removed and measurements made of gallbladder mucin synthesis, bile mucin concentration, bile acid concentration and cholesterol saturation. Serum nicotine concentrations (ng/mL were (± SE 0.4±0.1, 3.5±0.4, 8.8±0.8 and 16.2±1.8 in the controls and three treatment groups, respectively. Total bile acid concentration increased significantly in all three treated groups with the greatest increase in the group given low dose nicotine (P<0.001. Cholesterol saturation did not differ significantly in any group but soluble mucin concentration in gallbladder bile was significantly reduced (P=0.013, 95% CI: 16 to 111 with high dose nicotine. Gallbladder mucin synthesis, measured by 3H-glucosamine incorporation, did not change significantly with nicotine treatment. Subcutaneous nicotine 2.0 mg/kg/day for 14 days significantly reduced the concentration of biliary mucin, which could potentially reduce cholesterol nucleation and subsequent gallstone formation. This may be one of the mechanisms responsible for the relative reduction in gallstone disease among smokers.

  6. The role of the polymorphic efflux transporter P-glycoprotein on the brain accumulation of d-methylphenidate and d-amphetamine.

    Science.gov (United States)

    Zhu, Hao-Jie; Wang, Jun-Sheng; DeVane, C Lindsay; Williard, Robin L; Donovan, Jennifer L; Middaugh, Lawrence D; Gibson, Brian B; Patrick, Kennerly S; Markowitz, John S

    2006-07-01

    The psychostimulant medications methylphenidate (MPH) and amphetamine (AMP), available in various ratios or enantiopure formulations of their respective active dextrorotary isomers, constitute the majority of agents used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Substantial interindividual variability occurs in their pharmacokinetics and tolerability. Little is known regarding the potential role of drug transporters such as P-glycoprotein (P-gp) in psychostimulant pharmacokinetics and response. Therefore, experiments were carried out in P-gp knockout (KO) mice versus wild-type (WT) mice after intraperitoneal dosing (2.5 mg/kg) of d-MPH or (3.0 mg/kg) of d-AMP. After the administration of each psychostimulant, locomotor activity was assessed at 30-min intervals for 2 h. Total brain-to-plasma drug concentration ratios were determined at 10-, 30-, and 80-min postdosing time-points. The results showed no statistically supported genotypic difference in d-AMP-induced locomotor activity stimulation or in brain-to-plasma ratio of d-AMP. As for d-MPH, the P-gp KO mice had 33% higher brain concentrations (p gp compared with that for WT mice. These data indicate that P-gp has no apparent effect on the pharmacokinetics and pharmacodynamics of d-AMP. In addition, d-MPH is a relatively weak P-gp substrate, and its entry into the brain may be limited by P-gp. Furthermore, the mechanism by which d-MPH-induced locomotor activity was attenuated in P-gp KO mice remains to be elucidated.

  7. The effect of WIN 55,212-2 suggests a cannabinoid-sensitive component in the early toxicity induced by organic acids accumulating in glutaric acidemia type I and in related disorders of propionate metabolism in rat brain synaptosomes.

    Science.gov (United States)

    Colín-González, A L; Paz-Loyola, A L; Serratos, I N; Seminotti, B; Ribeiro, C A J; Leipnitz, G; Souza, D O; Wajner, M; Santamaría, A

    2015-12-01

    Several physiological processes in the CNS are regulated by the endocannabinoid system (ECS). Cannabinoid receptors (CBr) and CBr agonists have been involved in the modulation of the N-methyl-D-aspartate receptor (NMDAr) activation. Glutaric (GA), 3-hydroxyglutaric (3-OHGA), methylmalonic (MMA) and propionic (PA) acids are endogenous metabolites produced and accumulated in the brain of children affected by severe organic acidemias (OAs) with neurodegeneration. Oxidative stress and excitotoxicity have been involved in the toxic pattern exerted by these organic acids. Studying the early pattern of toxicity exerted by these metabolites is crucial to explain the extent of damage that they can produce in the brain. Herein, we investigated the effects of the synthetic CBr agonist WIN 55,212-2 (WIN) on early markers of GA-, 3-OHGA-, MMA- and PA-induced toxicity in brain synaptosomes from adult (90-day-old) and adolescent (30-day-old) rats. As pre-treatment, WIN exerted protective effects on the GA- and MMA-induced mitochondrial dysfunction, and prevented the reactive oxygen species (ROS) formation and lipid peroxidation induced by all metabolites. Our findings support a protective and modulatory role of cannabinoids in the early toxic events elicited by toxic metabolites involved in OAs.

  8. 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.

  9. Investigating the synchronization of hippocampal neural network in response to acute nicotine exposure

    Directory of Open Access Journals (Sweden)

    Akay Metin

    2010-07-01

    Full Text Available Abstract Previous studies suggested that γ oscillations in the brain are associated with higher order cognitive function including selective visual attention, motor task planning, sensory perception, working memory and dreaming REM sleep. These oscillations are mainly observed in cortical regions and also occur in neocortical and subcortical areas and the hippocampus. In this paper, we investigate the influence of acute exposure to nicotine on the complexity of hippocampal γ oscillations. Using the approximate entropy method, the influence of acute nicotine exposure on the hippocampal γ oscillations was investigated. The hippocampal γ oscillations have been generated in response to the 100 Hz stimulus and isolated using the visual inspection and spectral analysis method. Our central hypothesis is that acute exposure to nicotine significantly reduces the complexity of hippocampal γ oscillations. We used brain-slice recordings and the approximate entropy method to test this hypothesis. The approximate entropy (complexity values of the hippocampal γ oscillations are estimated from the 14 hippocampal slices. Our results show that it takes at least 100 msec to see any hippocampal activities in response to the 100 Hz stimulus. These patterns noticeably changed after 100 msec until 300 msec after the stimulus Finally, they were less prominent after 300 msec. We have analyzed the isolated hippocampal γ oscillations (between 150 and 250 msec after the stimulus using the approximate entropy (ApEn method. Our results showed that the ApEn (complexity values of hippocampal γ oscillations during nicotine exposure were reduced compared to those of hippocampal γ oscillations during control, and washout. This reduction was much more significant in response to acute nicotine exposure (p

  10. Menthol Enhances the Desensitization of Human α3β4 Nicotinic Acetylcholine Receptors.

    Science.gov (United States)

    Ton, Hoai T; Smart, Amanda E; Aguilar, Brittany L; Olson, Thao T; Kellar, Kenneth J; Ahern, Gerard P

    2015-08-01

    The α3β4 nicotinic acetylcholine receptor (nAChR) subtype is widely expressed in the peripheral and central nervous systems, including in airway sensory nerves. The nAChR subtype transduces the irritant effects of nicotine in tobacco smoke and, in certain brain areas, may be involved in nicotine addiction and/or withdrawal. Menthol, a widely used additive in cigarettes, is a potential analgesic and/or counterirritant at sensory nerves and may also influence nicotine's actions in the brain. We examined menthol's effects on recombinant human α3β4 nAChRs and native nAChRs in mouse sensory neurons. Menthol markedly decreased nAChR activity as assessed by Ca(2+) imaging, (86)Rb(+) efflux, and voltage-clamp measurements. Coapplication of menthol with acetylcholine or nicotine increased desensitization, demonstrated by an increase in the rate and magnitude of the current decay and a reduction of the current integral. These effects increased with agonist concentration. Pretreatment with menthol followed by its washout did not affect agonist-induced desensitization, suggesting that menthol must be present during the application of agonist to augment desensitization. Notably, menthol acted in a voltage-independent manner and reduced the mean open time of single channels without affecting their conductance, arguing against a simple channel-blocking effect. Further, menthol slowed or prevented the recovery of nAChRs from desensitization, indicating that it probably stabilizes a desensitized state. Moreover, menthol at concentrations up to 1 mM did not compete for the orthosteric nAChR binding site labeled by [(3)H]epibatidine. Taken together, these data indicate that menthol promotes desensitization of α3β4 nAChRs by an allosteric action.

  11. Differential Regulation of α7 Nicotinic Receptor Gene (CHRNA7) Expression in Schizophrenic Smokers

    OpenAIRE

    Mexal, Sharon; Berger, Ralph; Logel, Judy; Ross, Randal G.; Freedman, Robert; Leonard, Sherry

    2009-01-01

    The α7 neuronal nicotinic receptor gene (CHRNA7) has been implicated in the pathophysiology of schizophrenia by genetic and pharmacological studies. Expression of the α7* receptor, as measured by [125I]α-bungarotoxin autoradiography, is decreased in postmortem brain of schizophrenic subjects compared to non-mentally ill controls. Most schizophrenic patients are heavy smokers, with high levels of serum cotinine. Smoking changes the expression of multiple genes and differentially regulates gene...

  12. BDNF Up-Regulates α7 Nicotinic Acetylcholine Receptor Levels on Subpopulations of Hippocampal Interneurons

    OpenAIRE

    Massey, Kerri A; Zago, Wagner M.; Berg, Darwin K.

    2006-01-01

    In the hippocampus, brain-derived neurotrophic factor (BDNF) regulates a number of synaptic components. Among these are nicotinic acetylcholine receptors containing α7 subunits (α7-nAChRs), which are interesting because of their relative abundance in the hippocampus and their high relative calcium permeability. We show here that BDNF elevates surface and intracellular pools of α7-nAChRs on cultured hippocampal neurons and that glutamatergic activity is both necessary and sufficient for the ef...

  13. Effects of acute nicotine administration on cognitive event-related potentials in tacrine-treated and non-treated patients with Alzheimer's disease.

    Science.gov (United States)

    Knott, V; Mohr, E; Mahoney, C; Engeland, C; Ilivitsky, V

    2002-01-01

    Earlier studies of cognitive event-related brain potentials (ERPs) reporting diminished amplitudes and delayed latencies of the P300 potential in dementia of the Alzheimer type (DAT), together with independent findings of the P300- and performance-enhancing properties of nicotine in normal adults, stimulated this study to explore the single-dose effects of nicotine on auditory and visual P300s in DAT. Thirteen patients, 6 currently receiving treatment with the cholinesterase inhibitor tacrine (tetrahydroaminoacridine; THA) and the remaining being medication free, were administered 2 mg of nicotine polacrilex under double-blind, randomized, placebo-controlled conditions. Prior to nicotine administration, THA-treated patients exhibited shorter auditory P300 latencies than non-treated patients. Acutely administered nicotine failed to alter auditory P300, but increased the amplitudes of visual P300s in both DAT patient groups. Neither THA treatment nor single-dose nicotine altered behavioural performance in the visual and auditory task paradigms. The results are discussed in relation to nicotinic cholinergic, attentional and cognitive processes in DAT.

  14. 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;

    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...

  15. Lynx1 and Aβ1-42 bind competitively to multiple nicotinic acetylcholine receptor subtypes

    DEFF Research Database (Denmark)

    Thomsen, Morten S; Arvaniti, Maria; Jensen, Majbrit M

    2016-01-01

    Lynx1 regulates synaptic plasticity in the brain by regulating nicotinic acetylcholine receptors (nAChRs). It is not known to which extent Lynx1 can bind to endogenous nAChR subunits in the brain or how this interaction is affected by Alzheimer's disease pathology. We apply affinity purification...... to demonstrate that a water-soluble variant of human Lynx1 (Ws-Lynx1) isolates α3, α4, α5, α6, α7, β2, and β4 nAChR subunits from human and rat cortical extracts, and rat midbrain and olfactory bulb extracts, suggesting that Lynx1 forms complexes with multiple nAChR subtypes in the human and rodent brain....... Incubation with Ws-Lynx1 decreases nicotine-mediated extracellular signal-regulated kinase phosphorylation in PC12 cells and striatal neurons, indicating that binding of Ws-Lynx1 is sufficient to inhibit signaling downstream of nAChRs. The effect of nicotine in PC12 cells is independent of α7 or α4β2 n...

  16. 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

  17. Accidental ingestion of E-cigarette liquid nicotine in a 15-month-old child: an infant mortality case of nicotine intoxication

    Science.gov (United States)

    Seo, An Deok; Kim, Dong Chan; Yu, Hee Joon

    2016-01-01

    Electronic cigarettes are novel tobacco products that are frequently used these days. The cartridge contains liquid nicotine and accidental poisoning, even with a small oral dose, endangers children. We present here a mortality case of a 15-month-old child who ingested liquid nicotine mistaking it for cold medicine. When the emergency medical technicians arrived, she was found to have pulseless electrical activity. Spontaneous circulation was restored after approximately 40 minutes of cardiopulmonary resuscitation. The cotinine level in her urine was 1,716 ng/mL. Despite intensive supportive care, severe anoxic brain injury was found on computed tomography and the child ultimately died. This fatality highlights the need for public health efforts to minimize such accidents. PMID:28194215

  18. Physiological and biochemical characterization of a novel nicotine-degrading bacterium Pseudomonas geniculata N1.

    Directory of Open Access Journals (Sweden)

    Yanghui Liu

    Full Text Available Management of solid wastes with high nicotine content, such as those accumulated during tobacco manufacturing, poses a major challenge, which can be addressed by using bacteria such as Pseudomonas and Arthrobacter. In this study, a new species of Pseudomonas geniculata, namely strain N1, which is capable of efficiently degrading nicotine, was isolated and identified. The optimal growth conditions for strain N1 are a temperature of 30°C, and a pH 6.5, at a rotation rate of 120 rpm min(-1 with 1 g l(-1 nicotine as the sole source of carbon and nitrogen. Myosmine, cotinine, 6-hydroxynicotine, 6-hydroxy-N-methylmyosmine, and 6-hydroxy-pseudooxynicotine were detected as the five intermediates through gas chromatography-mass and liquid chromatography-mass analyses. The identified metabolites were different from those generated by Pseudomonas putida strains. The analysis also highlighted the bacterial metabolic diversity in relation to nicotine degradation by different Pseudomonas strains.

  19. Electronic cigarettes induce DNA strand breaks and cell death independently of nicotine in cell lines

    Science.gov (United States)

    Yu, Vicky; Rahimy, Mehran; Korrapati, Avinaash; Xuan, Yinan; Zou, Angela E.; Krishnan, Aswini R.; Tsui, Tzuhan; Aguilera, Joseph A.; Advani, Sunil; Crotty Alexander, Laura E.; Brumund, Kevin T.; Wang-Rodriguez, Jessica

    2016-01-01

    Objectives Evaluate the cytotoxicity and genotoxicity of short- and long-term e-cigarette vapor exposure on a panel of normal epithelial and head and neck squamous cell carcinoma (HNSCC) cell lines. Materials and Methods HaCaT, UMSCC10B, and HN30 were treated with nicotine-containing and nicotine-free vapor extract from two popular e-cigarette brands for periods ranging from 48 hours to 8 weeks. Cytotoxicity was assessed using Annexin V flow cytometric analysis, trypan blue exclusion, and clonogenic assays. Genotoxicity in the form of DNA strand breaks was quantified using the neutral comet assay and γ-H2AX immunostaining. Results E-cigarette-exposed cells showed significantly reduced cell viability and clonogenic survival, along with increased rates of apoptosis and necrosis, regardless of e-cigarette vapor nicotine content. They also exhibited significantly increased comet tail length and accumulation of γ-H2AX foci, demonstrating increased DNA strand breaks. Conclusion E-cigarette vapor, both with and without nicotine, is cytotoxic to epithelial cell lines and is a DNA strand break-inducing agent. Further assessment of the potential carcinogenic effects of e-cigarette vapor is urgently needed. PMID:26547127

  20. 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.

