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Sample records for norepinephrine transporter reduction

  1. Reserpine-induced Reduction in Norepinephrine Transporter Function Requires Catecholamine Storage Vesicles

    PubMed Central

    Mandela, Prashant; Chandley, Michelle; Xu, Yao-Yu; Zhu, Meng-Yang; Ordway, Gregory A.

    2010-01-01

    Treatment of rats with reserpine, an inhibitor of the vesicular monoamine transporter (VMAT), depletes norepinephrine (NE) and regulates NE transporter (NET) expression. The present study examined the molecular mechanisms involved in regulation of the NET by reserpine using cultured cells. Exposure of rat PC12 cells to reserpine for a period as short as 5 min decreased [3H]NE uptake capacity, an effect characterized by a robust decrease in the Vmax of the transport of [3H]NE. As expected, reserpine did not displace the binding of [3H]nisoxetine from the NET in membrane homogenates. The potency of reserpine for reducing [3H]NE uptake was dramatically lower in SK-N-SH cells that have reduced storage capacity for catecholamines. Reserpine had no effect on [3H]NE uptake in HEK-293 cells transfected with the rat NET (293-hNET), cells that lack catecholamine storage vesicles. NET regulation by reserpine was independent of trafficking of the NET from the cell surface. Pre-exposure of cells to inhibitors of several intracellular signaling cascades known to regulate the NET, including Ca2+/Ca2+-calmodulin dependent kinase and protein kinases A, C and G, did not affect the ability of reserpine to reduce [3H]NE uptake. Treatment of PC12 cells with the catecholamine depleting agent, α-methyl-p-tyrosine, increased [3H]NE uptake and eliminated the inhibitory effects of reserpine on [3H]NE uptake. Reserpine non-competitively inhibits NET activity through a Ca2+-independent process that requires catecholamine storage vesicles, revealing a novel pharmacological method to modify NET function. Further characterization of the molecular nature of reserpine's action could lead to the development of alternative therapeutic strategies for treating disorders known to be benefitted by treatment with traditional competitive NET inhibitors. PMID:20176067

  2. Familial orthostatic tachycardia due to norepinephrine transporter deficiency

    NASA Technical Reports Server (NTRS)

    Robertson, D.; Flattem, N.; Tellioglu, T.; Carson, R.; Garland, E.; Shannon, J. R.; Jordan, J.; Jacob, G.; Blakely, R. D.; Biaggioni, I.

    2001-01-01

    Orthostatic intolerance (OI) or postural tachycardia syndrome (POTS) is a syndrome primarily affecting young females, and is characterized by lightheadedness, palpitations, fatigue, altered mentation, and syncope primarily occurring with upright posture and being relieved by lying down. There is typically tachycardia and raised plasma norepinephrine levels on upright posture, but little or no orthostatic hypotension. The pathophysiology of OI is believed to be very heterogeneous. Most studies of the syndrome have focused on abnormalities in norepinephrine release. Here the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to the pathophysiology in some patients with OI was tested. In a proband with significant orthostatic symptoms and tachycardia, disproportionately elevated plasma norepinephrine with standing, impaired systemic, and local clearance of infused tritiated norepinephrine, impaired tyramine responsiveness, and a dissociation between stimulated plasma norepinephrine and DHPG elevation were found. Studies of NET gene structure in the proband revealed a coding mutation that converts a highly conserved transmembrane domain Ala residue to Pro. Analysis of the protein produced by the mutant cDNA in transfected cells demonstrated greater than 98% reduction in activity relative to normal. NE, DHPG/NE, and heart rate correlated with the mutant allele in this family. CONCLUSION: These results represent the first identification of a specific genetic defect in OI and the first disease linked to a coding alteration in a Na+/Cl(-)-dependent neurotransmitter transporter. Identification of this mechanism may facilitate our understanding of genetic causes of OI and lead to the development of more effective therapeutic modalities.

  3. Norepinephrine Transporter Heterozygous Knockout Mice Exhibit Altered Transport and Behavior

    PubMed Central

    Fentress, HM; Klar, R; Krueger, JK; Sabb, T; Redmon, SN; Wallace, NM; Shirey-Rice, JK; Hahn, MK

    2013-01-01

    The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically-driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET+/−), demonstrating that they display an ~50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity, assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET+/− mouse establishes an activated state of existing, surface NET proteins. NET+/− mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris Water Maze. These data suggest recovery of near basal activity in NET+/− mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET+/− mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders. PMID:24102798

  4. Norepinephrine transporter heterozygous knockout mice exhibit altered transport and behavior.

    PubMed

    Fentress, H M; Klar, R; Krueger, J J; Sabb, T; Redmon, S N; Wallace, N M; Shirey-Rice, J K; Hahn, M K

    2013-11-01

    The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET(+/-) ), demonstrating that they display an approximately 50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET(+/-) mouse establishes an activated state of existing surface NET proteins. The NET(+/-) mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris water maze. These data suggest that recovery of near basal activity in NET(+/-) mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET(+/-) mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders. PMID:24102798

  5. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency

    NASA Technical Reports Server (NTRS)

    Shannon, J. R.; Flattem, N. L.; Jordan, J.; Jacob, G.; Black, B. K.; Biaggioni, I.; Blakely, R. D.; Robertson, D.

    2000-01-01

    BACKGROUND: Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. METHODS: In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function. RESULTS: The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (+/-SD) concentration in normal subjects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56+/-63 pg per milliliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the proband's family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis. CONCLUSIONS: Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic

  6. Effects of various pharmacological agents on the function of norepinephrine transporter.

    PubMed

    Satoh, Noriaki; Toyohira, Yumiko; Takahashi, Keita; Yanagihara, Nobuyuki

    2015-03-01

    The norepinephrine transporter is selectively expressed in noradrenergic nerve terminals, where it can exert spatial and temporal control over the action of norepinephrine. The norepinephrine transporter mediates the termination of neurotransmission via the reuptake of norepinephrine released into the extracellular milieu. In the present brief review, we report our recent studies about the effects of various pharmacological agents such as fasudil, nicotine, pentazocine, ketamine and genistein on norepinephrine transporter function. PMID:25787100

  7. Rab11 Supports Amphetamine-Stimulated Norepinephrine Transporter Trafficking

    PubMed Central

    Matthies, Heinrich J.G.; Moore, Jessica L.; Saunders, Christine; Matthies, Dawn Signor; Lapierre, Lynne A.; Goldenring, James R.; Blakely, Randy D.; Galli, Aurelio