  1. Assessment of nicotine dependence in subjects with vascular dementia

    Directory of Open Access Journals (Sweden)

    Mina Chandra

    2015-06-01

    Full Text Available Background: Nicotine dependence is an important public health issue. Nicotine dependence is a risk factor for vascular diseases like myocardial infarction and vascular dementia. The rate of nicotine dependence in Indian subjects with vascular dementia is not known. Hence we decided to assess nicotine dependence in subjects with vascular dementia. Methods: Nicotine dependence in subjects with vascular dementia was assessed among subjects presenting to memory clinic of a tertiary care hospital over a period of 16 months. Data regarding sociodemographic profile and severity of nicotine dependence as per Fagerstrom nicotine dependence scale for smoking and smokeless tobacco was analysed using SPSS version 17. Results: Our study shows that in 159 subjects with vascular dementia continuing nicotine dependence was seen in nearly 12% of the subjects. Though the rates are less than the population prevalence for India, it is still relevant as nicotine is not just a risk factor for development of vascular dementia but severe nicotine dependence and longer duration of nicotine use were found to be poor prognostic factors associated with severe dementia. Further as all subjects continued to be nicotine dependent despite having been advised to quit tobacco, suggesting the need for a more comprehensive tobacco cessation intervention be offered to subjects with vascular dementia to improve outcomes. Conclusion: In subjects with vascular dementia continuing nicotine dependence is an important risk factor which must be addressed. [Int J Res Med Sci 2015; 3(3.000: 711-714

  2. Angiotensin AT1 and AT2 receptor antagonists modulate nicotine-evoked [³H]dopamine and [³H]norepinephrine release.

    Science.gov (United States)

    Narayanaswami, Vidya; Somkuwar, Sucharita S; Horton, David B; Cassis, Lisa A; Dwoskin, Linda P

    2013-09-01

    Tobacco smoking is the leading preventable cause of death in the United States. A major negative health consequence of chronic smoking is hypertension. Untoward addictive and cardiovascular sequelae associated with chronic smoking are mediated by nicotine-induced activation of nicotinic receptors (nAChRs) within striatal dopaminergic and hypothalamic noradrenergic systems. Hypertension involves both brain and peripheral angiotensin systems. Activation of angiotensin type-1 receptors (AT1) release dopamine and norepinephrine. The current study determined the role of AT1 and angiotensin type-2 (AT2) receptors in mediating nicotine-evoked dopamine and norepinephrine release from striatal and hypothalamic slices, respectively. The potential involvement of nAChRs in mediating effects of AT1 antagonist losartan and AT2 antagonist, 1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (PD123319) was evaluated by determining their affinities for α4β2* and α7* nAChRs using [³H]nicotine and [³H]methyllycaconitine binding assays, respectively. Results show that losartan concentration-dependently inhibited nicotine-evoked [³H]dopamine and [³H]norepinephrine release (IC₅₀: 3.9 ± 1.2 and 2.2 ± 0.7 μM; Imax: 82 ± 3 and 89 ± 6%, respectively). In contrast, PD123319 did not alter nicotine-evoked norepinephrine release, and potentiated nicotine-evoked dopamine release. These results indicate that AT1 receptors modulate nicotine-evoked striatal dopamine and hypothalamic norepinephrine release. Furthermore, AT1 receptor activation appears to be counteracted by AT2 receptor activation in striatum. Losartan and PD123319 did not inhibit [³H]nicotine or [³H]methyllycaconitine binding, indicating that these AT1 and AT2 antagonists do not interact with the agonist recognition sites on α4β2* and α7* nAChRs to mediate these effects of nicotine. Thus, angiotensin receptors contribute to the effects of

  3. Bimodal modulation by nicotine of anxiety in the social interaction test: role of the dorsal hippocampus.

    Science.gov (United States)

    File, S E; Kenny, P J; Ouagazzal, A M

    1998-12-01

    In conditions generating moderate levels of anxiety in the social interaction test (low light, unfamiliar arena or high light, familiar arena), parenteral administration of nicotine had bimodal actions, low doses (0.01 and 0.1 mg/kg i.p.) had anxiolytic effects and high doses (0.5 and 1.0 mg/kg i.p.) had anxiogenic effects. In test conditions where anxiety was lowest (low light, familiar arena) and highest (high light, unfamiliar arena), nicotine was without effect after intraperitoneal or hippocampal administration. Thus, nicotine plays a modulatory role in which the activity of other neurotransmitters is crucial to its expression. After bilateral administration to the dorsal hippocampus, nicotine (0.1-8.0 microg) had anxiogenic effects in conditions of moderate anxiety; mecamylamine (30 ng) was silent in these conditions, indicating no intrinsic tone. Our results show that the dorsal hippocampus is one area that can mediate anxiogenic effects in the social interaction test, but the brain region mediating anxiolytic effects remains to be identified.

  4. Regional Homogeneity Changes in Nicotine Addicts by Resting-State fMRI

    Science.gov (United States)

    2017-01-01

    Objective To reveal the brain functional changes of nicotine addicts compared with those of non-smokers and explore the objective biomarker for nicotine dependence evaluation. Methods A total of 14 smokers and 11 non-smoking controls were recruited for this study. Resting-state functional magnetic resonance imaging and regional homogeneity (ReHo) were applied in the neural activity analysis. Two-sample t-test was performed to examine the voxel-wise difference between the smokers and the controls. Correlation analysis between the ReHo values and the Fagerstrom Test for Nicotine Dependence (FTND) scores were performed to explore the biomarkers for the clinical characteristics of smokers. Results The ReHo values from the right superior frontal gyrus of the Brodmann’s area (BA) 9 to the right middle frontal gyrus and the ReHo value from the left and right precuneus (BA 23) to the left and right middle cingulum gyrus were lower in the smokers than in the non-smokers. The ReHo value in the precuneus (BA 23) was significantly and positively correlated with the FTND score of smokers. Conclusion The ReHo values in the right superior frontal gyrus and left precuneus can be used to separate the smokers from the non-smokers. In particular, the left precuneus is a potential neuroimaging biomarker for nicotine addicts. PMID:28081226

  5. 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.

  6. Repeated administration of alpha7 nicotinic acetylcholine receptor (nAChR) agonists, but not positive allosteric modulators, increases alpha7 nAChR levels in the brain

    DEFF Research Database (Denmark)

    Christensen, Ditte Z; Mikkelsen, Jens D; Hansen, Henrik H;

    2010-01-01

    -induced phosphorylation of Erk2 in the prefrontal cortex occurs following acute, but not repeated administration. Our results demonstrate that repeated agonist administration increases the number of alpha7 nAChRs in the brain, and leads to coupling versus uncoupling of specific intracellular signaling....... Here we investigate the effects of repeated agonism on alpha7 nAChR receptor levels and responsiveness in vivo in rats. Using [(125)I]-alpha-bungarotoxin (BTX) autoradiography we show that acute or repeated administration with the selective alpha7 nAChR agonist A-582941 increases the number of alpha7 n......-120596 and NS1738 do not increase [(125)I]-BTX binding. Furthermore, A-582941-induced increase in Arc and c-fos mRNA expression in the prefrontal cortex is enhanced and unaltered, respectively, after repeated administration, demonstrating that the alpha7 nAChRs remain responsive. Contrarily, A-582941...

  7. Electrophysiological changes in laterodorsal tegmental neurons associated with prenatal nicotine exposure: implications for heightened susceptibility to addict to drugs of abuse.

    Science.gov (United States)

    Christensen, M H; Nielsen, M L; Kohlmeier, K A

    2015-06-01

    Prenatal nicotine exposure (PNE) is a risk factor for developing an addiction to nicotine at a later stage in life. Understanding the neurobiological changes in reward related circuitry induced by exposure to nicotine prenatally is vital if we are to combat the heightened addiction liability in these vulnerable individuals. The laterodorsal tegmental nucleus (LDT), which is comprised of cholinergic, GABAergic and glutamatergic neurons, is importantly involved in reward mediation via demonstrated excitatory projections to dopamine-containing ventral tegmental neurons. PNE could lead to alterations in LDT neurons that would be expected to alter responses to later-life nicotine exposure. To examine this issue, we monitored nicotine-induced responses of LDT neurons in brain slices of PNE and drug naive mice using calcium imaging and whole-cell patch clamping. Nicotine was found to induce rises in calcium in a smaller proportion of LDT cells in PNE mice aged 7-15 days and smaller rises in calcium in PNE animals from postnatal ages 11-21 days when compared with age-matched control animals. While inward currents induced by nicotine were not found to be different, nicotine did induce larger amplitude excitatory postsynaptic currents in PNE animals in the oldest age group when compared with amplitudes induced in similar-aged control animals. Immunohistochemically identified cholinergic LDT cells from PNE animals exhibited slower spike rise and decay slopes, which likely contributed to the wider action potential observed. Further, PNE was associated with a more negative action potential afterhyperpolarization in cholinergic cells. Interestingly, the changes found in these parameters in animals exposed prenatally to nicotine were age related, in that they were not apparent in animals from the oldest age group examined. Taken together, our data suggest that PNE induces changes in cholinergic LDT cells that would be expected to alter cellular excitability. As the changes are

  8. Effects of the nicotinic receptor partial agonists varenicline and cytisine on the discriminative stimulus effects of nicotine in rats.

    Science.gov (United States)

    LeSage, Mark G; Shelley, David; Ross, Jason T; Carroll, F Ivy; Corrigall, William A

    2009-01-01

    The nicotinic partial agonist varenicline (VCL) is a recently approved medication for the treatment of tobacco dependence, yet very little preclinical research on this drug has been published. The present experiment examined the nicotinic partial agonist properties of VCL and its parent compound, cytisine (CYT), in a nicotine discrimination assay. Rats were trained to discriminate nicotine (0.4 mg/kg, s.c.) from saline using a two-lever discrimination procedure, followed by generalization and antagonism tests with VCL and CYT. Antagonism was examined across a range of nicotine doses. In generalization tests, VCL produced a maximum of 63% responding on the nicotine-appropriate lever, indicating partial generalization. In antagonism tests, VCL decreased the % responding on the nicotine-appropriate lever at 0.2 and 0.4 mg/kg nicotine, indicating antagonism of nicotine's discriminative stimulus effects. No dose of VCL produced significant effects on response rate. The two highest doses of CYT weakly substituted for nicotine, producing a maximum of 23% nicotine-appropriate responding. CYT produced a weak antagonism of the discrimination of moderate nicotine doses, but not of the training dose. These results demonstrate that VCL and CYT partially generalize to and partially antagonize nicotine's discriminative stimulus effects, consistent with a partial agonist mechanism of action.

  9. 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.

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

    Science.gov (United States)

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

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

  11. Central cholinergic regulation of respiration: nicotinic receptors

    Institute of Scientific and Technical Information of China (English)

    Xuesi M SHAO; Jack L FELDMAN

    2009-01-01

    Nicotinic acetylcholine receptors (nAChRs) are expressed in brainstem and spinal cord regions involved in the control of breathing. These receptors mediate central cholinergic regulation of respiration and effects of the exogenous ligand nicotine on respiratory pattern. Activation of a4* nAChRs in the preBotzinger Complex (preBotC), an essential site for normal respiratory rhythm generation in mammals, modulates excitatory glutamatergic neurotransmission and depolarizes preBotC inspiratory neurons, leading to increases in respiratory frequency. nAChRs are also present in motor nuclei innervating respiratory muscles. Activation of post- and/or extra-synaptic a4* nAChRs on hypoglossal (XII) motoneurons depolarizes these neurons, potentiating tonic and respiratory-related rhythmic activity. As perinatal nicotine exposure may contribute to the pathogenesis of sudden infant death syndrome (SIDS), we discuss the effects of perinatal nicotine exposure on development of the cholinergic and other neurotransmitter systems involved in control of breathing. Advances in understanding of the mechanisms underlying central cholinergic/nicotinic modulation of respiration provide a pharmacological basis for exploiting nAChRs as therapeutic targets for neurological disorders related to neural control of breathing such as sleep apnea and SIDS.

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

    Science.gov (United States)

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

    2017-01-01

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

  13. 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.

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

    Science.gov (United States)

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

    2015-01-01

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

  15. Caffeine plus nicotine improves motor function, spatial and non-spatial working memory and functional indices in BALB/c male mice.

    Science.gov (United States)

    Adeniyi, P A; Omatsuli, E P; Akinyemi, A J; Ishola, A O

    2016-12-01

    There is a greater prevalence of cigarette smoking among caffeine dependent individuals. This study therefore sought to assess the effect of nicotine and/or caffeine on some key biochemical indices and neurobehavioural parameters associated with brain function in male mice. Forty male BALB/c mice were divided into 4 groups of 10 animals each; Group A serve as the control and received normal saline (s.c), Group B received 2mg/kg body weight of nicotine (s.c), Group C received 2mg/kg body weight of caffeine (s.c) and Group D received 2mg/kg of nicotine and 2mg/kg of caffeine (s.c). The experiment lasted for 21 days, and then the animals were subjected to behavioral test. Thereafter the animals were sacrificed and their brain isolated for the determination of endothelial nitric oxide (NO) level, acetylcholinesterase (AChE), arginase (Arg) and adenosine deaminase (ADA) activities; as well as some antioxidant indices. Administration of nicotine or caffeine caused a significant (Pnicotine enhances caffeine cognitive properties through a significant increase in non-spatial working memory whereas; it was otherwise on the spatial working memory and motor coordination. Therefore, we can suggest from our present study that caffeine enhances the effect of nicotine either synergistically or additively on memory and motor function and some key biochemical indices associated with brain function in male mice.

  16. Habenular expression of rare missense variants of the β4 nicotinic receptor subunit alters nicotine consumption

    Science.gov (United States)

    Ślimak, Marta A.; Ables, Jessica L.; Frahm, Silke; Antolin-Fontes, Beatriz; Santos-Torres, Julio; Moretti, Milena; Gotti, Cecilia; Ibañez-Tallon, Inés

    2013-01-01

    The CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the α5, α3, and β4 nicotinic acetylcholine receptor (nAChR) subunits, has been linked to nicotine dependence. The habenulo-interpeduncular (Hb-IPN) tract is particularly enriched in α3β4 nAChRs. We recently showed that modulation of these receptors in the medial habenula (MHb) in mice altered nicotine consumption. Given that β4 is rate-limiting for receptor activity and that single nucleotide polymorphisms (SNPs) in CHRNB4 have been linked to altered risk of nicotine dependence in humans, we were interested in determining the contribution of allelic variants of β4 to nicotine receptor activity in the MHb. We screened for missense SNPs that had allele frequencies >0.0005 and introduced the corresponding substitutions in Chrnb4. Fourteen variants were analyzed by co-expression with α3. We found that β4A90I and β4T374I variants, previously shown to associate with reduced risk of smoking, and an additional variant β4D447Y, significantly increased nicotine-evoked current amplitudes, while β4R348C, the mutation most frequently encountered in sporadic amyotrophic lateral sclerosis (sALS), showed reduced nicotine currents. We employed lentiviruses to express β4 or β4 variants in the MHb. Immunoprecipitation studies confirmed that β4 lentiviral-mediated expression leads to specific upregulation of α3β4 but not β2 nAChRs in the Mhb. Mice injected with the β4-containing virus showed pronounced aversion to nicotine as previously observed in transgenic Tabac mice overexpressing Chrnb4 at endogenous sites including the MHb. Habenular expression of the β4 gain-of-function allele T374I also resulted in strong aversion, while transduction with the β4 loss-of function allele R348C failed to induce nicotine aversion. Altogether, these data confirm the critical role of habenular β4 in nicotine consumption, and identify specific SNPs in CHRNB4 that modify nicotine-elicited currents and alter nicotine consumption in

  17. Pre-clinical properties of the α4β2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence

    Science.gov (United States)

    Rollema, H; Shrikhande, A; Ward, KM; Tingley, FD; Coe, JW; O'Neill, BT; Tseng, E; Wang, EQ; Mather, RJ; Hurst, RS; Williams, KE; de Vries, M; Cremers, T; Bertrand, S; Bertrand, D

    2010-01-01

    Background and purpose: Smoking cessation trials with three high-affinity partial agonists of α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) have demonstrated differences in their clinical efficacy. This work examines the origin of the differences by taking into account brain exposure and pharmacological effects at human α4β2 nAChRs. Experimental approach: Rat plasma and brain pharmacokinetics were characterized and used to predict human steady-state plasma and brain concentrations following recommended doses of each of the three compounds. The pharmacological characterization included in vitro affinities at different nAChR subtypes, functional efficacies and potencies at the human α4β2 nAChR, as well as in vivo effects on rat mesolimbic dopamine turn-over. Key results: A comparison of predicted human brain concentrations following therapeutic doses demonstrated that varenicline and nicotine, but not dianicline and cytisine, can extensively desensitize and, to a lesser extent, activate α4β2 nAChRs. The limited clinical efficacy of dianicline may be accounted for by a combination of weak functional potency at α4β2 nAChRs and moderate brain penetration, while recommended doses of cytisine, despite its high in vitro potency, are predicted to result in brain concentrations that are insufficient to affect α4β2 nAChRs. Conclusions and implications: The data provide a plausible explanation for the higher abstinence rate in smoking cessation trials following treatment with varenicline than with the two other α4β2 nAChR partial agonists. In addition, this retrospective analysis demonstrates the usefulness of combining in vitro and in vivo parameters with estimated therapeutic human brain concentrations for translation to clinical efficacy. PMID:20331614

  18. 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.

  19. Nicotine replacement therapies: patient safety and persistence

    Directory of Open Access Journals (Sweden)

    Ferguson SG

    2011-06-01

    Full Text Available Stuart G Ferguson1,2, Saul Shiffman3,4, Joseph G Gitchell51School of Pharmacy, 2Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia; 3Pinney Associates, 4University of Pittsburgh, Pittsburgh, PA, USA; 5Pinney Associates, Bethesda, MD, USAAbstract: Nicotine replacement therapy (NRT has become a central part of the treatment of nicotine dependence. However, NRT’s potential efficacy is limited to some extent by patient adherence and persistence. Here we review the relationship between NRT compliance and adherence, and overall treatment outcome. We then examine the factors that likely impact on treatment compliance and persistence, with a special focus on users’ perceptions of treatment safety and efficacy as possible mediators. Potential clinical strategies for improving suboptimal medication use are also discussed.Keywords: nicotine replacement therapy, compliance, safety

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

    Energy Technology Data Exchange (ETDEWEB)

    Hanes, P.J.; Schuster, G.S.; Lubas, S. (Medical College of Georgia, Augusta (USA))

    1991-02-01

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

  1. Nicotine facilitates memory consolidation in perceptual learning.

    Science.gov (United States)

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

    2013-01-01

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

  2. 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.