    2010-01-01

    The norepinephrine transporter (NET) is a presynaptic plasma membrane protein that mediates reuptake of synaptically released norepinephrine (NE). NET is also a major target for medications used for the treatment of depression, attention-deficit hyperactivity disorder, narcolepsy, and obesity. NET is regulated by numerous mechanisms, including catalytic activation and membrane trafficking. Amphetamine (AMPH), a psychostimulant and NET substrate, has also been shown to induce NET trafficking. However, neither the molecular basis nor the nature of the relevant membrane compartments of AMPH-modulated NET trafficking has been defined. Indeed, direct visualization of drug-modulated NET trafficking in neurons has yet to be demonstrated. In this study, we utilized a recently developed NET antibody and the presence of large presynaptic boutons in sympathetic neurons to examine basal and AMPH-modulated NET trafficking. Specifically, we establish a role for Rab11 in AMPH-induced NET trafficking. First, we found that in cortical slices, AMPH induces a reduction in surface NET. Next, we observed AMPH-induced accumulation and colocalization of NET with Rab11a and Rab4 in presynaptic boutons of cultured neurons. Using tagged proteins, we demonstrated that NET and a truncated Rab11 effector (FIP2ΔC2) do not redistribute in synchrony whereas NET and wild type Rab11a do. Analysis of various Rab11a/b mutants further demonstrates that Rab11 regulates NET trafficking. Expression of the truncated Rab11a effector (FIP2ΔC2) attenuates endogenous Rab11 function and prevented AMPH-induced NET internalization as does GDP-locked Rab4 S22N. Our data demonstrate that AMPH leads to an increase of NET in endosomes of single boutons and varicosities in a Rab11-dependent manner. PMID:20534835

  8. Association of Norepinephrine Transporter Gene with Methylphenidate Response.

    ERIC Educational Resources Information Center

    Yang, Li; Wang, Yu-Feng; Li, Jun; Faraone, Stephen V.

    2004-01-01

    Objective: This study aimed to explore the association between alleles of the norepinephrine transporter gene and the methylphenidate response. Method: Chinese Han youths with attention-deficit/hyperactivity disorder recruited in the Outpatient Department of the Institute of Mental Health from 2001 to 2004 were treated with methylphenidate in…

  9. Inhibition of the norepinephrine transporter by χ-conotoxin dendrimers.

    PubMed

    Wan, Jingjing; Brust, Andreas; Bhola, Rebecca F; Jha, Prerna; Mobli, Mehdi; Lewis, Richard J; Christie, Macdonald J; Alewood, Paul F

    2016-05-01

    Peptide dendrimers are a novel class of macromolecules of emerging interest with the potential of delayed renal clearance due to their molecular size and enhanced activity due to the multivalency effect. In this work, an active analogue of the disulfide-rich χ-conotoxin χ-MrIA (χ-MrIA), a norepinephrine reuptake (norepinephrine transporter) inhibitor, was grafted onto a polylysine dendron. Dendron decoration was achieved by employing copper-catalyzed alkyne-azide cycloaddition with azido-PEG chain-modified χ-MrIA analogues, leading to homogenous 4-mer and 8-mer χ-MrIA dendrimers with molecular weights ranging from 8 to 22 kDa. These dendrimers were investigated for their impact on peptide secondary structure, in vitro functional activity, and potential anti-allodynia in vivo. NMR studies showed that the χ-MrIA tertiary structure was maintained in the χ-MrIA dendrimers. In a functional norepinephrine transporter reuptake assay, χ-MrIA dendrimers showed slightly increased potency relative to the azido-PEGylated χ-MrIA analogues with similar potency to the parent peptide. In contrast to χ-MrIA, no anti-allodynic action was observed when the χ-MrIA dendrimers were administered intrathecally in a rat model of neuropathic pain, suggesting that the larger dendrimer structures are unable to diffuse through the spinal column tissue and reach the norepinephrine transporter. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID:26910400

  10. Norepinephrine transport-mediated gene expression in noradrenergic neurogenesis

    PubMed Central

    Hu, Yao Fei; Caron, Marc G; Sieber-Blum, Maya

    2009-01-01

    Background We have identified a differential gene expression profile in neural crest stem cells that is due to deletion of the norepinephrine transporter (NET) gene. NET is the target of psychotropic substances, such as tricyclic antidepressants and the drug of abuse, cocaine. NET mutations have been implicated in depression, anxiety, orthostatic intolerance and attention deficit hyperactivity disorder (ADHD). NET function in adult noradrenergic neurons of the peripheral and central nervous systems is to internalize norepinephrine from the synaptic cleft. By contrast, during embryogenesis norepinephrine (NE) transport promotes differentiation of neural crest stem cells and locus ceruleus progenitors into noradrenergic neurons, whereas NET inhibitors block noradrenergic differentiation. While the structure of NET und the regulation of NET function are well described, little is known about downstream target genes of norepinephrine (NE) transport. Results We have prepared gene expression profiles of in vitro differentiating wild type and norepinephrine transporter-deficient (NETKO) mouse neural crest cells using long serial analysis of gene expression (LongSAGE). Comparison analyses have identified a number of important differentially expressed genes, including genes relevant to neural crest formation, noradrenergic neuron differentiation and the phenotype of NETKO mice. Examples of differentially expressed genes that affect noradrenergic cell differentiation include genes in the bone morphogenetic protein (BMP) signaling pathway, the Phox2b binding partner Tlx2, the ubiquitin ligase Praja2, and the inhibitor of Notch signaling, Numbl. Differentially expressed genes that are likely to contribute to the NETKO phenotype include dopamine-β-hydroxylase (Dbh), tyrosine hydroxylase (Th), the peptide transmitter 'cocaine and amphetamine regulated transcript' (Cart), and the serotonin receptor subunit Htr3a. Real-time PCR confirmed differential expression of key genes not

  11. Altered Reward Circuitry in the Norepinephrine Transporter Knockout Mouse

    PubMed Central

    Hall, F. Scott; Uhl, George R.; Bearer, Elaine L.; Jacobs, Russell E.

    2013-01-01

    Synaptic levels of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine are modulated by their respective plasma membrane transporters, albeit with a few exceptions. Monoamine transporters remove monoamines from the synaptic cleft and thus influence the degree and duration of signaling. Abnormal concentrations of these neuronal transmitters are implicated in a number of neurological and psychiatric disorders, including addiction, depression, and attention deficit/hyperactivity disorder. This work concentrates on the norepinephrine transporter (NET), using a battery of in vivo magnetic resonance imaging techniques and histological correlates to probe the effects of genetic deletion of the norepinephrine transporter on brain metabolism, anatomy and functional connectivity. MRS recorded in the striatum of NET knockout mice indicated a lower concentration of NAA that correlates with histological observations of subtle dysmorphisms in the striatum and internal capsule. As with DAT and SERT knockout mice, we detected minimal structural alterations in NET knockout mice by tensor-based morphometric analysis. In contrast, longitudinal imaging after stereotaxic prefrontal cortical injection of manganese, an established neuronal circuitry tracer, revealed that the reward circuit in the NET knockout mouse is biased toward anterior portions of the brain. This is similar to previous results observed for the dopamine transporter (DAT) knockout mouse, but dissimilar from work with serotonin transporter (SERT) knockout mice where Mn2+ tracings extended to more posterior structures than in wildtype animals. These observations correlate with behavioral studies indicating that SERT knockout mice display anxiety-like phenotypes, while NET knockouts and to a lesser extent DAT knockout mice display antidepressant-like phenotypic features. Thus, the mainly anterior activity detected with manganese-enhanced MRI in the DAT and NET knockout mice is likely indicative of

  12. Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters.