  3. 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 prote......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...

  4. Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine.

    Science.gov (United States)

    Levine, Amir; Huang, Yanyou; Drisaldi, Bettina; Griffin, Edmund A; Pollak, Daniela D; Xu, Shiqin; Yin, Deqi; Schaffran, Christine; Kandel, Denise B; Kandel, Eric R

    2011-11-02

    In human populations, cigarettes and alcohol generally serve as gateway drugs, which people use first before progressing to marijuana, cocaine, or other illicit substances. To understand the biological basis of the gateway sequence of drug use, we developed an animal model in mice and used it to study the effects of nicotine on subsequent responses to cocaine. We found that pretreatment of mice with nicotine increased the response to cocaine, as assessed by addiction-related behaviors and synaptic plasticity in the striatum, a brain region critical for addiction-related reward. Locomotor sensitization was increased by 98%, conditioned place preference was increased by 78%, and cocaine-induced reduction in long-term potentiation (LTP) was enhanced by 24%. The responses to cocaine were altered only when nicotine was administered first, and nicotine and cocaine were then administered concurrently. Reversing the order of drug administration was ineffective; cocaine had no effect on nicotine-induced behaviors and synaptic plasticity. Nicotine primed the response to cocaine by enhancing its ability to induce transcriptional activation of the FosB gene through inhibition of histone deacetylase, which caused global histone acetylation in the striatum. We tested this conclusion further and found that a histone deacetylase inhibitor simulated the actions of nicotine by priming the response to cocaine and enhancing FosB gene expression and LTP depression in the nucleus accumbens. Conversely, in a genetic mouse model characterized by reduced histone acetylation, the effects of cocaine on LTP were diminished. We achieved a similar effect by infusing a low dose of theophylline, an activator of histone deacetylase, into the nucleus accumbens. These results from mice prompted an analysis of epidemiological data, which indicated that most cocaine users initiate cocaine use after the onset of smoking and while actively still smoking, and that initiating cocaine use after smoking

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

    Science.gov (United States)

    Hiroi, N; Scott, D

    2009-07-01

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

  6. High reinforcing efficacy of nicotine in non-human primates.

    Directory of Open Access Journals (Sweden)

    Bernard Le Foll

    Full Text Available Although tobacco appears highly addictive in humans, there has been persistent controversy about the ability of its psychoactive ingredient nicotine to induce self-administration behavior in laboratory animals, bringing into question nicotine's role in reinforcing tobacco smoking. Because of ethical difficulties in inducing nicotine dependence in naïve human subjects, we explored reinforcing effects of nicotine in experimentally-naive non-human primates given access to nicotine for periods of time up to two years. Five squirrel monkeys with no experimental history were allowed to intravenously self-administer nicotine by pressing one of two levers. The number of presses on the active lever needed to obtain each injection was fixed (fixed-ratio schedule or increased progressively with successive injections during the session (progressive-ratio schedule, allowing evaluation of both reinforcing and motivational effects of nicotine under conditions of increasing response cost. Over time, a progressive shift toward high rates of responding on the active lever, but not the inactive lever, developed. The monkeys' behavior was clearly directed toward nicotine self-administration, rather than presentation of environmental stimuli associated with nicotine injection. Both schedules of reinforcement revealed a high motivation to self-administer nicotine, with monkeys continuing to press the lever when up to 600 lever-presses were needed for each injection of nicotine. Thus, nicotine, by itself, in the absence of behavioral or drug-exposure history, is a robust and highly effective reinforcer of drug-taking behavior in a non-human primate model predictive of human behavior. This supports the use of nicotinic ligands for the treatment of smokers, and this novel preclinical model offers opportunities to test future medications for the treatment of nicotine dependence.

  7. Nicotinic receptors and functional regulation of GABA cell microcircuitry in bipolar disorder and schizophrenia.

    Science.gov (United States)

    Benes, Francine M

    2012-01-01

    Studies of the hippocampus in postmortem brains from patients with schizophrenia and bipolar disorder have provided evidence for a defect of GABAergic interneurons. Significant decreases in the expression of GAD67, a marker for GABA cell function, have been found repeatedly in several different brain regions that include the hippocampus. In this region, nicotinic receptors are thought to play an important role in modulating the activity of GABAergic interneurons by influences of excitatory cholinergic afferents on their activity. In bipolar disorder, this influence appears to be particularly prominent in the stratum oriens of sectors CA3/2 and CA1, two sites where these cells constitute the exclusive neuronal cell type. In sector CA3/2, this layer receives a robust excitatory projection from the basolateral amygdala (BLA) and this is thought to play a central role in regulating GABA cells at this locus. Using laser microdissection, recent studies have focused selectively on these two layers and their associated GABA cells using microarray technology. The results have provided support for the idea that nicotinic cholinergic receptors play a particularly important role in regulating the activity of GABA neurons at these loci by regulating the progression of cell cycle and the repair of damaged DNA. In bipolar disorder, there is a prominent reduction in the expression of mRNAs for several different nicotinic subunit isoforms. These decreases could reflect a diminished influence of this receptor system on these GABA cells, particularly in sector CA3/2 where a preponderance of abnormalities have been observed in postmortem studies. In patients with bipolar disorder, excitatory nicotinic cholinergic fibers from the medial septum may converge with glutamatergic fibers from the BLA on GABAergic interneurons in the stratum oriens of CA3/2 and result in disturbances of their genomic and functional integrity, ones that may induce disruptions of the integration of

  8. Effects of imperatorin on nicotine-induced anxiety- and memory-related responses and oxidative stress in mice.

    Science.gov (United States)

    Budzynska, Barbara; Boguszewska-Czubara, Anna; Kruk-Slomka, Marta; Skalicka-Wozniak, Krystyna; Michalak, Agnieszka; Musik, Irena; Biala, Grazyna; Glowniak, Kazimierz

    2013-10-02

    The purpose of the reported experiments was to examine the effects of imperatorin [9-[(3-methylbut-2-en-1-yl)oxy]-7H-furo[3,2-g]chromen-7-one] on anxiety and memory-related responses induced by nicotine in mice and their relation to the level of nicotine-induced oxidative stress in brain as well as in the hippocampus and the prefrontal cortex. Male Swiss mice were tested for anxiety in the elevated plus maze test (EPM), and for cognition using passive avoidance (PA) procedures. Imperatorin, purified by high-speed counter-current chromatography from methanol extract of fruits of Angelica officinalis, acutely administered at the doses of 10 and 20mg/kg impaired the anxiogenic effect of nicotine (0.1mg/kg, s.c.). Furthermore, acute injections of subthreshold dose of imperatorin (1mg/kg, i.p.) improved processes of memory acquisition when co-administered with nicotine used at non-active dose of 0.05 mg/kg, s.c. Additionally, repeated administration of imperatorin (1mg/kg, i.p., twice daily, for 6 days) improved different stages of memory processes (both acquisition and consolidation) when injected in combination with non-active dose of nicotine (0.05 mg/kg, s.c.) in the PA task. Oxidative stress was assessed by determination of antioxidant enzymes (glutathione peroxidases (GPx), superoxide dismutase (SOD), glutathione reductase (GR)) activities as well as of malondialdehyde (MDA) concentration in the whole brain, the hippocampus and the prefrontal cortex after repeated administration of imperatorin (1mg/kg, 6 days) and single nicotine injection (0.05 mg/kgs.c.) on the seventh day. The results of our research suggest strong behavioural interaction between imperatorin and nicotine at the level of anxiety- and cognitive-like processes. Furthermore, imperatorin inhibited nicotine-induced changes in examined indicators of oxidative stress, especially in the hippocampus and the cortex.

  9. Effects of nicotine on electroencephalographic (EEG) and behavioural measures of visual working memory in non-smokers during a dual-task paradigm.

    Science.gov (United States)

    Fisher, Derek J; Knobelsdorf, Amy; Jaworska, Natalia; Daniels, Richelle; Knott, Verner J

    2013-01-01

    Research in smokers has shown that nicotine may have the ability to improve certain aspects of cognitive performance, including working memory and attention, processes which implicate frontal and frontal-parietal brain networks. There is limited research on the cognitive effects of nicotine and their associated neural underpinnings in non-smokers. This study examined the effects of acute nicotine on a working memory task alone or combined with a visual detection task (single- and dual-task conditions) using electroencephalographic (EEG) recordings and behavioural performance measures. Twenty non-smokers (13 females; 7 males) received nicotine gum (6 mg) in a double-blind, randomized, placebo-controlled, repeated measures design. Spectral EEG, together with response speed and accuracy measures, were obtained while participants completed a series of N-Back tasks under single- and dual-task conditions. Nicotine failed to exert any significant effects on performance measures, however, EEG changes were observed, primarily in frontal recordings, which varied with memory load, task condition and hemisphere. These findings, discussed in relation to previous studies in smokers, support the notion that nicotine may modulate central executive systems and contribute to smoking behaviour.

  10. 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.

  11. Docking to flexible nicotinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Sander, Tommy; Bruun, Anne T; Balle, Thomas

    2010-01-01

    Computational docking to nicotinic acetylcholine receptors (nAChRs) and other members of the Cys-loop receptor family is complicated by the flexibility of the so-called C-loop. As observed in the large number of published crystal structures of the acetylcholine binding protein (AChBP), a structural...

  12. Nicotinic Acetylcholine Receptors in Sensory Cortex

    Science.gov (United States)

    Metherate, Raju

    2004-01-01

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

  13. Genetic relationship between schizophrenia and nicotine dependence

    NARCIS (Netherlands)

    Chen, J.; Bacanu, S.A.; Yu, H.; Zhao, Z.; Jia, P.; Kendler, K.S.; Kranzler, H.R.; Gelernter, J.; Farrer, L.; Minica, C.C.; Pool, R.; Milaneschi, Y.; Boomsma, D.I.; Penninx, B.W.J.H.; Tyndale, R.F.; Ware, J.J.; Vink, J.M.; Kaprio, J.; Munafò, M.R.; Chen, X.

    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

  14. Structural Studies of Nicotinic Acetylcholine Receptors

    DEFF Research Database (Denmark)

    Shahsavar, Azadeh; Gajhede, Michael; Kastrup, Jette S;

    2015-01-01

    Nicotinic acetylcholine receptors (nAChRs) are members of the pentameric ligand-gated ion channel superfamily that play important roles in control of neurotransmitter release in the central and peripheral nervous system. These receptors are important therapeutic targets for development of drugs...

  15. Nicotinic Receptor Polymorphism in Lung Cancer

    Science.gov (United States)

    2013-10-01

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

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

    Science.gov (United States)

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

    2013-02-15

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

  17. Nicotine enhances contextual fear memory reconsolidation in rats.

    Science.gov (United States)

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

    2011-01-10

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

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

    Science.gov (United States)

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

    2016-02-01

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

  19. Nicotine activates the chemosensory cation channel TRPA1.

    Science.gov (United States)

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

    2009-10-01

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

  20. Opioid Analgesics and Nicotine: More Than Blowing Smoke.

    Science.gov (United States)

    Yoon, Jin H; Lane, Scott D; Weaver, Michael F

    2015-09-01

    Practitioners are highly likely to encounter patients with concurrent use of nicotine products and opioid analgesics. Smokers present with more severe and extended chronic pain outcomes and have a higher frequency of prescription opioid use. Current tobacco smoking is a strong predictor of risk for nonmedical use of prescription opioids. Opioid and nicotinic-cholinergic neurotransmitter systems interact in important ways to modulate opioid and nicotine effects: dopamine release induced by nicotine is dependent on facilitation by the opioid system, and the nicotinic-acetylcholine system modulates self-administration of several classes of abused drugs-including opioids. Nicotine can serve as a prime for the use of other drugs, which in the case of the opioid system may be bidirectional. Opioids and compounds in tobacco, including nicotine, are metabolized by the cytochrome P450 enzyme system, but the metabolism of opioids and tobacco products can be complicated. Accordingly, drug interactions are possible but not always clear. Because of these issues, asking about nicotine use in patients taking opioids for pain is recommended. When assessing patient tobacco use, practitioners should also obtain information on products other than cigarettes, such as cigars, pipes, smokeless tobacco, and electronic nicotine delivery systems (ENDS, or e-cigarettes). There are multiple forms of behavioral therapy and pharmacotherapy available to assist patients with smoking cessation, and opioid agonist maintenance and pain clinics represent underutilized opportunities for nicotine intervention programs.

  1. Adsorption of nicotine on different zeolite types, from aqueous solutions

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    Stošić Dušan K.

    2007-01-01

    Full Text Available The plant alkaloid, nicotine, is a strongly toxic heterocyclic compound: the lethal dose for an adult human being (40-60 mg is importantly lower in comparison with the other known poisons such as arsenic or strychni­ne. Cigarettes represent "the most toxic and addictive form of nicotine". Besides the negative effects of nicotine on public health produced by self-administration, recently another potentially very dangerous effect has been recognized: because of its miscibility with water, nicotine can be found in industrial wastewaters, and consequently, in groundwater. Therefore, the problem of nicotine removal from aqueous solutions has became an interesting topic. In this work, the removal of nicotine has been probed by adsorption on solid materials. Adsorption of nicotine on different zeolites (clinoptilolite, ZSM-5 and β zeolite and on activated carbon was investigated from aqueous solutions, at 298 K. The obtained results are presented as adsorption isotherms: the amount of adsorbed nicotine as a function of equilibrium concentration. These data were obtained from the residual amount of nicotine in the aqueous phase, by the use of UV spectroscopy. The highest amounts of adsorbed nicotine was found for activated carbon and p zeolite (~ mmol·g-1. The attempt to modify the adsorption properties of ZSM-5 zeolite has been also done: ZSM-5 was modified by ion-exchange with VIII group metal (Cu2+ and Fe3+. In addition, the adsorption of nicotine on ZSM-5 zeolite with different Si/Al ratios has been done. It has been noticed that ion-exchange did not improve the adsorption possibilities, while the adsorption was importantly lower in the case of higher silicon content in ZMS-5 structure. 13C NMR spectra were collected for suspensions formed of solid adsorbent and aqueous solution of nicotine; in this way, the part of nicotine molecule which is most probably connected with the adsorbent was recognized.

  2. 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

  3. Octopamine and Dopamine differentially modulate the nicotine-induced calcium response in Drosophila Mushroom Body Kenyon Cells.

    Science.gov (United States)

    Leyton, V; Goles, N I; Fuenzalida-Uribe, N; Campusano, J M

    2014-02-07

    In Drosophila associative olfactory learning, an odor, the conditioned stimulus (CS), is paired to an unconditioned stimulus (US). The CS and US information arrive at the Mushroom Bodies (MB), a Drosophila brain region that processes the information to generate new memories. It has been shown that olfactory information is conveyed through cholinergic inputs that activate nicotinic acetylcholine receptors (nAChRs) in the MB, while the US is coded by biogenic amine (BA) systems that innervate the MB. In this regard, the MB acts as a coincidence detector. A better understanding of the properties of the responses gated by nicotinic and BA receptors is required to get insights on the cellular and molecular mechanisms responsible for memory formation. In recent years, information has become available on the properties of the responses induced by nAChR activation in Kenyon Cells (KCs), the main neuronal MB population. However, very little information exists on the responses induced by aminergic systems in fly MB. Here we have evaluated some of the properties of the calcium responses gated by Dopamine (DA) and Octopamine (Oct) in identified KCs in culture. We report that exposure to BAs induces a fast but rather modest increase in intracellular calcium levels in cultured KCs. The responses to Oct and DA are fully blocked by a VGCC blocker, while they are differentially modulated by cAMP. Moreover, co-application of BAs and nicotine has different effects on intracellular calcium levels: while DA and nicotine effects are additive, Oct and nicotine induce a synergistic increase in calcium levels. These results suggest that a differential modulation of nicotine-induced calcium increase by DA and Oct could contribute to the events leading to learning and memory in flies.

  4. Agonist and antagonist effects of tobacco-related nitrosamines on human α4β2 nicotinic acetylcholine receptors.

    Directory of Open Access Journals (Sweden)

    Simone eBrusco

    2015-09-01

    Full Text Available Regulation of the ‘neuronal’ nicotinic acetylcholine receptors (nAChRs is implicated in both tobacco addiction and smoking-dependent tumor promotion. Some of these effects are caused by the tobacco-derived N-nitrosamines, which are carcinogenic compounds that avidly bind to nAChRs. However, the functional effects of these drugs on specific nAChR subtypes are largely unknown. By using patch-clamp methods, we tested 4-(methylnitrosamine-1-(3-pyridyl-1-butanone (NNK and N’-nitrosonornicotine (NNN on human α4β2 nAChRs. These latter are widely distributed in the mammalian brain and are also frequently expressed outside the nervous system. NNK behaved as a partial agonist, with an apparent EC50 of 16.7 μM. At 100 μM, it activated 16 % of the maximal current activated by nicotine. When NNK was co-applied with nicotine, it potentiated the currents elicited by nicotine concentrations ≤ 100 nM. At higher concentrations of nicotine, NNK always inhibited the α4β2 nAChR. In contrast, NNN was a pure inhibitor of this nAChR subtype, with IC50 of approximately 1 nM in the presence of 10 μM nicotine. The effects of both NNK and NNN were mainly competitive and largely independent of Vm. The different actions of NNN and NNK must be taken into account when interpreting their biological effects in vitro and in vivo.

  5. Cycloxaprid insecticide: nicotinic acetylcholine receptor binding site and metabolism.

    Science.gov (United States)

    Shao, Xusheng; Swenson, Tami L; Casida, John E

    2013-08-21

    Cycloxaprid (CYC) is a novel neonicotinoid prepared from the (nitromethylene)imidazole (NMI) analogue of imidacloprid. In this study we consider whether CYC is active per se or only as a proinsecticide for NMI. The IC50 values (nM) for displacing [(3)H]NMI binding are 43-49 for CYC and 2.3-3.2 for NMI in house fly and honeybee head membranes and 302 and 7.2, respectively, in mouse brain membranes, potency relationships interpreted as partial conversion of some CYC to NMI under the assay conditions. The 6-8-fold difference in toxicity of injected CYC and NMI to house flies is consistent with their relative potencies as in vivo nicotinic acetylcholine receptor (nAChR) inhibitors in brain measured with [(3)H]NMI binding assays. CYC metabolism in mice largely involves cytochrome P450 pathways without NMI as a major intermediate. Metabolites of CYC tentatively assigned are five monohydroxy derivatives and one each of dihydroxy, nitroso, and amino modifications. CYC appears be a proinsecticide, serving as a slow-release reservoir for NMI with selective activity for insect versus mammalian nAChRs.

  6. 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

    2016-04-01

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

  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...

  8. 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.

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

    Science.gov (United States)

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

    2012-01-01

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

  10. 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.

  11. Nicotine acts on growth plate chondrocytes to delay skeletal growth through the alpha7 neuronal nicotinic acetylcholine receptor.

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    Atsuo Kawakita

    Full Text Available BACKGROUND: Cigarette smoking adversely affects endochondral ossification during the course of skeletal growth. Among a plethora of cigarette chemicals, nicotine is one of the primary candidate compounds responsible for the cause of smoking-induced delayed skeletal growth. However, the possible mechanism of delayed skeletal growth caused by nicotine remains unclarified. In the last decade, localization of neuronal nicotinic acetylcholine receptor (nAChR, a specific receptor of nicotine, has been widely detected in non-excitable cells. Therefore, we hypothesized that nicotine affect growth plate chondrocytes directly and specifically through nAChR to delay skeletal growth. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effect of nicotine on human growth plate chondrocytes, a major component of endochondral ossification. The chondrocytes were derived from extra human fingers. Nicotine inhibited matrix synthesis and hypertrophic differentiation in human growth plate chondrocytes in suspension culture in a concentration-dependent manner. Both human and murine growth plate chondrocytes expressed alpha7 nAChR, which constitutes functional homopentameric receptors. Methyllycaconitine (MLA, a specific antagonist of alpha7 nAChR, reversed the inhibition of matrix synthesis and functional calcium signal by nicotine in human growth plate chondrocytes in vitro. To study the effect of nicotine on growth plate in vivo, ovulation-controlled pregnant alpha7 nAChR +/- mice were given drinking water with or without nicotine during pregnancy, and skeletal growth of their fetuses was observed. Maternal nicotine exposure resulted in delayed skeletal growth of alpha7 nAChR +/+ fetuses but not in alpha7 nAChR -/- fetuses, implying that skeletal growth retardation by nicotine is specifically mediated via fetal alpha7 nAChR. CONCLUSIONS/SIGNIFICANCE: These results suggest that nicotine, from cigarette smoking, acts directly on growth plate chondrocytes to decrease

  12. Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal.

    Science.gov (United States)

    Watkins, S S; Koob, G F; Markou, A

    2000-02-01

    The neurobiology of nicotine addiction is reviewed within the context of neurobiological and behavioral theories postulated for other drugs of abuse. The roles of various neurotransmitter systems, including acetylcholine, dopamine, serotonin, glutamate, gamma-aminobutyric acid, and opioid peptides in acute nicotine reinforcement and withdrawal from chronic administration are examined followed by a discussion of potential neuroadaptations within these neurochemical systems that may lead to the development of nicotine dependence. The link between nicotine administration, depression and schizophrenia are also discussed. Finally, a theoretical model of the neurobiological mechanisms underlying acute nicotine withdrawal and protracted abstinence involves alterations within dopaminergic, serotonergic, and stress systems that are hypothesized to contribute to the negative affective state associated with nicotine abstinence.

  13. Pathogenesis of Abdominal Aortic Aneurysms: Role of Nicotine and Nicotinic Acetylcholine Receptors

    Directory of Open Access Journals (Sweden)

    Zong-Zhuang Li

    2012-01-01

    Full Text Available Inflammation, proteolysis, smooth muscle cell apoptosis, and angiogenesis have been implicated in the pathogenesis of abdominal aortic aneurysms (AAAs, although the well-defined initiating mechanism is not fully understood. Matrix metalloproteinases (MMPs such as MMP-2 and -9 and other proteinases degrading elastin and extracellular matrix are the critical pathogenesis of AAAs. Among the risk factors of AAAs, cigarette smoking is an irrefutable one. Cigarette smoke is practically involved in various aspects of the AAA pathogenesis. Nicotine, a major alkaloid in tobacco leaves and a primary component in cigarette smoke, can stimulate the MMPs expression by vascular SMCs, endothelial cells, and inflammatory cells in vascular wall and induce angiogenesis in the aneurysmal tissues. However, for the inflammatory and apoptotic processes in the pathogenesis of AAAs, nicotine seems to be moving in just the opposite direction. Additionally, the effects of nicotine are probably dose dependent or associated with the exposure duration and may be partly exerted by its receptors—nicotinic acetylcholine receptors (nAChRs. In this paper, we will mainly discuss the pathogenesis of AAAs involving inflammation, proteolysis, smooth muscle cell apoptosis and angiogenesis, and the roles of nicotine and nAChRs.

  14. Brain-Actuated Interaction

    OpenAIRE

    Millán, José del R.; Renkens, F.; Mouriño, 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...

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

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    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

  16. Cellular basis for the olfactory response to nicotine.

    Science.gov (United States)

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

    2010-03-17

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

  17. Prompt but inefficient: nicotine differentially modulates discrete components of attention

    OpenAIRE

    Vangkilde, Signe; Bundesen, Claus; Coull, Jennifer T.

    2011-01-01

    Rationale Nicotine has been shown to improve both memory and attention when assessed through speeded motor responses. Since very few studies have assessed effects of nicotine on visual attention using measures that are uncontaminated by motoric effects, nicotine’s attentional effects may, at least partially, be due to speeding of motor function. Objectives Using an unspeeded, accuracy-based test, the CombiTVA paradigm, we examined whether nicotine enhances attention when it is measured indepe...

  18. Noribogaine reduces nicotine self-administration in rats

    OpenAIRE

    2015-01-01

    Noribogaine, a polypharmacological drug with activities at opioid receptors, ionotropic nicotinic receptors, and serotonin reuptake transporters, has been investigated for treatment of substance abuse-related disorders. Smoking cessation has major benefits for both individuals and society, therefore the aim of this study was to evaluate the potential of noribogaine for use as a treatment for nicotine dependence. Adult male Sprague-Dawley rats were trained to self-administer nicotine intraveno...

  19. Nicotinic receptor abnormalities in Alzheimer's and Parkinson's diseases.

    OpenAIRE

    1987-01-01

    The status of cholinergic receptors in dementia is related to the question of potential cholinergic therapy. Whilst muscarinic receptor binding is generally reported to be normal or near normal, findings are reported which indicate substantial reductions of hippocampal nicotinic (high affinity nicotine) binding (occurring in conjunction with decreased choline acetyltransferase) in both Alzheimer's and Parkinson's but not Huntington's disease. A further indication that nicotinic receptor funct...

  20. Generation, Release, and Uptake of the NAD Precursor Nicotinic Acid Riboside by Human Cells*

    Science.gov (United States)

    Kulikova, Veronika; Shabalin, Konstantin; Nerinovski, Kirill; Dölle, Christian; Niere, Marc; Yakimov, Alexander; Redpath, Philip; Khodorkovskiy, Mikhail; Migaud, Marie E.; Ziegler, Mathias; Nikiforov, Andrey

    2015-01-01

    NAD is essential for cellular metabolism and has a key role in various signaling pathways in human cells. To ensure proper control of vital reactions, NAD must be permanently resynthesized. Nicotinamide and nicotinic acid as well as nicotinamide riboside (NR) and nicotinic acid riboside (NAR) are the major precursors for NAD biosynthesis in humans. In this study, we explored whether the ribosides NR and NAR can be generated in human cells. We demonstrate that purified, recombinant human cytosolic 5′-nucleotidases (5′-NTs) CN-II and CN-III, but not CN-IA, can dephosphorylate the mononucleotides nicotinamide mononucleotide and nicotinic acid mononucleotide (NAMN) and thus catalyze NR and NAR formation in vitro. Similar to their counterpart from yeast, Sdt1, the human 5′-NTs require high (millimolar) concentrations of nicotinamide mononucleotide or NAMN for efficient catalysis. Overexpression of FLAG-tagged CN-II and CN-III in HEK293 and HepG2 cells resulted in the formation and release of NAR. However, NAR accumulation in the culture medium of these cells was only detectable under conditions that led to increased NAMN production from nicotinic acid. The amount of NAR released from cells engineered for increased NAMN production was sufficient to maintain viability of surrounding cells unable to use any other NAD precursor. Moreover, we found that untransfected HeLa cells produce and release sufficient amounts of NAR and NR under normal culture conditions. Collectively, our results indicate that cytosolic 5′-NTs participate in the conversion of NAD precursors and establish NR and NAR as integral constituents of human NAD metabolism. In addition, they point to the possibility that different cell types might facilitate each other's NAD supply by providing alternative precursors. PMID:26385918

  1. Generation, Release, and Uptake of the NAD Precursor Nicotinic Acid Riboside by Human Cells.

    Science.gov (United States)

    Kulikova, Veronika; Shabalin, Konstantin; Nerinovski, Kirill; Dölle, Christian; Niere, Marc; Yakimov, Alexander; Redpath, Philip; Khodorkovskiy, Mikhail; Migaud, Marie E; Ziegler, Mathias; Nikiforov, Andrey

    2015-11-06

    NAD is essential for cellular metabolism and has a key role in various signaling pathways in human cells. To ensure proper control of vital reactions, NAD must be permanently resynthesized. Nicotinamide and nicotinic acid as well as nicotinamide riboside (NR) and nicotinic acid riboside (NAR) are the major precursors for NAD biosynthesis in humans. In this study, we explored whether the ribosides NR and NAR can be generated in human cells. We demonstrate that purified, recombinant human cytosolic 5'-nucleotidases (5'-NTs) CN-II and CN-III, but not CN-IA, can dephosphorylate the mononucleotides nicotinamide mononucleotide and nicotinic acid mononucleotide (NAMN) and thus catalyze NR and NAR formation in vitro. Similar to their counterpart from yeast, Sdt1, the human 5'-NTs require high (millimolar) concentrations of nicotinamide mononucleotide or NAMN for efficient catalysis. Overexpression of FLAG-tagged CN-II and CN-III in HEK293 and HepG2 cells resulted in the formation and release of NAR. However, NAR accumulation in the culture medium of these cells was only detectable under conditions that led to increased NAMN production from nicotinic acid. The amount of NAR released from cells engineered for increased NAMN production was sufficient to maintain viability of surrounding cells unable to use any other NAD precursor. Moreover, we found that untransfected HeLa cells produce and release sufficient amounts of NAR and NR under normal culture conditions. Collectively, our results indicate that cytosolic 5'-NTs participate in the conversion of NAD precursors and establish NR and NAR as integral constituents of human NAD metabolism. In addition, they point to the possibility that different cell types might facilitate each other's NAD supply by providing alternative precursors.

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

    Science.gov (United States)

    Stoker, Astrid K; Markou, Athina

    2013-08-01

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

  3. 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.

  4. Nicotine vaccines for smoking cessation-present and future

    Directory of Open Access Journals (Sweden)

    Richa

    2013-01-01

    Full Text Available Background: Worldwide tobacco is the leading cause of preventable death. Anew treatment in smoking cessation and relapse prevention is nicotine vaccination which is based on active immunization against the nicotine molecule. This article aimed to review the mechanism of action, current status of research and future aspects for the development of vaccines against nicotine. Materials & Method: The literature search of publications indexed was carried out in PubMed, Medline, Google scholar databases. Total 25 animal trials, human trials under various phases of clinical trials, unpublished document and cross-sectional survey were reviewed. Results: This immunization will act on immune system to produce nicotine-specific antibodies that sequester nicotine in the blood stream, after inhaling tobacco products. Nicotine vaccines are irreversible, provide protection over years and need booster injections. Efficiency of the vaccines is directly related to the antibody levels which help to optimize the vaccine effect. Nicotine vaccines are today in an advanced stage of clinical evaluation trials. Conclusions: Though, nicotine vaccine has considerable therapeutic potential, they do not target the non pharmacological factors that maintain tobacco dependence. So combination of nicotine vaccine with behavioral interventions would be effective mode to motivate abstinence from tobacco use.

  5. Rigid analogs of DMPP as probes for the nicotinic receptors.

    Science.gov (United States)

    Guandalini, Luca; Martini, Elisabetta; Martelli, Cecilia; Romanelli, M Novella; Varani, Katia

    2005-02-01

    Chemical manipulation of the nicotinic agonist DMPP, endowed with modest activity on the central receptors, definitely improved its affinity and pharmacokinetic properties. Although their pharmacophore is somehow different from that of classical nicotinic ligands, some DMPP derivatives show low nanomolar affinity for the central nicotinic receptors. Introduction of rigidity in the structure of DMPP and in that of its analogue 1-(3-pyridyl)piperazine, resulted in molecules with lower or null affinity for the central nicotinic receptors. This suggests that the frozen structures chosen either do not represent the bioactive conformation, or their volume is not compatible with the space available within the interaction site.

  6. Effects of exogenous agents on brain development: stress, abuse and therapeutic compounds.

    Science.gov (United States)

    Archer, Trevor

    2011-10-01

    The range of exogenous agents likely to affect, generally detrimentally, the normal development of the brain and central nervous system defies estimation although the amount of accumulated evidence is enormous. The present review is limited to certain types of chemotherapeutic and "use-and-abuse" compounds and environmental agents, exemplified by anesthetic, antiepileptic, sleep-inducing and anxiolytic compounds, nicotine and alcohol, and stress as well as agents of infection; each of these agents have been investigated quite extensively and have been shown to contribute to the etiopathogenesis of serious neuropsychiatric disorders. To greater or lesser extent, all of the exogenous agents discussed in the present treatise have been investigated for their influence upon neurodevelopmental processes during the period of the brain growth spurt and during other phases uptill adulthood, thereby maintaining the notion of critical phases for the outcome of treatment whether prenatal, postnatal, or adolescent. Several of these agents have contributed to the developmental disruptions underlying structural and functional brain abnormalities that are observed in the symptom and biomarker profiles of the schizophrenia spectrum disorders and the fetal alcohol spectrum disorders. In each case, the effects of the exogenous agents upon the status of the affected brain, within defined parameters and conditions, is generally permanent and irreversible.

  7. 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...

  8. Relation between nicotine intake and Alzheimer's disease.

    OpenAIRE

    1991-01-01

    OBJECTIVE--To study the association between Alzheimer's disease and nicotine intake through smoking. DESIGN--Population based case-control study. SETTING--City of Rotterdam and four northern provinces of The Netherlands. SUBJECTS--198 patients with early onset Alzheimer's disease, 198 controls matched for age and sex, and families of 17 patients in whom Alzheimer's disease was apparently inherited as an autosomal dominant disorder. MAIN OUTCOME MEASURES--Age of onset of dementia, relative ris...

  9. An fMRI study of nicotine-deprived smokers' reactivity to smoking cues during novel/exciting activity.

    Directory of Open Access Journals (Sweden)

    Xiaomeng Xu

    Full Text Available Engaging in novel/exciting ("self-expanding" activities activates the mesolimbic dopamine pathway, a brain reward pathway also associated with the rewarding effects of nicotine. This suggests that self-expanding activities can potentially substitute for the reward from nicotine. We tested this model among nicotine-deprived smokers who, during fMRI scanning, played a series of two-player cooperative games with a relationship partner. Games were randomized in a 2 (self-expanding vs. not x 2 (cigarette cue present vs. absent design. Self-expansion conditions yielded significantly greater activation in a reward region (caudate than did non-self-expansion conditions. Moreover, when exposed to smoking cues during the self-expanding versus the non-self-expanding cooperative games, smokers showed less activation in a cigarette cue-reactivity region, a priori defined [temporo-parietal junction (TPJ] from a recent meta-analysis of cue-reactivity. In smoking cue conditions, increases in excitement associated with the self-expanding condition (versus the non-self-expanding condition were also negatively correlated with TPJ activation. These results support the idea that a self-expanding activity promoting reward activation attenuates cigarette cue-reactivity among nicotine-deprived smokers. Future research could focus on the parameters of self-expanding activities that produce this effect, as well as test the utility of self-expansion in clinical interventions for smoking cessation.