    PubMed

    Gatley, S J; Pan, D; Chen, R; Chaturvedi, G; Ding, Y S

    1996-01-01

    We have synthesized several derivative of dl-threo-methylphenidate (Ritalin) bearing substituents on the phenyl ring. IC50 values for binding these compounds to rat brain monoamine transporters were assessed using [3H]WIN 35,428 (striatal membranes, dopamine transporters, DAT), [3H]nisoxetine (frontal cortex membranes, norepinephrine transporters, NET) and [3H]paroxetine (brain stem membranes, 5HT transporters, 5HTT). Affinities (1/Ki) decreased in the order: DAT > NET > 5HTT. Substitution at the para position of dl-threo-methylphenidate generally led to retained or increased affinity for the dopamine transporter (bromo > iodo > methoxy > hydroxy). Substitution at the meta position also increased affinity for the DAT (m-bromo > methylphenidate; m-iodo-p-hydroxy > p-hydroxy). Substitution at the ortho position with bromine considerably decreased affinity. Similar IC50 values for binding of o-bromomethylphenidate to the dopamine transporter were measured at 0, 22 and 37 degrees. N-Methylation of the piperidine ring of methylphenidate also considerably reduced affinity. The dl-erythro isomer of o-bromomethylphenidate did not bind to the DAT (IC50 > 50,000 nM). Affinities at the dopamine and norepinephrine transporters for substituted methylphenidate derivatives were well correlated (r2=0.90). Abilities of several methylphenidate derivatives to inhibit [3H]dopamine uptake in striatal synaptosomes corresponded well with inhibition of [3H]WIN 35, 428 binding. None of the compounds examined exhibited significant affinity to dopamine D1 or D2 receptors (IC50 > 500 or 5,000 nM, respectively), as assessed by inhibition of binding of [3H]SCH 23390 or [123I]epidepride, respectively, to striatal membranes. PMID:8786705

  13. Insulin reveals Akt signaling as a novel regulator of norepinephrine transporter trafficking and norepinephrine homeostasis.

    PubMed

    Robertson, Sabrina D; Matthies, Heinrich J G; Owens, W Anthony; Sathananthan, Vidiya; Christianson, Nicole S Bibus; Kennedy, J Phillip; Lindsley, Craig W; Daws, Lynette C; Galli, Aurelio

    2010-08-25

    Noradrenergic signaling in the CNS plays an essential role in circuits involving attention, mood, memory, and stress as well as providing pivotal support for autonomic function in the peripheral nervous system. The high-affinity norepinephrine (NE) transporter (NET) is the primary mechanism by which noradrenergic synaptic transmission is terminated. Data indicate that NET function is regulated by insulin, a hormone critical for the regulation of metabolism. Given the high comorbidity of metabolic disorders such as diabetes and obesity with mental disorders such as depression and schizophrenia, we sought to determine how insulin signaling regulates NET function and thus noradrenergic homeostasis. Here, we show that acute insulin treatment, through the downstream kinase protein kinase B (Akt), significantly decreases NET surface expression in mouse hippocampal slices and superior cervical ganglion neuron boutons (sites of synaptic NE release). In vivo manipulation of insulin/Akt signaling, with streptozotocin, a drug that induces a type 1-like diabetic state in mice, also results in aberrant NET function and NE homeostasis. Notably, we also demonstrate that Akt inhibition or stimulation, independent of insulin, is capable of altering NET surface availability. These data suggest that aberrant states of Akt signaling such as in diabetes and obesity have the potential to alter NET function and noradrenergic tone in the brain. Furthermore, they provide one potential molecular mechanism by which Akt, a candidate gene for mood disorders such as schizophrenia and depression, can impact brain monoamine homeostasis. PMID:20739551

  14. Norepinephrine transporter function and autonomic control of metabolism.

    PubMed

    Boschmann, Michael; Schroeder, Christoph; Christensen, Niels Juel; Tank, Jens; Krupp, Goetz; Biaggioni, Italo; Klaus, Susanne; Sharma, Arya M; Luft, Friedrich C; Jordan, Jens

    2002-11-01

    Genetic variability, numerous medications, and some illicit drugs influence norepinephrine transporter (NET) function; however, the metabolic consequences of NET inhibition are poorly understood. We performed a randomized, double-blind, cross-over trial in 15 healthy subjects who ingested 8 mg of the selective NET inhibitor reboxetine or placebo. Energy expenditure and substrate oxidation rates were determined by indirect calorimetry before and during iv infusion of 0.25, 0.5, 1, and 2 micro g isoproterenol/min. Adipose tissue metabolism was studied by microdialysis before and during local isoproterenol perfusion. At rest, energy expenditure and substrate oxidation rates did not differ between reboxetine and placebo treatment. At 1 micro g/min isoproterenol, energy expenditure was significantly increased in men (+15%) and women (+20%) with both reboxetine and placebo treatment. However, carbohydrate oxidation rate was significantly higher with reboxetine compared with placebo. Baseline and isoproterenol-stimulated adipose tissue blood flow was about 2-fold higher with reboxetine vs. placebo. Furthermore, glucose supply and metabolism was significantly increased and lipid mobilization much more stimulated in adipose tissue under reboxetine when compared with placebo at all isoproterenol concentrations used. We conclude that acute NET inhibition increases adipose tissue glucose uptake and metabolism. While lipid mobilization is increased, overall lipid oxidation is decreased during beta-adrenergic stimulation. This effect cannot be explained by increased systemic or adipose tissue norepinephrine concentrations. Instead, NET inhibition may sensitize adipose tissue to beta-adrenergic stimulation. PMID:12414883

  15. Antipeptide antibodies confirm the topology of the human norepinephrine transporter.

    PubMed

    Brüss, M; Hammermann, R; Brimijoin, S; Bönisch, H

    1995-04-21

    We have raised polyclonal antibodies (N6-28, L211-226, L371-384, and C590-607) against peptides corresponding to hydrophilic sequences of the human norepinephrine transporter (hNET). The antisera immunoprecipitated the [35S]Met-labeled hNET. Antiserum L211-226, directed against a sequence of the putative second (large) extracellular loop of hNET, also immunoprecipitated the human dopamine transporter. Antisera N6-28 and C590-607, raised against a hNET peptide region of the N and the C termini, respectively, recognized a 58-kDa protein from transfected COS-7 cells expressing the hNET. This 58-kDa species represents a functional, glycosylated form of the hNET and not a degradation product. Tunicamycin treatment of transfected COS-7 cells as well as peptide-N-glycosidase F digestion of the transporter converted the 58-kDa species to a 50-kDa form, indicating that the latter represents the hNET core protein. In indirect immunofluorescence studies, our antisera confirmed the originally proposed topology of hNET. Antisera N6-28 and C590-607 detected hNET only in permeabilized cells. In contrast, antisera L211-226 and L371-384 directed against peptide sequences of the second and fourth putative extracellular loop displayed fluorescence signals with the intact cells. PMID:7721836

  16. Chronic desipramine treatment alters tyrosine hydroxylase but not norepinephrine transporter immunoreactivity in norepinephrine axons in the rat prefrontal cortex

    PubMed Central

    Erickson, Susan L.; Gandhi, Anjalika R.; Asafu-Adjei, Josephine K.; Sampson, Allan R.; Miner, LeeAnn; Blakely, Randy D.; Sesack, Susan R.