  10. Nicotine and cannabinoids: parallels, contrasts and interactions.

    Science.gov (United States)

    Viveros, Maria-Paz; Marco, Eva M; File, Sandra E

    2006-01-01

    After a brief outline of the nicotinic and cannabinoid systems, we review the interactions between the pharmacological effects of nicotine and cannabis, two of the most widely used drugs of dependence. These drugs are increasingly taken in combination, particularly among the adolescents and young adults. The review focuses on addiction-related processes, gateway and reverse gateway theories of addiction and therapeutic implications. It then reviews studies on the important period of adolescence, an area that is in urgent need of further investigation and in which the importance of sex differences is emerging. Three other areas of research, which might be particularly relevant to the onset and/or maintenance of dependence, are then reviewed. Firstly, the effects of the two drugs on anxiety-related behaviours are discussed and then their effects on food intake and cognition, two areas in which they have contrasting effects. Certain animal studies suggest that reinforcing effects are likely to be enhanced by joint consumption of nicotine and cannabis, as also may be anxiolytic effects. If this was the case in humans, the latter might be viewed as an advantage particularly by adolescent girls, although the increased weight gain associated with cannabis would be a disadvantage. The two drugs also have opposite effects on cognition and the possibility of long-lasting cognitive impairments resulting from adolescent consumption of cannabis is of particular concern.

  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.

  12. Limits of learning enhancements with nicotine in old male rats.

    Science.gov (United States)

    Taylor, George T; Bassi, Carl J; Weiss, Juergen

    2005-01-01

    Findings with young adult humans and animal models suggest that nicotine may serve both neuroprotective and cognition enhancing roles in old animals. A pair of experiments was conducted to examine drug-induced modification of the cholinergic nicotinic receptor subtype on rates of learning by young and aged rats. In experiment I males (4-7 months or 20-25 months old) were administered nicotine (0.0, 0.3 or 0.7 mg/kg injected s.c. daily) and tested in both a T-maze non-spatial discrimination paradigm and a hole board spatial task. Nicotine failed to improve acquisition by young animals on either task. Nicotine also failed to improve non-spatial learning by old animals. However, both dosages of nicotine improved performance by the old males in the spatial paradigm. In experiment II, a 5-choice serial discrimination paradigm designed to better evaluate visual attention and spatial working memory in aging was used. Groups of old male rats were administered nicotine or mecamylamine (2 or 8 mg/kg), an antagonist of the nicotinic cholinergic receptor. Results were that the 0.3 mg nicotine group learned the task fastest and achieved the highest learning asymptote. Both learning rates and final levels of performance were worst in the 8 mg mecamylamine group. However, the 2 mg mecamylamine rats were the equals of the control group and both reached a higher asymptote than the 0.7 mg nicotine group. These data suggest that healthy old animals can accrue benefits from nicotinic activation but that the benefits are complex, being limited to certain dosages and to specific cognitive skills.

  13. Impact of nicotine metabolism on nicotine's pharmacological effects and behavioral responses: insights from a Cyp2a(4/5)bgs-null mouse.

    Science.gov (United States)

    Li, Lei; Jia, Kunzhi; Zhou, Xin; McCallum, Sarah E; Hough, Lindsay B; Ding, Xinxin

    2013-12-01

    Nicotine metabolism is believed to affect not only nicotine's pharmacological effects but also nicotine addiction. As a key step toward testing this hypothesis, we have studied nicotine metabolism and nicotine's pharmacological and behavioral effects in a novel knockout mouse model [named Cyp2a(4/5)bgs-null] lacking a number of cytochrome P450 genes known to be or possibly involved in nicotine metabolism, including two Cyp2a and all Cyp2b genes. We found that, compared with wild-type mice, the Cyp2a(4/5)bgs-null mice showed >90% decreases in hepatic microsomal nicotine oxidase activity in vitro, and in rates of systemic nicotine clearance in vivo. Further comparisons of nicotine metabolism between Cyp2a(4/5)bgs-null and Cyp2a5-null mice revealed significant roles of both CYP2A5 and CYP2B enzymes in nicotine clearance. Compared with the behavioral responses in wild-type mice, the decreases in nicotine metabolism in the Cyp2a(4/5)bgs-null mice led to prolonged nicotine-induced acute pharmacological effects, in that null mice showed enhanced nicotine hypothermia and antinociception. Furthermore, we found that the Cyp2a(4/5)bgs-null mice developed a preference for nicotine in a conditioned place preference test, a commonly used test of nicotine's rewarding effects, at a nicotine dose that was 4-fold lower than what was required by wild-type mice. Thus, CYP2A/2B-catalyzed nicotine clearance affects nicotine's behavioral response as well as its acute pharmacological effects in mice. This result provides direct experimental support of the findings of pharmacogenetic studies that suggest linkage between rates of nicotine metabolism and smoking behavior in humans.

  14. The Activity and Enthalpy of Vaporization of Nicotine from Tobacco at Moderate Temperatures

    Directory of Open Access Journals (Sweden)

    St.Charles F. Kelley

    2016-01-01

    Full Text Available The vapor pressure of nicotine has been reported for unprotonated nicotine and for nicotine-water solutions. Yet no published values exist for nicotine in any commercially relevant matrix or for protonated forms (e.g., tobacco, smoke, electronic cigarette solutions, nicotine replacement products, nicotine salts. Therefore a methodology was developed to measure nicotine activity (defined as the vapor pressure from a matrix divided by the vapor pressure of pure nicotine. The headspace concentration of nicotine was measured for pure nicotine and tobacco stored at 23, 30, and 40 °C which allowed for conversion to vapor pressure and nicotine activity and for the estimation of enthalpy of vaporization. Burley, Flue-cured, Oriental, and cigarette blends were tested. Experiments were conducted with pure nicotine initially until the storage and sampling techniques were validated by comparison with previously published values. We found that the nicotine activity from tobacco was less than 1% with Burley > Flue-cured > Oriental. At 23 °C the nicotine vapor pressure averaged by tobacco type was 0.45 mPa for Oriental tobacco, 1.8 mPa for Flue-cured, 13 mPa for Burley while pure nicotine was 2.95 Pa. In general, the nicotine activity increased as the (calculated unprotonated nicotine concentration increased. The nicotine enthalpy of vaporization from tobacco ranged from 77 kJ/mol to 92 kJ/mol with no obvious trends with regard to tobacco origin, type, stalk position or even the wide range of nicotine activity. The mean value for all tobacco types was 86.7 kJ/mol with a relative standard deviation of 6.5% indicating that this was an intrinsic property of the nicotine form in tobacco rather than the specific tobacco properties. This value was about 30 kJ/mol greater than that of pure nicotine and is similar to the energy needed to remove a proton from monoprotonated nicotine.

  15. Effects of cigarette smoking and nicotine metabolite ratio on leukocyte telomere length.

    Science.gov (United States)

    Verde, Zoraida; Reinoso-Barbero, Luis; Chicharro, Luis; Garatachea, Nuria; Resano, Pilar; Sánchez-Hernández, Ignacio; Rodríguez González-Moro, Jose Miguel; Bandrés, Fernando; Santiago, Catalina; Gómez-Gallego, Félix

    2015-07-01

    Studies of the effects of smoking on leukocyte telomere length (LTL) using cigarettes smoked per day or pack years smoked (PYS) present limitations. Reported high levels of smoking may not increase toxin exposure levels proportionally. Nicotine metabolism ratio (NMR) predicts total cigarette puff volume and overall exposure based on total N-nitrosamines, is highly reproducible and independent of time since the last cigarette. We hypothesized that smokers with higher NMRs will exhibit increased total puff volume, reflecting efforts to extract more nicotine from their cigarettes and increasing toxin exposure. In addition, higher levels of smoking could cause a gross damage in LTL. The urinary cotinine, 3-OH cotinine and nicotine levels of 147 smokers were analyzed using a LC/MS system Triple-Q6410. LTL and CYP2A6 genotype was determined by PCR in blood samples. We found a significant association between NMR and CYP2A6 genotype. Reduction in LTL was seen in relation to accumulated tobacco consumption and years smoking when we adjusted for age and gender. However, there were no significant differences between NMR values and LTL. In our study the higher exposure was associated with lower number of PYS. Smokers with reduced cigarette consumption may exhibit compensatory smoking behavior that results in no reduced tobacco toxin exposure. Our results suggest that lifetime accumulated smoking exposure could cause a gross damage in LTL rather than NMR or PYS. Nevertheless, a combination of smoking topography (NMR) and consumption (PYS) measures may provide useful information about smoking effects on health outcomes.

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

    Science.gov (United States)

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

    1994-09-01

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

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

    Science.gov (United States)

    Mobascher, A; Winterer, G

    2008-09-01

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

  18. Nicotinamide metabolism in ferns: formation of nicotinic acid glucoside.

    Science.gov (United States)

    Ashihara, Hiroshi; Yin, Yuling; Watanabe, Shin

    2011-03-01

    The metabolic fate of [carbonyl-(14)C]nicotinamide was investigated in 9 fern species, Psilotum nudum, Angiopteris evecta, Lygodium japonicum, Acrostichum aureum, Asplenium antiquum, Diplazium subsinuatum, Thelypteris acuminate, Blechnum orientale and Crytomium fortune. All fern species produce a large quantity of nicotinic acid glucoside from [(14)C]nicotinamide, but trigonelline formation is very low. Increases in the release of (14)CO(2) with incubation time was accompanied by decreases in [carboxyl-(14)C]nicotinic acid glucoside. There was slight stimulation of nicotinic acid glucoside formation by 250 mM NaCl in mature leaves of the mangrove fern, Acrostichum aureum, but it is unlikely that this compound acts as a compatible solute. Nicotinamide and nicotinic acid salvage for pyridine nucleotide synthesis was detected in all fern species, although this activity was always less than nicotinic acid glucoside synthesis. Predominant formation of nicotinic acid glucoside is characteristic of nicotinic acid metabolism in ferns. This reaction appears to act as a detoxication mechanism, removing excess nicotinic acid.

  19. 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

  20. 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

  1. Noribogaine reduces nicotine self-administration in rats.

    Science.gov (United States)

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

    2015-06-01

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

  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 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...

  3. Nicotinic, glutamatergic and dopaminergic synaptic transmission and plasticity in the mesocorticolimbic system: focus on nicotine effects.

    Science.gov (United States)

    Pistillo, Francesco; Clementi, Francesco; Zoli, Michele; Gotti, Cecilia

    2015-01-01

    Cigarette smoking is currently the leading cause of preventable deaths and disability throughout the world, being responsible for about five million premature deaths/year. Unfortunately, fewer than 10% of tobacco users who try to stop smoking actually manage to do so. The main addictive agent delivered by cigarette smoke is nicotine, which induces psychostimulation and reward, and reduces stress and anxiety. The use of new technologies (including optogenetics) and the development of mouse models characterised by cell-specific deletions of receptor subtype genes or the expression of gain-of-function nAChR subunits has greatly increased our understanding of the molecular mechanisms and neural substrates of nicotine addiction first revealed by classic electrophysiological, neurochemical and behavioural approaches. It is now becoming clear that various aspects of nicotine dependence are mediated by close interactions of the glutamatergic, dopaminergic and γ-aminobutyric acidergic systems in the mesocorticolimbic system. This review is divided into two parts. The first provides an updated overview of the circuitry of the ventral tegmental area, ventral striatum and prefrontal cortex, the neurotransmitter receptor subtypes expressed in these areas, and their physiological role in the mesocorticolimbic system. The second will focus on the molecular, functional and behavioural mechanisms involved in the acute and chronic effects of nicotine on the mesocorticolimbic system.

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

    Science.gov (United States)

    Cruz, S L; Vidrio, H

    1997-01-01

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

  5. Early Life Stress, Nicotinic Acetylcholine Receptors and Alcohol Use Disorders

    Directory of Open Access Journals (Sweden)

    Joan Y. Holgate

    2015-06-01

    Full Text Available Stress is a major driving force in alcohol use disorders (AUDs. It influences how much one consumes, craving intensity and whether an abstinent individual will return to harmful alcohol consumption. We are most vulnerable to the effects of stress during early development, and exposure to multiple traumatic early life events dramatically increases the risk for AUDs. However, not everyone exposed to early life stress will develop an AUD. The mechanisms determining whether an individual’s brain adapts and becomes resilient to the effects of stress or succumbs and is unable to cope with stress remain elusive. Emerging evidence suggests that neuroplastic changes in the nucleus accumbens (NAc following early life stress underlie the development of AUDs. This review discusses the impact of early life stress on NAc structure and function, how these changes affect cholinergic signaling within the mesolimbic reward pathway and the role nicotinic acetylcholine receptors (nAChRs play in this process. Understanding the neural pathways and mechanism determining stress resilience or susceptibility will improve our ability to identify individuals susceptible to developing AUDs, formulate cognitive interventions to prevent AUDs in susceptible individuals and to elucidate and enhance potential therapeutic targets, such as the nAChRs, for those struggling to overcome an AUD.

  6. 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.

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

    Directory of Open Access Journals (Sweden)

    Herman S. Cheung

    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.

  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. Nicotine evoked improvement in learning and memory is mediated through NPY Y1 receptors in rat model of Alzheimer's disease.

    Science.gov (United States)

    Rangani, Ritesh J; Upadhya, Manoj A; Nakhate, Kartik T; Kokare, Dadasaheb M; Subhedar, Nishikant K

    2012-02-01

    We investigated the role of endogenous neuropeptide Y (NPY) system in nicotine-mediated improvement of learning and memory in rat model of Alzheimer's disease (AD). Intracerebroventricular (icv) colchicine treatment induced AD-like condition in rats and showed increased escape latency (decreased learning), and amnesic condition in probe test in Morris water maze. In these rats, nicotine (0.5mg/kg, intraperitoneal), NPY (100 ng/rat, icv) or NPY Y1 receptor agonist [Leu(31), Pro(34)]-NPY (0.04 ng/rat, icv) decreased escape latency by 54.76%, 55.81% and 44.18%, respectively, on day 4 of the acquisition. On the other hand, selective NPY Y1 receptor antagonist, BIBP3226 (icv) produced opposite effect (44.18%). In the probe test conducted at 24h time point, nicotine, NPY or [Leu(31), Pro(34)]-NPY increased the time spent by 72.72%, 44.11% and 26.47%, respectively; while BIBP3226 caused reduction (8.82%). It seems that while NPY or [Leu(31), Pro(34)]-NPY potentiated, BIBP3226 attenuated the learning and memory enhancing effects of nicotine. Brains of colchicine treated rats showed significant reduction in NPY-immunoreactivity in the nucleus accumbens shell (cells 62.23% and fibers 50%), bed nucleus of stria terminalis (fibers 71.58%), central nucleus of amygdala (cells 74.33%), arcuate nucleus (cells 70.97% and fibers 69.65%) and dentate gyrus (cells 58.54%). However, in these rats nicotine treatment for 4 days restored NPY-immunoreactivity to the control level. We suggest that NPY, perhaps acting via NPY Y1 receptors, might interact with the endogenous cholinergic system and play a role in improving the learning and memory processes in the rats with AD-like condition.

  10. Combined exposure to nicotine and ethanol in adolescent mice differentially affects memory and learning during exposure and withdrawal.

    Science.gov (United States)

    Abreu-Villaça, Yael; Medeiros, Ana H; Lima, Carla S; Faria, Felipe P; Filgueiras, Cláudio C; Manhães, Alex C

    2007-07-19

    Human adolescents often associate tobacco smoking and consumption of alcoholic beverages. In spite of this frequent association, little is known about the basic neurobiology of the dual exposure in the adolescent brain. In the present work, we assessed, through the use of the step-through passive avoidance box (2mA, 2s; test-retest interval of 24h), short- and long-term memory/learning effects of nicotine (NIC) and/or ethanol (ETOH) exposure during adolescence (postnatal days 30-45: PN30-45) in four groups of male and female C57BL/6 mice: (1) concomitant NIC [nicotine free base solution (50microg/ml) in 2% saccharin to drink] and ETOH [ethanol solution (25%, 2g/kg) i.p. injected every other day] exposure; (2) NIC exposure; (3) ETOH exposure; (4) vehicle. During exposure (PN44-45), deficits in memory/learning due to concomitant NIC+ETOH exposure reflected the summation of the two individual sets of effects. During a short-term drug withdrawal (PN49-50), nicotine improved memory/learning, however, ethanol blocked nicotine-induced improvements. One month post-exposure (PN74-75), a significant female-only improvement in memory/learning was observed as a result of co-administration. In conclusion, our results suggest that detrimental effects of nicotine and ethanol on memory/learning during adolescent combined exposure represent a worsened outcome from the dual exposure. However, negative effects of the combined exposure fail to persist during withdrawal. In fact, the combined exposure elicits a sex-dependent late onset beneficial effect on memory/learning during withdrawal.

  11. 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.

  12. Alteration in nicotine binding sites in Parkinson's disease, Lewy body dementia and Alzheimer's disease: possible index of early neuropathology.

    Science.gov (United States)

    Perry, E K; Morris, C M; Court, J A; Cheng, A; Fairbairn, A F; McKeith, I G; Irving, D; Brown, A; Perry, R H

    1995-01-01

    High-affinity nicotine binding, considered to primarily reflect the presence of CNS alpha 4 beta 2 nicotinic receptor subunits, was examined autoradiographically in brain regions most severely affected by Alzheimer and Parkinson types of pathology. In the midbrain, the high density of binding associated with the pars compacta of the substantia nigra was extensively reduced (65-75%, particularly in the lateral portion) in both Lewy body dementia and Parkinson's disease. Since loss of dopaminergic neurons in Lewy body dementia was only moderate (40%), loss or down-regulation of the nicotinic receptor may precede degeneration of dopaminergic neurons in this region. In the dorsolateral tegmentum, where diffuse cholinergic perikarya are located, nicotine binding was highly significantly decreased in both Lewy body dementia and Parkinson's disease with almost no overlap between the normal and disease groups, indicative of a major pathological involvement in or around the pedunculopontine cholinergic neurons. In the hippocampus, binding was decreased around the granular layer in Lewy body dementia and Alzheimer's disease, although unchanged in the stratum lacunosum moleculare, where binding was relatively higher. Dense bands of receptor binding in the presubiculum and parahippocampal gyrus--areas of highest binding in human cortex--were diminished in Alzheimer's disease but not Lewy body dementia. In temporal neocortex there were reductions in Alzheimer's disease throughout the cortical layers but in Lewy body dementia only in lower layers, in which Lewy bodies are concentrated. Abnormalities of the nicotinic receptor in the diseases examined appear to be closely associated with primary histopathological changes: dopaminergic cell loss in Parkinson's disease and Lewy body dementia, amyloid plaques and tangles in subicular and entorhinal areas in Alzheimer's disease. Loss or down-regulation of the receptor may precede neurodegeneration.

  13. NEURODEGENERATION WITH IRON ACCUMULATION TYPE1

    Directory of Open Access Journals (Sweden)

    Shrikhande D Y

    2010-03-01

    Full Text Available Neurodegeneration with iron accumulation type 1 is a rare degenerative disorder presenting with dementia and progressive extrapyramidal dysfunction. A 10 yrs old girl reported with complaints of difficulty in speech and involuntary movements. MRI Brain showed ‘eye of tiger appearance’ which is suggestive of neurodegeneration with iron accumulation type 1. Treatment is symptomatic and chelating agents have no effect. The disease is progressivelyfatal

  14. 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

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

    Science.gov (United States)

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

    2007-01-01

    Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.

  16. Nicotine-Derived Compounds as Therapeutic Tools Against Post-Traumatic Stress Disorder.

    Science.gov (United States)

    Barreto, George E; Yarkov, Alexander; Avila-Rodriguez, Marcos; Aliev, Gjumrakch; Echeverria, Valentina

    2015-01-01

    Post-traumatic stress disorder (PTSD) is an anxiety disorder that develops after experiencing trauma. Actual therapies do not help majority of patients with PTSD. Moreover, extinguished fear memories usually reappear in the individuals when exposed to trauma cues. New drugs to reduce the impact of conditioned cues in eliciting abnormal fear responses are urgently required. Cotinine, the main metabolite of nicotine, decreased anxiety and depressive-like behavior, and enhanced fear extinction in mouse models of PTSD. Cotinine, considered a positive modulator of the α7 nicotinic acetylcholine receptor (α7nAChR), enhances fear extinction in rodents in a manner dependent on the activity of the αnAChRs. Cotinine stimulates signaling pathways downstream of α7nAChR including the protein kinase B (Akt)/glycogen synthase kinase 3β (GSK3β) pathway and the extracellular signal-regulated kinases (ERKs). The stimulation of these factors promotes synaptic plasticity and the extinction of fear. In this review, we discuss the hypothesis that cotinine relieves PTSD symptoms and facilitates fear memory extinction by promoting brain plasticity through the positive modulation of presynaptic nAChRs and its effectors in the brain.

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

    Science.gov (United States)

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

    2006-11-03

    Nicotine, the primary addictive substance in tobacco, induces profound behavioral responses in mammals, but the underlying genetic mechanisms are not well understood. Here we develop a C. elegans model of nicotine-dependent behavior. We show that worms exhibit behavioral responses to nicotine that parallel those observed in mammals, including acute response, tolerance, withdrawal, and sensitization. These nicotine responses require nicotinic acetylcholine receptor (nAChR) family genes that are known to mediate nicotine dependence in mammals, suggesting functional conservation of nAChRs in nicotine responses. Importantly, we find that mutant worms lacking TRPC (transient receptor potential canonical) channels are defective in their response to nicotine and that such a defect can be rescued by a human TRPC channel, revealing an unexpected role for TRPC channels in regulating nicotine-dependent behavior. Thus, C. elegans can be used to characterize known genes as well as to identify new genes regulating nicotine responses.

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

    Science.gov (United States)

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

    2010-01-01

    Summary Nicotine, the primary addictive substance in tobacco, induces profound behavioral responses in mammals, but the underlying genetic mechanisms are not well understood. Here we develop a C. elegans model of nicotine-dependent behavior. We show that worms exhibit behavioral responses to nicotine that parallel those observed in mammals, including acute response, tolerance, withdrawal and sensitization. These nicotine responses require nicotinic acetylcholine receptor (nAChR) family genes that are known to mediate nicotine dependence in mammals, suggesting functional conservation of nAChRs in nicotine responses. Importantly, we find that mutant worms lacking TRPC (transient-receptor-potential canonical) channels are defective in response to nicotine and that such a defect can be rescued by a human TRPC channel, revealing an unexpected role for TRPC channels in regulating nicotine-dependent behavior. Thus, C. elegans can be used to characterize known genes as well as to identify new genes regulating nicotine responses. PMID:17081982

  19. Behavioral effects of nicotine exposure from secondhand tobacco smoke among bar and restaurant workers.

    Science.gov (United States)

    Okoli, Chizimuzo T C; Rayens, Mary Kay; Hahn, Ellen J

    2007-09-01

    This study explores the behavioral effects of nicotine exposure from secondhand tobacco smoke (SHS) on bar and restaurant workers. Baseline data were obtained from a longitudinal study of 105 bar and restaurant workers. Hair nicotine, self-reported SHS exposure, smoking status, symptoms of nicotine exposure after being exposed to a smoky environment, and nicotine dependence were assessed. Nonsmokers reporting four or more symptoms of nicotine exposure had higher hair nicotine levels than those reporting less than four symptoms. Nonsmokers with higher hair nicotine levels were 2.2 times more likely to report 4 or more behavioral symptoms. Self-reported secondhand tobacco smoke exposure and hair nicotine were not predictive of nicotine dependence among smokers. Nicotine exposure from secondhand tobacco smoke may have important behavioral outcomes in nonsmokers. This study provides further evidence for the importance of prohibiting smoking in hospitality venues to protect the health of workers.

  20. Cellular trafficking of nicotinic acetylcholine receptors

    Institute of Scientific and Technical Information of China (English)

    Paul A ST JOHN

    2009-01-01

    Nicotinic acetylcholine receptors (nAChRs) play critical roles throughout the body. Precise regulation of the cellular location and availability of nAChRs on neurons and target cells is critical to their proper function. Dynamic, post-translational regulation of nAChRs, particularly control of their movements among the different compartments of cells, is an important aspect of that regulation. A combination of new information and new techniques has the study of nAChR trafficking poised for new breakthroughs.

  1. Conotoxins Targeting Nicotinic Acetylcholine Receptors: An Overview

    OpenAIRE

    2014-01-01

    Marine snails of the genus Conus are a large family of predatory gastropods with an unparalleled molecular diversity of pharmacologically active compounds in their venom. Cone snail venom comprises of a rich and diverse cocktail of peptide toxins which act on a wide variety of ion channels such as voltage-gated sodium- (NaV), potassium- (KV), and calcium- (CaV) channels as well as nicotinic acetylcholine receptors (nAChRs) which are classified as ligand-gated ion channels. The mode of action ...

  2. 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.

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

    Science.gov (United States)

    Neumann, Silke; Shields, Nicholas J; Balle, Thomas; Chebib, Mary; Clarkson, Andrew N

    2015-12-04

    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.

  4. 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.

  5. 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.

  6. Expectancy and Pharmacology Influence the Subjective Effects of Nicotine using a Balanced-Placebo Design

    OpenAIRE

    Kelemen, William L.; Kaighobadi, Farnaz

    2007-01-01

    The expectancy and pharmacological effects of nicotine (0.60 mg) on memory and the subjective effects of cigarettes were examined using a balanced-placebo design (i.e., expect either nicotine or no nicotine and receive either nicotine or no nicotine). A total of 120 college students who smoke were assigned to 1 of the 4 experimental groups and rated the cigarettes on a number of dimensions and completed questionnaires on smoking urges, tension, and energy. Participants also completed tests of...

  7. Intensification of long-term memory deficit by chronic stress and prevention by nicotine in a rat model of Alzheimer's disease.

    Science.gov (United States)

    Alkadhi, Karim A; Srivareerat, Marisa; Tran, Trinh T

    2010-11-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cholinergic dysfunction and deposition of beta-amyloid (Aβ) in regions of the brain associated with learning and memory. The sporadic nature and late onset of most AD cases suggests that aside from biological determinants, environmental factors such as stress may also play a role in the progression of the disease. Behavioral and molecular studies were utilized to evaluate the effects of chronic nicotine treatment in the prevention of impairment of long-term memory. The rat model of AD was induced by i.c.v. osmotic pump infusion of Aβ peptides. Chronic psychosocial stress and chronic nicotine treatment were instituted for 6weeks. Spatial memory testing in the Radial Arm Water Maze revealed that, although stress, by itself, did not affect long-term memory, the combination of chronic stress and Aβ infusion impaired long-term memory significantly more than Aβ peptides infusion alone. Chronic nicotine treatment completely prevented Aβ- and stress/Aβ combination-induced memory impairment. Furthermore, molecular findings in hippocampal CA1 region of stress/Aβ rats indicated marked reduction in the protein levels of phosphorylated cAMP response element binding (p-CREB) and calcium-calmodulin-dependent protein kinase IV (CaMKIV), with significant increases in the levels of brain-derived neurotrophic factor (BDNF). These disturbances in signaling pathways, which may be the underlying mechanisms of impairment of long-term memory in these rats, were totally prevented by chronic nicotine treatment.

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

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    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

  9. Mimicking maternal smoking and pharmacotherapy of preterm labor: fetal nicotine exposure enhances the effect of late gestational dexamethasone treatment on noradrenergic circuits.

    Science.gov (United States)

    Slotkin, Theodore A; Seidler, Frederic J

    2011-11-25

    Smoking during pregnancy increases the risk of preterm delivery, which in turn necessitates the common use of glucocorticoids to prevent respiratory distress syndrome. Accordingly, there is a substantial population exposed conjointly to fetal nicotine and glucocorticoids (typically dexamethasone). We administered nicotine to pregnant rats throughout gestation, using a regimen (3 mg/kg/day by osmotic minipump) that maintains plasma nicotine levels within the range seen in smokers; on gestational days 17, 18 and 19, we gave 0.2 mg/kg of dexamethasone. We assessed norepinephrine levels in three brain regions (frontal/parietal cortex, brainstem, cerebellum) throughout adolescence, young adulthood and later adulthood, and contrasted the persistent effects with comparable measures in peripheral tissues (heart, liver). In adolescence, males showed initial deficits in the frontal/parietal cortex with either dexamethasone alone or the combined treatment, with resolution to normal by young adulthood; the group exposed to both nicotine+dexamethasone showed subsequent elevations that emerged in full adulthood and persisted through five months of age, an effect not seen with either agent separately. In females, the combined exposure produced an initial deficit that resolved by young adulthood, without any late-emerging changes. We did not see comparable effects in the other brain regions or peripheral tissues. This indicates that nicotine exposure sensitizes the developing brain to the adverse effects of dexamethasone treatment, producing sex-selective changes in innervation and/or activity of specific noradrenergic circuits. The fact that the combined treatment produced greater effects points to potentially worsened neurobehavioral outcomes after pharmacotherapy of preterm labor in the offspring of smokers.

  10. MOLECULAR MECHANISMS REGULATING LPS-INDUCED INFLAMMATION IN THE BRAIN

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    Olena eLykhmus

    2016-03-01

    Full Text Available Neuro-inflammation, one of the pathogenic causes of neurodegenerative diseases, is regulated through the cholinergic anti-inflammatory pathway via the 7 nicotinic acetylcholine receptor (7 nAChR. We previously showed that either bacterial lipopolysaccharide (LPS or immunization with the 7(1-208 nAChR fragment decrease 7 nAChRs density in the mouse brain, exacerbating chronic inflammation, beta-amyloid accumulation and episodic memory decline, which mimic the early stages of Alzheimer’s disease. To study the molecular mechanisms underlying the LPS and antibody effects in the brain, we employed an in vivo model of acute LPS-induced inflammation and an in vitro model of cultured glioblastoma U373 cells. Here, we report that LPS challenge decreased the levels of 7 nAChR RNA and protein and of acetylcholinesterase (AChE RNA and activity in distinct mouse brain regions, sensitized brain mitochondria to the apoptogenic effect of Ca2+ and modified brain microRNA profiles, including the cholinergic-regulatory CholinomiRs-132/212, in favor of anti-inflammatory and pro-apoptotic ones. Adding 7(1-208-specific antibodies to the LPS challenge prevented elevation of both the anti-inflammatory and pro-apoptotic miRNAs while supporting the resistance of brain mitochondria to Ca2+ and maintaining 7 nAChR/AChE decreases. In U373 cells, 7-specific antibodies and LPS both stimulated interleukin-6 production through the p38/Src-dependent pathway. Our findings demonstrate that acute LPS-induced inflammation induces the cholinergic anti-inflammatory pathway in the brain, that 7 nAChR down-regulation limits this pathway, and that 7-specific antibodies aggravate neuroinflammation by inducing the pro-inflammatory interleukin-6 and dampening anti-inflammatory miRNAs; however, these antibodies may protect brain mitochondria and decrease the levels of pro-apoptotic miRNAs, preventing LPS-induced neurodegeneration.

  11. Molecular Mechanisms Regulating LPS-Induced Inflammation in the Brain

    Science.gov (United States)

    Lykhmus, Olena; Mishra, Nibha; Koval, Lyudmyla; Kalashnyk, Olena; Gergalova, Galyna; Uspenska, Kateryna; Komisarenko, Serghiy; Soreq, Hermona; Skok, Maryna

    2016-01-01

    Neuro-inflammation, one of the pathogenic causes of neurodegenerative diseases, is regulated through the cholinergic anti-inflammatory pathway via the α7 nicotinic acetylcholine receptor (α7 nAChR). We previously showed that either bacterial lipopolysaccharide (LPS) or immunization with the α7(1–208) nAChR fragment decrease α7 nAChRs density in the mouse brain, exacerbating chronic inflammation, beta-amyloid accumulation and episodic memory decline, which mimic the early stages of Alzheimer’s disease (AD). To study the molecular mechanisms underlying the LPS and antibody effects in the brain, we employed an in vivo model of acute LPS-induced inflammation and an in vitro model of cultured glioblastoma U373 cells. Here, we report that LPS challenge decreased the levels of α7 nAChR RNA and protein and of acetylcholinesterase (AChE) RNA and activity in distinct mouse brain regions, sensitized brain mitochondria to the apoptogenic effect of Ca2+ and modified brain microRNA profiles, including the cholinergic-regulatory CholinomiRs-132/212, in favor of anti-inflammatory and pro-apoptotic ones. Adding α7(1–208)-specific antibodies to the LPS challenge prevented elevation of both the anti-inflammatory and pro-apoptotic miRNAs while supporting the resistance of brain mitochondria to Ca2+ and maintaining α7 nAChR/AChE decreases. In U373 cells, α7-specific antibodies and LPS both stimulated interleukin-6 production through the p38/Src-dependent pathway. Our findings demonstrate that acute LPS-induced inflammation induces the cholinergic anti-inflammatory pathway in the brain, that α7 nAChR down-regulation limits this pathway, and that α7-specific antibodies aggravate neuroinflammation by inducing the pro-inflammatory interleukin-6 and dampening anti-inflammatory miRNAs; however, these antibodies may protect brain mitochondria and decrease the levels of pro-apoptotic miRNAs, preventing LPS-induced neurodegeneration. PMID:27013966

  12. Perinatal hypoxia-ischemia reduces α 7 nicotinic receptor expression and selective α 7 nicotinic receptor stimulation suppresses inflammation and promotes microglial Mox phenotype.