    2011-01-01

    Pharmacological blockade of norepinephrine (NE) reuptake is clinically effective in treating several mental disorders. Drugs that bind to the NE transporter (NET) alter both protein levels and activity of NET and also the catecholamine synthetic enzyme tyrosine hydroxylase (TH). We examined the rat prefrontal cortex (PFC) by electron microscopy to determine whether the density and subcellular distribution of immunolabeling for NET and colocalization of NET with TH within individual NE axons were altered by chronic treatment with the selective NE uptake inhibitor desipramine (DMI). Following DMI treatment (21 days, 15 mg/kg/day), NET-immunoreactive (-ir) axons were significantly less likely to colocalize TH. This finding is consistent with reports of reduced TH levels and activity in the locus coeruleus after chronic DMI and indicates a reduction of NE synthetic capacity in the PFC. Measures of NET expression and membrane localization, including the number of NET-ir profiles per tissue area sampled, the number of gold particles per NET-ir profile area, and the proportion of gold particles associated with the plasma membrane, were similar in DMI and vehicle treated rats. These findings were verified using two different antibodies directed against distinct epitopes of the NET protein. The results suggest that chronic DMI treatment does not reduce NET expression within individual NE axons in vivo or induce an overall translocation of NET protein away from the plasma membrane in the PFC as measured by ultrastructural immunogold labeling. Our findings encourage consideration of possible postranslational mechanisms for regulating NET activity in antidepressant-induced modulation of NE clearance. PMID:21208501

  17. Radiotracers for Cardiac Sympathetic Innervation: Transport Kinetics and Binding Affinities for the Human Norepinephrine Transporter

    PubMed Central

    Raffel, David M.; Chen, Wei; Jung, Yong-Woon; Jang, Keun Sam; Gu, Guie; Cozzi, Nicholas V.

    2013-01-01

    Introduction Most radiotracers for imaging of cardiac sympathetic innervation are substrates of the norepinephrine transporter (NET). The goal of this study was to characterize the NET transport kinetics and binding affinities of several sympathetic nerve radiotracers, including [11C]-(−)-meta-hydroxyephedrine, [11C]-(−)-epinephrine, and a series of [11C]-labeled phenethylguanidines under development in our laboratory. For comparison, the NET transport kinetics and binding affinities of some [3H]-labeled biogenic amines were also determined. Methods Transport kinetics studies were performed using rat C6 glioma cells stably transfected with the human norepinephrine transporter (C6-hNET cells). For each radiolabeled NET substrate, saturation transport assays with C6-hNET cells measured the Michaelis-Menten transport constants Km and Vmax for NET transport. Competitive inhibition binding assays with homogenized C6-hNET cells and [3H]mazindol provided estimates of binding affinities (KI) for NET. Results Km, Vmax and KI values were determined for each NET substrate with a high degree of reproducibility. Interestingly, C6-hNET transport rates for ‘tracer concentrations’ of substrate, given by the ratio Vmax/Km, were found to be highly correlated with neuronal transport rates measured previously in isolated rat hearts (r2 = 0.96). This suggests that the transport constants Km and Vmax measured using the C6-hNET cells accurately reflect in vivo transport kinetics. Conclusion The results of these studies show how structural changes in NET substrates influence NET binding and transport constants, providing valuable insights that can be used in the design of new tracers with more optimal kinetics for quantifying regional sympathetic nerve density. PMID:23306137

  18. A greater role for the norepinephrine transporter than the serotonin transporter in murine nociception

    PubMed Central

    Hall, F. Scott; Schwarzbaum, Joshua M.; Perona, Maria T.G.; Templin, J. Scott; Caron, Marc G.; Lesch, Klaus-Peter; Murphy, Dennis L.; Uhl, George R.

    2010-01-01

    Norepinephrine and serotonin involvement in nociceptive functions is supported by observations of analgesic effects of norepinephrine transporter (NET) and serotonin transporter (SERT) inhibitors such as amitriptyline. However, the relative contribution of NET and SERT to baseline nociception, as well as amitriptyline analgesia, is unclear. Amitriptyline and morphine analgesia in wild-type (WT) mice and littermates with gene knockout (KO) of SERT, NET or both transporters was conducted using the hotplate and tail-flick tests. Hypoalgesia was observed in NET KO mice, and to a lesser extent in SERT KO mice. The magnitude of this hypoalgesia in NET KO mice was so profound that it limited the assessment of drug-induced analgesia. Nonetheless, the necessary exclusion of these subjects because of profound baseline hypoalgesia strongly supports the role of norepinephrine and NET in basal nociceptive behavior while indicating a much smaller role for serotonin and SERT. To further clarify the role of NET and SERT in basal nociceptive sensitivity further experiments were conducted in SERT KO and NET KO mice across a range of temperatures. NET KO mice were again found to have pronounced thermal hypoalgesia compared to WT mice in both the hotplate and tail-flick tests, and only limited effects were observed in SERT KO mice. Furthermore, in the acetic acid writhing test of visceral nociception pronounced hypoalgesia was again found in NET KO mice, but no effect in SERT KO mice. As some of these effects may have resulted from developmental consequences of NET KO, the effects of the selective NET blocker nisoxetine and the selective SERT blocker fluoxetine were also examined in WT mice: only nisoxetine produced analgesia in these mice. Collectively these data suggest that NET has a far greater role in determining baseline analgesia, and perhaps other analgesic effects, than SERT. PMID:21129446

  19. The neuronal norepinephrine transporter in experimental heart failure: evidence for a posttranscriptional downregulation.

    PubMed

    Backs, J; Haunstetter, A; Gerber, S H; Metz, J; Borst, M M; Strasser, R H; Kübler, W; Haass, M

    2001-03-01

    An impairment of norepinephrine (NE) re-uptake by the neuronal NE transporter (NET) has been shown to contribute to the increased cardiac net-release of NE in congestive heart failure (CHF). The present study investigated which mechanisms are involved in the impairment of NET. Rats with supracoronary aortic banding characterized by myocardial hypertrophy, elevated left ventricular end diastolic pressures and severe pulmonary congestion were used as an experimental model for CHF. Compared to sham-operated controls, aortic-banded rats had enhanced plasma NE concentrations and decreased cardiac NE stores. In isolated perfused hearts of aortic-banded rats, functional impairment of NET was indicated by a 37% reduction in [(3)H]-NE-uptake. In addition, pharmacological blockade of NET with desipramine led to a markedly attenuated increase in the overflow of endogenous NE from hearts of aortic-banded rats. Determination of cardiac NET protein and of NET mRNA in the left stellate ganglion by [(3)H]-desipramine binding and competitive RT-PCR, respectively, revealed a 41% reduction of binding sites but no difference in gene expression. The density of sympathetic nerve fibers within the heart was unchanged, as shown by glyoxylic acid-induced histofluorescence. In conclusion, as impairment of intracardiac NE re-uptake by a reduction of NET binding sites is neither mediated by a decreased NET gene expression nor by a loss of noradrenergic nerve terminals, a posttranscriptional downregulation of NET per neuron is suggested in CHF. PMID:11181015

  20. Discovery of WAY-260022, a Potent and Selective Inhibitor of the Norepinephrine Transporter.

    PubMed

    Gavrin, Lori K; Mahaney, Paige E; Jenkins, Douglas; Nogle, Lisa M; Mugford, Cheryl A; Huselton, Christine; Leiter, Jennifer; Johnston, Grace H; Bray, Jenifer A; Burroughs, Kevin D; Cosmi, Scott A; Alfinito, Peter; Ho, Douglas M; Deecher, Darlene C; Trybulski, Eugene J

    2010-06-10

    The potency and selectivity of a series of 1-{(1S)-2-[amino]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol analogues are described. These compounds were prepared to improve in vitro metabolic stability and achieve brain penetration. Compound 13 (WAY-260022, NRI-022) was found to be a potent inhibitor of norepinephrine reuptake and demonstrated excellent selectivity over the serotonin and dopamine transporters. Additionally, 13 exhibited oral efficacy in a rat model of thermoregulatory dysfunction. PMID:24900182

  1. Discovery of WAY-260022, a Potent and Selective Inhibitor of the Norepinephrine Transporter

    PubMed Central

    2010-01-01

    The potency and selectivity of a series of 1-{(1S)-2-[amino]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol analogues are described. These compounds were prepared to improve in vitro metabolic stability and achieve brain penetration. Compound 13 (WAY-260022, NRI-022) was found to be a potent inhibitor of norepinephrine reuptake and demonstrated excellent selectivity over the serotonin and dopamine transporters. Additionally, 13 exhibited oral efficacy in a rat model of thermoregulatory dysfunction. PMID:24900182

  2. Fluorine-18 Radiolabeled PET Tracers for Imaging Monoamine Transporters: Dopamine, Serotonin, and Norepinephrine

    PubMed Central

    Stehouwer, Jeffrey S.; Goodman, Mark M.

    2009-01-01

    Synopsis This review focuses on the development of fluorine-18 radiolabeled PET tracers for imaging the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). All successful DAT PET tracers reported to date are members of the 3β-phenyl tropane class and are synthesized from cocaine. Currently available carbon-11 SERT PET tracers come from both the diphenylsulfide and 3β-phenyl nortropane class, but so far only the nortropanes have found success with fluorine-18 derivatives. NET imaging has so far employed carbon-11 and fluorine-18 derivatives of reboxetine but due to defluorination of the fluorine-18 derivatives further research is still necessary. PMID:20216936

  3. Decreased Norepinephrine Transporter Availability in Obesity: Positron Emission Tomography Imaging with (S,S)-[11C]O-Methylreboxetine

    PubMed Central

    Li, Chiang-shan R.; Potenza, Marc N.; Lee, Dianne E.; Planeta, Beata; Gallezot, Jean-Dominique; Labaree, David; Henry, Shannan; Nabulsi, Nabeel; Sinha, Rajita; Ding, Yu-Shin; Carson, Richard E.; Neumeister, Alexander

    2013-01-01

    Objectives Noradrenergic dysfunction is implicated in obesity. The norepinephrine transporter (NET) regulates the synaptic availability of norepinephrine. However, NET availability has not been previously characterized in vivo in obese people using Positron Emission Tomography (PET) imaging. Here we report findings evaluating NET availability in individuals with obesity and matched lean (i.e., normal weight) comparison subjects. Methods Seventeen obese but otherwise healthy individuals with a mean±SD body mass index (BMI) of 34.7±2.6 and 17 lean individuals with a mean±SD BMI of 23.1±1.4 were studied using a High-Resolution Research Tomograph (HRRT) and (S,S)-[11C]O-methylreboxetine ([11C]-MRB), a radioligand selective for the NET. The regional brain NET binding potential (BPND) was estimated by the multilinear reference tissue model 2 (MRTM2) with the occipital cortex as a reference region. BPND for regions of interest were obtained with the Automated Anatomic Labeling (AAL) template registered to individual’s structural MR scans. Results Obese individuals had lower NET BPND values in the thalamus (p<0.038, 27% reduction) including within the pulvinar (p<0.083, 30% reduction), but not in the hypothalamus, locus coeruleus or the raphe nuclei, compared to lean individuals. When age was included as a covariate, the difference in NET BPND values remained significant in the thalamus (p<0.025) and pulvinar (p<0.042). Conclusions These results indicate that NET availability is decreased in the thalamus, including the pulvinar, in obese individuals. These findings further support data indicating noradrenergic dysfunction in obesity and suggest impaired NE clearance in obesity. PMID:24121204

  4. Synthesis and in silico evaluation of novel compounds for PET-based investigations of the norepinephrine transporter.

    PubMed

    Neudorfer, Catharina; Seddik, Amir; Shanab, Karem; Jurik, Andreas; Rami-Mark, Christina; Holzer, Wolfgang; Ecker, Gerhard; Mitterhauser, Markus; Wadsak, Wolfgang; Spreitzer, Helmut

    2015-01-01

    Since the norepinephrine transporter (NET) is involved in a variety of diseases, the investigation of underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest. Based on the previously described highly potent and selective NET ligand 1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1,3-dihydro-2H-benzimidaz- ol-2-one (Me@APPI), this paper aims at the development of several fluorinated methylamine-based analogs of this compound. The newly synthesized compounds were computationally evaluated for their interactions with the monoamine transporters and represent reference compounds for PET-based investigation of the NET. PMID:25608857

  5. Norepinephrine Transporter Regulation Mediates the Long-Term Behavioral Effects of the Antidepressant Desipramine

    PubMed Central

    Zhao, Zaorui; Baros, Alicia M; Zhang, Han-Ting; Lapiz, M Danet S; Bondi, Corina O; Morilak, David A; O’Donnell, James M