    Science.gov (United States)

    Hua, Sansan; Ek, C Joakim; Mallard, Carina; Johansson, Maria E

    2014-01-01

    Inflammation plays a central role in neonatal brain injury. During brain inflammation the resident macrophages of the brain, the microglia cells, are rapidly activated. In the periphery, α 7 nicotinic acetylcholine receptors ( α 7R) present on macrophages can regulate inflammation by suppressing cytokine release. In the current study we investigated α 7R expression in neonatal mice after hypoxia-ischemia (HI). We further examined possible anti-inflammatory role of α 7R stimulation in vitro and microglia polarization after α 7R agonist treatment. Real-time PCR analysis showed a 33% reduction in α 7R expression 72 h after HI. Stimulation of primary microglial cells with LPS in combination with increasing doses of the selective α 7R agonist AR-R 17779 significantly attenuated TNF α release and increased α 7R transcript in microglial cells. Gene expression of M1 markers CD86 and iNOS, as well as M2 marker CD206 was not influenced by LPS and/or α 7R agonist treatment. Further, Mox markers heme oxygenase (Hmox1) and sulforedoxin-1 (Srx1) were significantly increased, suggesting a polarization towards the Mox phenotype after α 7R stimulation. Thus, our data suggest a role for the α 7R also in the neonatal brain and support the anti-inflammatory role of α 7R in microglia, suggesting that α 7R stimulation could enhance the polarization towards a reparative Mox phenotype.

  13. Perinatal Hypoxia-Ischemia Reduces α7 Nicotinic Receptor Expression and Selective α7 Nicotinic Receptor Stimulation Suppresses Inflammation and Promotes Microglial Mox Phenotype

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    Sansan Hua

    2014-01-01

    Full Text Available Inflammation plays a central role in neonatal brain injury. During brain inflammation the resident macrophages of the brain, the microglia cells, are rapidly activated. In the periphery, α7 nicotinic acetylcholine receptors (α7R present on macrophages can regulate inflammation by suppressing cytokine release. In the current study we investigated α7R expression in neonatal mice after hypoxia-ischemia (HI. We further examined possible anti-inflammatory role of α7R stimulation in vitro and microglia polarization after α7R agonist treatment. Real-time PCR analysis showed a 33% reduction in α7R expression 72 h after HI. Stimulation of primary microglial cells with LPS in combination with increasing doses of the selective α7R agonist AR-R 17779 significantly attenuated TNFα release and increased α7R transcript in microglial cells. Gene expression of M1 markers CD86 and iNOS, as well as M2 marker CD206 was not influenced by LPS and/or α7R agonist treatment. Further, Mox markers heme oxygenase (Hmox1 and sulforedoxin-1 (Srx1 were significantly increased, suggesting a polarization towards the Mox phenotype after α7R stimulation. Thus, our data suggest a role for the α7R also in the neonatal brain and support the anti-inflammatory role of α7R in microglia, suggesting that α7R stimulation could enhance the polarization towards a reparative Mox phenotype.

  14. Cooperative regulation of non-small cell lung carcinoma by nicotinic and beta-adrenergic receptors: a novel target for intervention.

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    Hussein A N Al-Wadei

    Full Text Available Lung cancer is the leading cause of cancer death; 80-85% of lung cancer cases are non-small cell lung cancer (NSCLC. Smoking is a documented risk factor for the development of this cancer. Although nicotine does not have the ability to initiate carcinogenic events, recent studies have implicated nicotine in growth stimulation of NSCLC. Using three NSCLC cell lines (NCI-H322, NCI-H441 and NCI-H1299, we identified the cooperation of nicotinic acetylcholine receptors (nAChRs and β-adrenergic receptors (β-ARs as principal regulators of these effects. Proliferation was measured by thymidine incorporation and MTT assays, and Western blots were used to monitor the upregulation of the nAChRs and activation of signaling molecules. Noradrenaline and GABA were measured by immunoassays. Nicotine-treated NSCLC cells showed significant induction of the α7nAChR and α4nAChR, along with significant inductions of p-CREB and p-ERK1/2 accompanied by increases in the stress neurotransmitter noradrenaline, which in turn led to the observed increase in DNA synthesis and cell proliferation. Effects on cell proliferation and signaling proteins were reversed by the α7nAChR antagonist α-BTX or the β-blocker propranolol. Nicotine treatment also down-regulated expression of the GABA synthesizing enzyme GAD 65 and the level of endogenous GABA, while treatment of NSCLC cells with GABA inhibited cell proliferation. Interestingly, GABA acts by reducing β-adrenergic activated cAMP signaling. Our findings suggest that nicotine-induced activation of this autocrine noradrenaline-initiated signaling cascade and concomitant deficiency in inhibitory GABA, similar to modulation of these neurotransmitters in the nicotine-addicted brain, may contribute to the development of NSCLC in smokers. Our data suggest that exposure to nicotine either by tobacco smoke or nicotine supplements facilitates growth and progression of NSCLC and that pharmacological intervention by β blocker may

  15. Direct action and modulating effect of (+)- and (-)-nicotine on ion channels expressed in trigeminal sensory neurons.

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    Schreiner, Benjamin S P; Lehmann, Ramona; Thiel, Ulrike; Ziemba, Paul M; Beltrán, Leopoldo R; Sherkheli, Muhammad A; Jeanbourquin, Philippe; Hugi, Alain; Werner, Markus; Gisselmann, Günter; Hatt, Hanns

    2014-04-05

    Nicotine sensory perception is generally thought to be mediated by nicotinic acetylcholine (nACh) receptors. However, recent data strongly support the idea that other receptors (e.g., transient receptor potential A1 channel, TRPA1) and other pathways contribute to the detection mechanisms underlying the olfactory and trigeminal cell response to nicotine flavor. This is in accordance with the reported ability of humans to discriminate between (+)- and (-)- nicotine enantiomers. To get a more detailed understanding of the molecular and cellular basis underlying the sensory perception of nicotine, we studied the activity of (+)- and (-)-nicotine on cultured murine trigeminal sensory neurons and on a range of heterologously expressed receptors. The human TRPA1 channel is activated by (-)-nicotine. In this work, we show that (+)-nicotine is also an activator of this channel. Pharmacological experiments using nicotinic acetylcholine receptors and transient receptor potential blockers revealed that trigeminal neurons express one or more unidentified receptors that are sensitive to (+)- and/or (-)-nicotine. Results also indicate that the presence of extracellular calcium ions is required to elicit trigeminal neuron responses to (+)- and (-)-nicotine. Results also show that both (+)-nicotine and (-)-nicotine can block 5-hydroxytryptamine type 3 (5-HT3) receptor-mediated responses in recombinant expression systems and in cultured trigeminal neurons expressing 5-HT3 receptors. Our investigations broaden the spectra of receptors that are targets for nicotine enantiomers and give new insights into the physiological role of nicotine.

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

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

    2017-01-11

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

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

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

    2017-01-01

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

  18. Schizophrenia and the alpha7 nicotinic acetylcholine receptor.

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    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.

  19. Nicotine effects and the endogenous opioid system.

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    Kishioka, Shiroh; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro

    2014-01-01

    Nicotine (NIC) is an exogenous ligand of the nicotinic acetylcholine receptor (nAChR), and it influences various functions in the central nervous system. Systemic administration of NIC elicits the release of endogenous opioids (endorphins, enkephalins, and dynorphins) in the supraspinal cord. Additionally, systemic NIC administration induces the release of methionine-enkephalin in the spinal dorsal horn. NIC has acute neurophysiological actions, including antinociceptive effects, and the ability to activate the hypothalamic-pituitary-adrenal (HPA) axis. The endogenous opioid system participates in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception is mediated by α4β2 and α7 nAChRs, while NIC-induced HPA axis activation is mediated by α4β2, not α7, suggesting that the effects of NIC on the endogenous opioid system are mediated by α7, not α4β2. NIC has substantial physical dependence liability. The opioid-receptor antagonist naloxone (NLX) elicits NIC withdrawal after repeated NIC administration, and NLX-induced NIC withdrawal is inhibited by concomitant administration of an opioid-receptor antagonist. NLX-induced NIC withdrawal is also inhibited by concomitant administration of an α7 antagonist, but not an α4β2 antagonist. Taken together, these findings suggest that NIC-induced antinociception and the development of physical dependence are mediated by the endogenous opioid system, via the α7 nAChR.

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

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

    2016-06-01

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

  1. Carbon disulfide mediates socially-acquired nicotine self-administration.

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    Tengfei Wang

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

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

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

    2014-01-01

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

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

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    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.

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

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

    2005-11-25

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

  5. Characterization of a series of anabaseine-derived compounds reveals that the 3-(4)-dimethylaminocinnamylidine derivative is a selective agonist at neuronal nicotinic alpha 7/125I-alpha-bungarotoxin receptor subtypes.

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    de Fiebre, C M; Meyer, E M; Henry, J C; Muraskin, S I; Kem, W R; Papke, R L

    1995-01-01

    Investigation of the naturally occurring, nicotinic agonist anabaseine and novel derivatives has shown that these compounds have cytoprotective and memory-enhancing effects. The hypothesis that these arise at least in part through actions on brain nicotinic receptors was evaluated by examining the ability of these compounds to displace the binding of nicotinic ligands and to affect the function of the alpha 4 beta 2 and alpha 7 receptor subtypes expressed in Xenopus oocytes. The derivative 3-(4)-dimethylaminocinnamylidine anabaseine (DMAC) was found to be a selective alpha 7 receptor agonist; it was more potent than nicotine, acetylcholine, anabaseine, and other derivatives at activating the alpha 7 receptor subtype, while displaying little agonist activity at alpha 4 beta 2 and other receptor subtypes. Compared with anabaseine and the other derivatives, DMAC was the most potent at displacing 125I-alpha-bungarotoxin binding (putative alpha 7) and the least potent at displacing [3H]cytisine binding (putative alpha 4 beta 2) to brain membranes. Independently of agonist activities, all of the novel compounds displayed secondary inhibitory activity at both receptor subtypes. At the alpha 4 beta 2 receptor subtype, inhibition by the 3-(2,4)-dimethoxybenzylidene derivative was enhanced by coapplication of acetylcholine, suggesting a noncompetitive form of inhibition. Anabaseine and nicotine prolonged the time course of activation of alpha 4 beta 2 receptors, compared with acetylcholine, suggesting sequential channel-blocking activity. As selective agonists, anabaseine derivatives such as DMAC may be useful for elucidating the function of alpha 7 nicotinic receptors, including their potential role(s) in the cytoprotective and memory-enhancing effects of nicotinic agents.

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

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

    2007-05-01

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

  7. Presynaptic calcium stores contribute to nicotine-elicited potentiation of evoked synaptic transmission at CA3-CA1 connections in the neonatal rat hippocampus.

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    Le Magueresse, Corentin; Cherubini, Enrico

    2007-01-01

    Nicotine acetylcholine (ACh) receptors (nAChRs) are ligand-gated ion channels that are widely expressed throughout the central nervous system. It is well established that presynaptic, alpha7-containing nAChRs modulate glutamate release in several brain areas, and that this modulation requires extracellular calcium. However, the intracellular mechanisms consecutive to nAChR opening are unclear. Recent studies have suggested a role for presynaptic calcium stores in the increase of neurotransmitter release following nAChR activation. Using the minimal stimulation protocol at low-probability Schaffer collateral synapses in acute hippocampal slices from neonatal rats, we show that nicotine acting on presynaptic alpha7 nAChRs persistently upregulates glutamate release. We tested the role of calcium stores in this potentiation. First, we examined the relationship between calcium stores and glutamate release. We found that bath application of SERCA pump inhibitors (cyclopiazonic acid and thapsigargin), as well as an agonist of ryanodine receptors (ryanodine 2 microM) increases the probability of glutamate release at CA3-CA1 synapses, decreases the coefficient of variation and the paired-pulse ratio, indicating that presynaptic activation of calcium-induced calcium release can modulate glutamatergic transmission. Next, we investigated whether blocking calcium release from internal stores could alter the effect of nicotine. Preincubation with thapsigargin (10 microM), cyclopiazonic acid (30 microM), or with a high (blocking) concentration of ryanodine (100 microM) for 30 min to 5 h failed to block the effect of nicotine. However, after preincubation in ryanodine, nicotine-elicited potentiation was significantly shortened. These results indicate that at immature Schaffer collateral-CA1 synapses, activation of presynaptic calcium stores is not necessary for but contributes to nicotine-elicited increase of neurotransmitter release.

  8. Probing into the Interaction of Nicotine and Bovine Submaxillary Mucin: NMR, Fluorescence, and FTIR Approaches

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    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.

  9. Nicotine and the effect of antisympathomimetic agents on the aorta of the rabbit.

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    MILLSON, D R

    1959-06-01

    The responses of strips of rabbit aorta to almost maximal doses of nicotine were less readily antagonized by five antisympathomimetic agents than were comparable responses to noradrenaline. The effect was most marked with dibenamine, ergotamine, and tolazoline: approximately twice the dose of noradrenaline was required to match the test dose of nicotine after treatment with the antagonists. Dose/response curves for nicotine before and after phentolamine 10(-7) indicate that the phenomenon may be reversed with low doses of nicotine and that the release of noradrenaline by nicotine within the tissues is probably a graded response. The pattern of nicotine/phentolamine antagonism in this preparation is consistent with the view that nicotine acts indirectly by releasing a noradrenaline-like substance, and the difficulty found in antagonizing responses to nicotine with antisympathomimetic agents is probably similar to that responsible for failure of atropine to block some parasympathomimetic responses to nicotine.

  10. Animal models of nicotine exposure: relevance to second-hand smoking, electronic cigarette use and compulsive smoking

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    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.

  11. The effects of nicotine injection in rat nucleus accumbens on anxiety

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    Ghorbani Yekta B

    2013-05-01

    Full Text Available Background: Previous reports showed that nucleus accumbens involved in the etiology and pathophysiology of major depression, anxiety and addiction. It is not clear that how these mechanisms occur in the brain. In the present study, the influence of direct nicotine injection in the nucleus accumbens in rats’ anxiety-related behavior was investigated. Methods: Wistar rats were used in this study. Male Wistar rats bred in an animal house, in a temperature-controlled (22±2 ◦C room with a 12 hour light/darkcycle. Rats were anesthetized using intraperitoneal injection of ketamine hydrochloride and xylazine, then placed in an stereotactic instrument for microinjection cannula implantation The stainless steel guide cannula was implanted bilaterally in the right and left dorsal the nucleus accumbens shell according to Paxinos and Watson atlas. After recovery, anxiety behavior and locomotor activity were tested. We used the elevated plus maze to test anxiety. This apparatus has widely been employed to test parameters of anxiety-related behaviors including the open armtime percentage (%OAT, open arm entries percentage (%OAE, locomotor activity and we record effect of drugs after injection directly in the nucleus accumbens on anxiety-related behavior.Results: Experiments showed that bilateral injections into the nucleus accumbens Nicotine, acetylcholine receptor agonist, dose 0.1 of the dose (0.05 and 0.1, 0.25, 0.5 microgram per rat caused a significant increase in the percentage of time spent in the open arms (%OAT, compared to the control group. We did not record any significant change locomotor activity and open arm entries percentage (%OAE in rats.Conclusion: Nicotinic receptors in the nucleus accumbens shell involved to anxiety-like behavior in male rats.

  12. Function of Partially Duplicated Human α7 Nicotinic Receptor Subunit CHRFAM7A Gene

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    de Lucas-Cerrillo, Ana M.; Maldifassi, M. Constanza; Arnalich, Francisco; Renart, Jaime; Atienza, Gema; Serantes, Rocío; Cruces, Jesús; Sánchez-Pacheco, Aurora; Andrés-Mateos, Eva; Montiel, Carmen

    2011-01-01

    The neuronal α7 nicotinic receptor subunit gene (CHRNA7) is partially duplicated in the human genome forming a hybrid gene (CHRFAM7A) with the novel FAM7A gene. The hybrid gene transcript, dupα7, has been identified in brain, immune cells, and the HL-60 cell line, although its translation and function are still unknown. In this study, dupα7 cDNA has been cloned and expressed in GH4C1 cells and Xenopus oocytes to study the pattern and functional role of the expressed protein. Our results reveal that dupα7 transcript was natively translated in HL-60 cells and heterologously expressed in GH4C1 cells and oocytes. Injection of dupα7 mRNA into oocytes failed to generate functional receptors, but when co-injected with α7 mRNA at α7/dupα7 ratios of 5:1, 2:1, 1:1, 1:5, and 1:10, it reduced the nicotine-elicited α7 current generated in control oocytes (α7 alone) by 26, 53, 75, 93, and 94%, respectively. This effect is mainly due to a reduction in the number of functional α7 receptors reaching the oocyte membrane, as deduced from α-bungarotoxin binding and fluorescent confocal assays. Two additional findings open the possibility that the dominant negative effect of dupα7 on α7 receptor activity observed in vitro could be extrapolated to in vivo situations. (i) Compared with α7 mRNA, basal dupα7 mRNA levels are substantial in human cerebral cortex and higher in macrophages. (ii) dupα7 mRNA levels in macrophages are down-regulated by IL-1β, LPS, and nicotine. Thus, dupα7 could modulate α7 receptor-mediated synaptic transmission and cholinergic anti-inflammatory response. PMID:21047781

  13. Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers.