    2009-01-01

    The relationship between the ability of repeated desipramine treatment to cause downregulation of the norepinephrine transporter (NET) and produce antidepressant-like effects on behavior was determined. Treatment of rats with 15 mg/kg per day desipramine reduced NET expression, measured by 3H-nisoxetine binding and SDS–PAGE/immunoblotting, in cerebral cortex and hippocampus and reduced the time of immobility in the forced-swim test. The antidepressant-like effect on forced-swim behavior was evident 2 days following discontinuation of desipramine treatment when plasma and brain levels of desipramine and its major metabolite desmethyldesipramine were not detectable. Reduced NET expression resulted in reduced norepinephrine uptake, measured in vitro, and increased noradrenergic neurotransmission, measured in vivo using microdialysis. Overall, the dose–response and time-of-recovery relationships for altered NET expression matched those for production of antidepressant-like effects on behavior. The importance of increased noradrenergic neurotransmission in the persistent antidepressant-like effect on behavior was confirmed by demonstrating that it was blocked by inhibition of catecholamine synthesis with α-methyl-p-tyrosine. The present results suggest an important role for NET regulation in the long-term behavioral effects of desipramine and are consistent with clinical data suggesting that enhanced noradrenergic neurotransmission is necessary, but not sufficient, for its antidepressant actions. Understanding the mechanisms underlying NET regulation in vivo may suggest novel targets for therapeutic intervention in the treatment of depression. PMID:18418364

  6. Norepinephrine transporter function and tolerance to hypergravitational stress: A pilot study

    NASA Astrophysics Data System (ADS)

    Schroeder, Christoph; Strempel, Sebastian; Boese, Andrea; Hemmersbach, Ruth; Tank, Jens; Luft, Friedrich C.; Jordan, Jens

    Pharmacological norepinephrine transporter (NET) inhibition improves orthostatic tolerance on a tilt table while increasing heart rate. We tested the cardiovascular response to NET inhibition during a graded human centrifuge run in seven healthy men. g-Load was increased in 0.5 g steps with 3 g maximal g-load. On two separate days, patients were tested after selective NET inhibition with reboxetine or with placebo in a double-blind, randomized, crossover fashion. Resting diastolic blood pressure increased moderately with NET inhibition. Resting heart rate was profoundly increased by NET inhibition. NET inhibition augmented the heart rate response while attenuating the increase in blood pressure during hypergravitation. NET inhibition could be tested for its potential to improve cardiovascular g-tolerance.

  7. Luminal angiotensin II stimulates rat medullary thick ascending limb chloride transport in the presence of basolateral norepinephrine.

    PubMed

    Baum, Michel

    2016-02-15

    Angiotensin II (ANG II) is secreted by the proximal tubule resulting in a luminal concentration that is 100- to 1,000-fold greater than that in the blood. Luminal ANG II has been shown to stimulate sodium transport in the proximal tubule and distal nephron. Surprisingly, luminal ANG II inhibits NaCl transport in the medullary thick ascending limb (mTAL), a nephron segment responsible for a significant amount of NaCl absorption from the glomerular ultrafiltrate. We confirmed that addition of 10(-8) M ANG II to the lumen inhibited mTAL chloride transport (220 ± 19 to 165 ± 25 pmol·mm(-1)·min(-1), P < 0.01) and examined whether an interaction with basolateral norepinephrine existed to simulate the in vivo condition of an innervated tubule. We found that in the presence of a 10(-6) M norepinephrine bath, luminal ANG II stimulated mTAL chloride transport from 298 ± 18 to 364 ± 42 pmol·mm(-1)·min(-1) (P < 0.05). Stimulation of chloride transport by luminal ANG II was also observed with 10(-3) M bath dibutyryl cAMP in the bathing solution and bath isoproterenol. A bath of 10(-5) H-89 blocked the stimulation of chloride transport by norepinephrine and prevented the effect of luminal ANG II to either stimulate or inhibit chloride transport. Bath phentolamine, an α-adrenergic agonist, also prevented the decrease in mTAL chloride transport by luminal ANG II. Thus luminal ANG II increases chloride transport with basolateral norepinephrine; an effect likely mediated by stimulation of cAMP. Alpha-1 adrenergic stimulation prevents the inhibition of chloride transport by luminal ANG II. PMID:26661654

  8. Association of Changes in Norepinephrine and Serotonin Transporter Expression with the Long-Term Behavioral Effects of Antidepressant Drugs

    PubMed Central

    Zhao, Zaorui; Zhang, Han-Ting; Bootzin, Elianna; Millan, Mark J; O’Donnell, James M

    2009-01-01

    Previous work has shown that repeated desipramine treatment causes downregulation of the norepinephrine transporter (NET) and persistent antidepressant-like effects on behavior, ie effects observed 2 days after discontinuation of drug treatment when acute effects are minimized. The present study examined whether this mechanism generalizes to other antidepressants and also is evident for the serotonin transporter (SERT). Treatment of rats for 14 days with 20 mg/kg per day protriptyline or 7.5 mg/kg per day sertraline reduced NET and SERT expression, respectively, in cerebral cortex and hippocampus; these treatments also induced a persistent antidepressant-like effect on forced-swim behavior. Increased serotonergic neurotransmission likely mediated the behavioral effect of sertraline, as it was blocked by inhibition of serotonin synthesis with p-chlorophenylalanine; a parallel effect was observed previously for desipramine and noradrenergic neurotransmission. Treatment with 20 mg/kg per day reboxetine for 42, but not 14, days reduced NET expression; antidepressant-like effects on behavior were observed for both treatment durations. Treatment for 14 days with 70 mg/kg per day venlafaxine, which inhibits both the NET and SERT, or 10 mg/kg per day phenelzine, a monoamine oxidase inhibitor, produced antidepressant-like effects on behavior without altering NET or SERT expression. For all drugs tested, reductions of NET and SERT protein were not accompanied by reduced NET or SERT mRNA in locus coeruleus or dorsal raphe nucleus, respectively. Overall, the present results suggest an important, though not universal, role for NET and SERT regulation in the long-term behavioral effects of antidepressants. Understanding the mechanisms underlying transporter regulation in vivo may suggest novel targets for the development of antidepressant drugs. PMID:18923402

  9. Relative contributions of norepinephrine and serotonin transporters to antinociceptive synergy between monoamine reuptake inhibitors and morphine in the rat formalin model.

    PubMed

    Shen, Fei; Tsuruda, Pamela R; Smith, Jacqueline A M; Obedencio, Glenmar P; Martin, William J

    2013-01-01

    Multimodal analgesia is designed to optimize pain relief by coadministering drugs with distinct mechanisms of action or by combining multiple pharmacologies within a single molecule. In clinical settings, combinations of monoamine reuptake inhibitors and opioid receptor agonists have been explored and one currently available analgesic, tapentadol, functions as both a µ-opioid receptor agonist and a norepinephrine transporter inhibitor. However, it is unclear whether the combination of selective norepinephrine reuptake inhibition and µ-receptor agonism achieves an optimal antinociceptive synergy. In this study, we assessed the pharmacodynamic interactions between morphine and monoamine reuptake inhibitors that possess different affinities and selectivities for norepinephrine and serotonin transporters. Using the rat formalin model, in conjunction with measurements of ex vivo transporter occupancy, we show that neither the norepinephrine-selective inhibitor, esreboxetine, nor the serotonin-selective reuptake inhibitor, fluoxetine, produce antinociceptive synergy with morphine. Atomoxetine, a monoamine reuptake inhibitor that achieves higher levels of norepinephrine than serotonin transporter occupancy, exhibited robust antinociceptive synergy with morphine. Similarly, a fixed-dose combination of esreboxetine and fluoxetine which achieves comparable levels of transporter occupancy potentiated the antinociceptive response to morphine. By contrast, duloxetine, a monoamine reuptake inhibitor that achieves higher serotonin than norepinephrine transporter occupancy, failed to potentiate the antinociceptive response to morphine. However, when duloxetine was coadministered with the 5-HT3 receptor antagonist, ondansetron, potentiation of the antinociceptive response to morphine was revealed. These results support the notion that inhibition of both serotonin and norepinephrine transporters is required for monoamine reuptake inhibitor and opioid-mediated antinociceptive

  10. Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue.