    Science.gov (United States)

    Brody, Arthur L; Mukhin, Alexey G; La Charite, Jaime; Ta, Karen; Farahi, Judah; Sugar, Catherine A; Mamoun, Michael S; Vellios, Evan; Archie, Meena; Kozman, Maggie; Phuong, Jonathan; Arlorio, Franca; Mandelkern, Mark A

    2013-06-01

    One-third of smokers primarily use menthol cigarettes and usage of these cigarettes leads to elevated serum nicotine levels and more difficulty quitting in standard treatment programmes. Previous brain imaging studies demonstrate that smoking (without regard to cigarette type) leads to up-regulation of β(2)*-containing nicotinic acetylcholine receptors (nAChRs). We sought to determine if menthol cigarette usage results in greater nAChR up-regulation than non-menthol cigarette usage. Altogether, 114 participants (22 menthol cigarette smokers, 41 non-menthol cigarette smokers and 51 non-smokers) underwent positron emission tomography scanning using the α(4)β(2)* nAChR radioligand 2-[(18)F]fluoro-A-85380 (2-FA). In comparing menthol to non-menthol cigarette smokers, an overall test of 2-FA total volume of distribution values revealed a significant between-group difference, resulting from menthol smokers having 9-28% higher α(4)β(2)* nAChR densities than non-menthol smokers across regions. In comparing the entire group of smokers to non-smokers, an overall test revealed a significant between-group difference, resulting from smokers having higher α(4)β(2)* nAChR levels in all regions studied (36-42%) other than thalamus (3%). Study results demonstrate that menthol smokers have greater up-regulation of nAChRs than non-menthol smokers. This difference is presumably related to higher nicotine exposure in menthol smokers, although other mechanisms for menthol influencing receptor density are possible. These results provide additional information about the severity of menthol cigarette use and may help explain why these smokers have more trouble quitting in standard treatment programmes.

  14. Nicotine addiction: studies about vulnerability, epigenesis and animal models

    Directory of Open Access Journals (Sweden)

    Bernabeu, Ramon

    2013-07-01

    Full Text Available This article is a summary about the current research of nicotine effects on the nervous system and its relationship to the generation of an addictive behavior. Like other drugs of abuse, nicotine activates the reward pathway, which in turn is involved in certain psychiatric diseases. There are individuals who have a high vulnerability to nicotine addiction. This may be due to genetic and epigenetic factors and/or the environment. In this review, we described some epigenetic factors that may be involved in those phenomena. The two animal models most widely used for studying the reinforcing effects of nicotine are: self-administration and conditioning place preference (CPP. Here, we emphasized the CPP, due to its potential application in humans. In addition, we described the locomotor activity model (as a measure of psychostimulant effects to study vulnerability to drugs of abuse

  15. PLANT GROWTH REGULATORS IN THE SERIES OF NICOTINIC ACID DERIVATIVES

    Directory of Open Access Journals (Sweden)

    Kaigorodova E. A.

    2014-06-01

    Full Text Available The article shows the information of the use of 2-R-sulfanyl nicotinates of potassium on rice crops. We have found that the compounds described increase yield and improve its quality

  16. Experimental Study of Nicotine on Angiogenesis and Restenosis

    Institute of Scientific and Technical Information of China (English)

    Yin Ruixing; Bi Qi; Liu Tangwei

    2005-01-01

    Objectives To investigate the effects of nicotine on angiogenesis and restenosis in a rabbit model of critical limb ischemia and balloon catheter denuding injury iliac artery. Methods Forty male New Zealand White rabbits were randomly divided into control, low-, middle-, and high-dose (0.005,0.05 or 5 μg/kg, respectively) nicotine groups.Balloon catheter denuding injury iliac artery and ligation of a femoral artery were performed in all animals fed with a high-cholesterol diet (HCD)beginning 2 weeks before operation. Nicotine was administered daily by intramuscular injection in the ischemic hindlimb for 3 weeks. Control rabbits received an equal volume of phosphate-buffered saline alone.Collateral vessels of the ischemic hindlimb were observed by angiography of abdominal aorta, and the density of intramuscular microvessels in ischemic hindlimb was examined by immunohistochemistry. The levels of blood lipids and the indexes of hepatic or renal functions were also determined before HCD and after nicotine treatment. Results One rabbit in control, two in low-, one in middle- and two in high-dose group died during the experiment. The remaining 34 rabbits were included in the study. Two or five weeks after HCD, the levels of blood lipids were significantly increased in all groups, but there was no significant difference on the levels between control and nicotine-treated groups three weeks after nicotine treatment; The indexes of hepatic or renal functions were no significant changes three weeks after nicotine treatment; There were no significant differences on collateral vessels shown by angiography in all four groups; The density of intramuscular microvessels in three nicotine-treated groups was significantly higher than that in control group; But the intimal area in all three nicotine-treated groups was also larger than that in control group.Conclusions The present study shows that intramuscular administration of nicotine for three weeks could not increase

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

    Science.gov (United States)

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

    2016-01-01

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

  18. Conotoxins Targeting Nicotinic Acetylcholine Receptors: An Overview

    Directory of Open Access Journals (Sweden)

    Eline K. M. Lebbe

    2014-05-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

  20. 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....

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

    OpenAIRE

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

    2014-01-01

    Urgency (i.e. the tendency to act rashly during negative/positive affect) may increase vulnerability to a variety of risky behaviors. This cross-sectional study of non-treatment-seeking smokers examined the relationship between urgency, level of nicotine dependence, and smoking reinforcement expectancies. Both positive and negative urgency were associated with nicotine dependence. Mediational analyses illustrated that smoking reinforcement expectancies significantly accounted for urgency-depe...

  2. First trimester nicotine exposure and the risk of infantile colic

    DEFF Research Database (Denmark)

    Milidou, Ioanna; Henriksen, Tine Brink; Jensen, Morten Søndergaard;

    Background: Although prenatal exposure to maternal smoking has been associated with infantile colic (IC), to date no published studies have reported on the relationship between the prenatal use of nicotine replacement therapy (NRT) and IC. Aim: We aimed to assess the relationship between fetal......: The results indicate that prenatal exposure to nicotine from any source during the first trimester of the pregnancy increases the risk of infantile colic....

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

    Science.gov (United States)

    Florek, Ewa; Enko, Jolanta; Piekoszewski, Wojciech

    2009-01-01

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

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

    Science.gov (United States)

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

    2015-02-01

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

  5. RNA interference (RNAi)-induced suppression of nicotine demethylase activity reduces levels of a key carcinogen in cured tobacco leaves.

    Science.gov (United States)

    Lewis, Ramsey S; Jack, Anne M; Morris, Jerry W; Robert, Vincent J M; Gavilano, Lily B; Siminszky, Balazs; Bush, Lowell P; Hayes, Alec J; Dewey, Ralph E

    2008-05-01

    Technologies for reducing the levels of tobacco product constituents that may contribute to unwanted health effects are desired. Target compounds include tobacco-specific nitrosamines (TSNAs), a class of compounds generated through the nitrosation of pyridine alkaloids during the curing and processing of tobacco. Studies have reported the TSNA N'-nitrosonornicotine (NNN) to be carcinogenic in laboratory animals. NNN is formed via the nitrosation of nornicotine, a secondary alkaloid produced through enzymatic N-demethylation of nicotine. Strategies to lower nornicotine levels in tobacco (Nicotiana tabacum L.) could lead to a corresponding decrease in NNN accumulation in cured leaves. The major nicotine demethylase gene of tobacco has recently been isolated. In this study, a large-scale field trial was conducted to evaluate transgenic lines of burley tobacco carrying an RNA interference (RNAi) construct designed to inhibit the expression of this gene. Selected transgenic lines exhibited a six-fold decrease in nornicotine content relative to untransformed controls. Analysis of cured leaves revealed a commensurate decrease in NNN and total TSNAs. The inhibition of nicotine demethylase activity is an effective means of decreasing significantly the level of a key defined animal carcinogen present in tobacco products.

  6. Anti-nicotine vaccines: Comparison of adjuvanted CRM197 and Qb-VLP conjugate formulations for immunogenicity and function in non-human primates.

    Science.gov (United States)

    McCluskie, Michael J; Thorn, Jennifer; Gervais, David P; Stead, David R; Zhang, Ningli; Benoit, Michelle; Cartier, Janna; Kim, In-Jeong; Bhattacharya, Keshab; Finneman, Jari I; Merson, James R; Davis, Heather L

    2015-12-01

    Anti-nicotine vaccines comprise nicotine-like haptens conjugated to a carrier protein plus adjuvant(s). Unfortunately, those tested clinically have failed to improve overall long term quit rates. We had shown in mice that carrier, hapten, linker, hapten load (number of haptens per carrier molecule), aggregation and adducts, as well as adjuvants influence the function of antibodies (Ab) induced. Herein, we tested an optimized antigen, NIC7-CRM, comprised of 5-aminoethoxy-nicotine (NIC7) conjugated to genetically detoxified diphtheria toxin (CRM197), with hapten load of ~16, no aggregation (~100% monomer) and minimal adducts. NIC7-CRM was tested in non-human primates (NHP) and compared to NIC-VLP, which has the same hapten and carrier as the clinical-stage CYT002-NicQb but a slightly different linker and lower hapten load. With alum as sole adjuvant, NIC7-CRM was superior to NIC-VLP for Ab titer, avidity and ex vivo function (83% and 27% nicotine binding at 40ng/mL respectively), but equivalent for in vivo function after intravenous [IV] nicotine challenge (brain levels reduced ~10%). CpG adjuvant added to NIC7-CRM/alum further enhanced the Ab responses and both ex vivo function (100% bound) and in vivo function (~80% reduction in brain). Thus, both optimal antigen design and CpG adjuvant were required to achieve a highly functional vaccine. The compelling NHP data with NIC7-CRM with alum/CpG supported human testing, currently underway.

  7. Ethanol enhances Nicotine's effects on DRL performance in rats.

    Science.gov (United States)

    Popke, E J; Fogle, C M; Paule, M G

    2000-08-01

    The present experiment examined effects of nicotine (0.0, 0.3, 0.56, and 1.0 mg/kg; IP) and ethanol (0.0, 0.5, 1.5, and 3.0 g/kg; IG) on operant behavior using a differential reinforcement of low response rate (DRL) schedule in rats. DRL schedules are sensitive to effects of nicotine and provide an assessment of the subject's ability to accurately estimate time and to inhibit schedule-controlled responding. When administered alone, nicotine shifted the mode of the interresponse time distribution to the left and reduced the percentage of reinforced responses. Nicotine also had an inverted U-shaped dose effect on the number of "bursting" responses. When administered after pretreatment with ethanol, nicotine's effects on the distribution of interresponse times and bursting were potentiated. These effects are consistent with previous reports and with the suggestion that ethanol pretreatment can potentiate effects of subsequently administered nicotine. Published by Elsevier Science Inc.

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

    Science.gov (United States)

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

    2003-12-01

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

  9. 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.

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

    Science.gov (United States)

    Hawkins, Kirsten A; Cougle, Jesse R

    2013-12-01

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

  11. Nicotine Dependence among Rural-Urban Migrants in China

    Directory of Open Access Journals (Sweden)

    Li Yuyan

    2011-05-01

    Full Text Available Abstract Background The complex mechanism of nicotine dependency makes it challenging to evaluate dependence or progress towards dependence. The aim of this study was to estimate nicotine dependence levels and identify determinants of dependence among Chinese rural-urban migrants. Methods Multi-stage systematic sampling was used to select 4,198 rural-urban migrants aged 18 years or older from three metropolises in China. A structured questionnaire was administered during face-to-face interviews. Nicotine dependence among participants was assessed by means of the six-item Mandarin Chinese Version of the Fagerström Test for Nicotine Dependence (CFTND. Determinants of dependence were analyzed using multivariate analysis of variance (MANOVA. Results Among 4,198 participants, estimated current, daily, and occasional smoking rates were 28.3%, 21.2%, and 7.1%, respectively. The CTFND score for the 894 daily smokers was 3.39(SD: 2.32. MANOVA showed that work type, age at first migration, length of migration, and number of cities ever lived were associated with nicotine dependence. Conclusion A migratory lifestyle is associated with nicotine dependence. Results could inform the design of tobacco control programs that target Chinese rural-urban migrant workers as a special at-risk population.

  12. Effects of nicotinic acetylcholine receptor agonists in assays of acute pain-stimulated and pain-depressed behaviors in rats.

    Science.gov (United States)

    Freitas, Kelen C; Carroll, F Ivy; Negus, S Stevens

    2015-11-01

    Agonists at nicotinic acetylcholine receptors (nAChRs) constitute one drug class being evaluated as candidate analgesics. Previous preclinical studies have implicated α4β2 and α7 nAChRs as potential mediators of the antinociceptive effects of (–)-nicotine hydrogen tartrate (nicotine) and other nAChR agonists; however, these studies have relied exclusively on measures of pain-stimulated behavior, which can be defined as behaviors that increase in frequency, rate, or intensity after presentation of a noxious stimulus. Pain is also associated with depression of many behaviors, and drug effects can differ in assays of pain-stimulated versus pain-depressed behavior. Accordingly, this study compared the effects of nicotine, the selective α4/6β2 agonist 5-(123I)iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380), and the selective α7 agonist N-(3R)-1-azabicyclo(2.2.2)oct-3-yl-4-chlorobenzamide in assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats. Intraperitoneal injection of dilute lactic acid served as an acute noxious stimulus to either stimulate a stretching response or depress the operant responding, which is maintained by electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. Nicotine produced a dose-dependent, time-dependent, and mecamylamine-reversible blockade of both acid-stimulated stretching and acid-induced depression of ICSS. 5-I-A-85380 also blocked both acid-stimulated stretching and acid-induced depression of ICSS, whereas N-(3R)-1-azabicyclo(2.2.2)oct-3-yl-4-chlorobenzamide produced no effect in either procedure. Both nicotine and 5-I-A-85380 were ≥10-fold more potent in blocking the acid-induced depression of ICSS than in blocking the acid-induced stimulation of stretching. These results suggest that stimulation of α4β2 and/or α6β2 nAChRs may be especially effective to alleviate the signs of pain-related behavioral depression in rats; however, nonselective behavioral effects

  13. Promoted neuronal differentiation after activation of alpha4/beta2 nicotinic acetylcholine receptors in undifferentiated neural progenitors.

    Directory of Open Access Journals (Sweden)

    Takeshi Takarada

    Full Text Available BACKGROUND: Neural progenitor is a generic term used for undifferentiated cell populations of neural stem, neuronal progenitor and glial progenitor cells with abilities for proliferation and differentiation. We have shown functional expression of ionotropic N-methyl-D-aspartate (NMDA and gamma-aminobutyrate type-A receptors endowed to positively and negatively regulate subsequent neuronal differentiation in undifferentiated neural progenitors, respectively. In this study, we attempted to evaluate the possible functional expression of nicotinic acetylcholine receptor (nAChR by undifferentiated neural progenitors prepared from neocortex of embryonic rodent brains. METHODOLOGY/PRINCIPAL FINDINGS: Reverse transcription polymerase chain reaction analysis revealed mRNA expression of particular nAChR subunits in undifferentiated rat and mouse progenitors prepared before and after the culture with epidermal growth factor under floating conditions. Sustained exposure to nicotine significantly inhibited the formation of neurospheres composed of clustered proliferating cells and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction activity at a concentration range of 1 µM to 1 mM without affecting cell survival. In these rodent progenitors previously exposed to nicotine, marked promotion was invariably seen for subsequent differentiation into cells immunoreactive for a neuronal marker protein following the culture of dispersed cells under adherent conditions. Both effects of nicotine were significantly prevented by the heteromeric α4β2 nAChR subtype antagonists dihydro-β-erythroidine and 4-(5-ethoxy-3-pyridinyl-N-methyl-(3E-3-buten-1-amine, but not by the homomeric α7 nAChR subtype antagonist methyllycaconitine, in murine progenitors. Sustained exposure to nicotine preferentially increased the expression of Math1 among different basic helix-loop-helix proneural genes examined. In undifferentiated progenitors from embryonic mice

  14. 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

    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 induced larger...... intracellular calcium transients and inward currents. Nicotine induced a greater number of excitatory synaptic currents in the youngest animals, whereas larger amplitude inhibitory synaptic events were induced in cells from the oldest animals (P15–P34). Nicotine increased neuronal firing of cholinergic cells...

  15. Nicotine Dehydrogenase Complexed with 6-