    PubMed

    Ayala-Lopez, Nadia; Jackson, William F; Burnett, Robert; Wilson, James N; Thompson, Janice M; Watts, Stephanie W

    2015-12-01

    Perivascular adipose tissue (PVAT) reduces vasoconstriction to norepinephrine (NE). A mechanism by which PVAT could function to reduce vascular contraction is by decreasing the amount of NE to which the vessel is exposed. PVATs from male Sprague-Dawley rats were used to test the hypothesis that PVAT has a NE uptake mechanism. NE was detected by HPLC in mesenteric PVAT and isolated adipocytes. Uptake of NE (10 μM) in mesenteric PVAT was reduced by the NE transporter (NET) inhibitor nisoxetine (1 μM, 73.68 ± 7.62%, all values reported as percentages of vehicle), the 5-hydroxytryptamine transporter (SERT) inhibitor citalopram (100 nM) with the organic cation transporter 3 (OCT3) inhibitor corticosterone (100 μM, 56.18 ± 5.21%), and the NET inhibitor desipramine (10 μM) with corticosterone (100 μM, 61.18 ± 6.82%). Aortic PVAT NE uptake was reduced by corticosterone (100 μM, 53.01 ± 10.96%). Confocal imaging of mesenteric PVAT stained with 4-[4-(dimethylamino)-styrl]-N-methylpyridinium iodide (ASP(+)), a fluorescent substrate of cationic transporters, detected ASP(+) uptake into adipocytes. ASP(+) (2 μM) uptake was reduced by citalopram (100 nM, 66.68 ± 6.43%), corticosterone (100 μM, 43.49 ± 10.17%), nisoxetine (100 nM, 84.12 ± 4.24%), citalopram with corticosterone (100 nM and 100 μM, respectively, 35.75 ± 4.21%), and desipramine with corticosterone (10 and 100 μM, respectively, 50.47 ± 5.78%). NET protein was not detected in mesenteric PVAT adipocytes. Expression of Slc22a3 (OCT3 gene) mRNA and protein in PVAT adipocytes was detected by RT-PCR and immunocytochemistry, respectively. These end points support the presence of a transporter-mediated NE uptake system within PVAT with a potential mediator being OCT3. PMID:26432838

  11. Nothing but NET: A review of norepinephrine transporter expression and efficacy of 131I-mIBG therapy

    PubMed Central

    Streby, Keri A; Shah, Nilay; Ranalli, Mark A; Kunkler, Anne; Cripe, Timothy P

    2015-01-01

    Neuroblastoma is unique amongst common pediatric cancers for its expression of the norepinephrine transporter (NET), enabling tumor-selective imaging and therapy with radioactive analogues of norepinephrine. The majority of neuroblastoma tumors are avid for 123I-metaiodobenzaguanidine (mIBG) on imaging, yet the therapeutic response to 131I-mIBG is only 30% in clinical trials, and off-target effects cause short- and long-term morbidity. We review the contemporary understanding of the tumor-selective uptake, retention, and efflux of meta-iodobenzylguanidine (mIBG) and strategies currently in development for improving its efficacy. Combination treatment strategies aimed at enhancing NET are likely necessary to reach the full potential of 131I-mIBG therapy. PMID:25175627

  12. Nothing but NET: a review of norepinephrine transporter expression and efficacy of 131I-mIBG therapy.

    PubMed

    Streby, Keri A; Shah, Nilay; Ranalli, Mark A; Kunkler, Anne; Cripe, Timothy P

    2015-01-01

    Neuroblastoma is unique amongst common pediatric cancers for its expression of the norepinephrine transporter (NET), enabling tumor-selective imaging and therapy with radioactive analogues of norepinephrine. The majority of neuroblastoma tumors are avid for (123)I-metaiodobenzaguanidine (mIBG) on imaging, yet the therapeutic response to (131) I-mIBG is only 30% in clinical trials, and off-target effects cause short- and long-term morbidity. We review the contemporary understanding of the tumor-selective uptake, retention, and efflux of meta-iodobenzylguanidine (mIBG) and strategies currently in development for improving its efficacy. Combination treatment strategies aimed at enhancing NET are likely necessary to reach the full potential of (131)I-mIBG therapy. PMID:25175627

  13. Ethylenedioxy homologs of N-methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) and its corresponding cathinone analog methylenedioxymethcathinone: Interactions with transporters for serotonin, dopamine, and norepinephrine.

    PubMed

    Del Bello, Fabio; Sakloth, Farhana; Partilla, John S; Baumann, Michael H; Glennon, Richard A

    2015-09-01

    N-Methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; 'Ecstasy'; 1) and its β-keto analog methylone (MDMC; 2) are popular drugs of abuse. Little is known about their ring-expanded ethylenedioxy homologs. Here, we prepared N-methyl-(3,4-ethylenedioxyphenyl)-2-aminopropane (EDMA; 3), both of its optical isomers, and β-keto EDMA (i.e., EDMC; 4) to examine their effects at transporters for serotonin (SERT), dopamine (DAT), and norepinephrine (NET). In general, ring-expansion of the methylenedioxy group led to a several-fold reduction in potency at all three transporters. With respect to EDMA (3), S(+)3 was 6-fold, 50-fold, and 8-fold more potent than its R(-) enantiomer at SERT, DAT, and NET, respectively. Overall, in the absence of a β-carbonyl group, the ethylenedioxy (i.e., 1,4-dioxane) substituent seems better accommodated at SERT than at DAT and NET. PMID:26233799

  14. Ethylenedioxy Homologs of N-Methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) and its Corresponding Cathinone Analog Methylenedioxymethcathinone: Interactions with Transporters for Serotonin, Dopamine, and Norepinephrine

    PubMed Central

    Del Bello, Fabio; Sakloth, Farhana; Partilla, John S.; Baumann, Michael H.; Glennon, Richard A.

    2015-01-01

    N -Methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; ‘Ecstasy’; 1) and its β-keto analog methylone (MDMC; 2) are popular drugs of abuse. Little is known about their ring-expanded ethylenedioxy homologs. Here, we prepared N-methyl-(3,4-ethylenedioxyphenyl)-2-aminopropane (EDMA; 3), both of its optical isomers, and β-keto EDMA (i.e., EDMC; 4) to examine their effects at transporters for serotonin (SERT), dopamine (DAT), and norepinephrine (NET). In general, ring-expansion of the methylenedioxy group led to a several-fold reduction in potency at all three transporters. With respect to EDMA (3), S(+)3 was 6-fold, 50-fold, and 8-fold more potent than its R(−) enantiomer at SERT, DAT, and NET, respectively. Overall, in the absence of a β-carbonyl group, the ethylenedioxy (i.e., 1,4-dioxane) substituent seems better accommodated at SERT than at DAT and NET. PMID:26233799

  15. Association Study between Norepinephrine Transporter Gene Polymorphism and Schizophrenia in a Korean Population

    PubMed Central

    Choo, Mira; Hwang, Jung-A; Jeon, Sang Won; Oh, So-Young; Yoon, Ho-kyoung; Lee, Heon-Jeong

    2015-01-01

    Objective We aimed to investigate possible associations between three norepinephrine transporter gene (SLC6A2) single nucleotide polymorphisms (T182C, A3081T, and G1287A) and schizophrenia. Also, we investigated the relationships of those polymorphisms with clinical severity and characteristics of schizophrenia. Methods Participants were 220 schizophrenia patients in the acute phase and 167 healthy controls. The genotype, allele frequency, and haplotype of each group were analyzed for T182C, A3081T, and G1287A polymorphisms. Of the 220 schizophrenia patients, 163 patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) and the Korean version of the Calgary depression scale for schizophrenia (K-CDSS) at baseline. Results We found no significant differences between the schizophrenia patient group and the control group in genotype distribution or allele frequency of the three tested polymorphisms. Likewise, we could not find any significant differences in genotype or allele frequency by analyzing according to gender. In the haplotype study, no significant association emerged between specific haplotype combinations and schizophrenia. We also found no association between clinical scales (PANSS and K-CDSS) and the studied polymorphisms. Conclusion Our results suggest that the investigated polymorphisms of the NET gene are not associated with susceptibility to schizophrenia or its clinical features in a Korean population. However, this study remains significant because it is the first haplotype study to investigate associations between NET gene (SLC6A2) single nucleotide polymorphisms and schizophrenia in a Korean population. Future research with a larger sample size and more genetic markers is needed to replicate our results. PMID:26508968

  16. Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype

    PubMed Central

    Sengupta, Sarojini M.; Grizenko, Natalie; Thakur, Geeta A.; Bellingham, Johanne; DeGuzman, Rosherrie; Robinson, Sandra; TerStepanian, Marina; Poloskia, Anna; Shaheen, S.M.; Fortier, Marie-Eve; Choudhry, Zia; Joober, Ridha

    2012-01-01

    Background Pharmacologic and animal studies have strongly implicated the norepinephrine transporter (NET) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We conducted a family-based study, with stratification based on sex and subtype, to test the association between 30 tag single-nucleotide polymorphisms (SNPs) within the gene encoding NET (SLC6A2) and ADHD. Methods Family-based association tests were conducted with the categorical diagnosis of ADHD, as well as quantitative phenotypes of clinical relevance (Conners Global Index for Teachers and Parents, and Child Behavior Checklist measures). Sliding window haplotype analysis was conducted with screening based on conditional power using PBAT. Results A previously reported association with rs3785143 was confirmed in this study. Further, extensive association was observed with haplotype blocks, with a differential pattern observed based on sex and subtype. The 5′ region of the gene (encompassing haplotype block 1 and including a functional promoter SNP, rs28386840) showed an association with ADHD in girls (irrespective of subtype). A different region of the gene (distributed around haplotype block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2. Limitations The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype. Conclusion The results obtained in this family-based study suggest that haplotype blocks within different regions of SLC6A2 show differential association with the disorder based on sex and subtype. These associations may have been masked in previous studies when tests were conducted with pooled samples. PMID:22297068

  17. The Norepinephrine Transporter in Attention-Deficit/Hyperactivity Disorder Investigated With Positron Emission Tomography

    PubMed Central

    Rami-Mark, Christina; Savli, Markus; Höflich, Anna; Kranz, Georg S.; Hahn, Andreas; Kutzelnigg, Alexandra; Traub-Weidinger, Tatjana; Mitterhauser, Markus; Wadsak, Wolfgang; Hacker, Marcus; Volkow, Nora D.; Kasper, Siegfried; Lanzenberger, Rupert

    2015-01-01

    IMPORTANCE Attention-deficit/hyperactivity disorder (ADHD) research has long focused on the dopaminergic system’s contribution to pathogenesis, although the results have been inconclusive. However, a case has been made for the involvement of the noradrenergic system, which modulates cognitive processes, such as arousal, working memory, and response inhibition, all of which are typically affected in ADHD. Furthermore, the norepinephrine transporter (NET) is an important target for frequently prescribed medication in ADHD. Therefore, the NET is suggested to play a critical role in ADHD. OBJECTIVE To explore the differences in NET nondisplaceable binding potential (NET BPND) using positron emission tomography and the highly selective radioligand (S,S)-[18F]FMeNER-D2 [(S,S)-2-(α-(2-[18F]fluoro[2H2]methoxyphenoxy)benzyl)morpholine] between adults with ADHD and healthy volunteers serving as controls. DESIGN, SETTING, AND PARTICIPANTS Twenty-two medication-free patients with ADHD (mean [SD] age, 30.7 [10.4] years; 15 [68%] men) without psychiatric comorbidities and 22 age- and sex-matched healthy controls (30.9 [10.6] years; 15 [68%] men) underwent positron emission tomography once. A linear mixed model was used to compare NET BPND between groups. MAIN OUTCOMES AND MEASURES The NET BPND in selected regions of interest relevant for ADHD, including the hippocampus, putamen, pallidum, thalamus, midbrain with pons (comprising a region of interest that includes the locus coeruleus), and cerebellum. In addition, the NET BPND was evaluated in thalamic subnuclei (13 atlas-based regions of interest). RESULTS We found no significant differences in NET availability or regional distribution between patients with ADHD and healthy controls in all investigated brain regions (F1,41 < 0.01; P = .96). Furthermore, we identified no significant association between ADHD symptom severity and regional NET availability. Neither sex nor smoking status influenced NET availability. We determined

  18. No Evidence for Association Between Norepinephrine Transporter-3081 (A/T) Polymorphism and Attention Deficit Hyperactivity Disorder in Iranian Population

    PubMed Central

    Eslami Amirabadi, Mohammad Reza; Davari-Ashtiani, Rozita; Khademi, Mojgan; RajeziEsfahani, Sepideh; Emamalizadeh, Babak; Movafagh, Abolfazl; Arabgol, Fariba; Sadr, Said; Darvish, Hossein; Razjouyan, Katayoon

    2015-01-01

    Background: Attention Deficit Hyperactivity Disorder (ADHD) can lead to drastic problems for the patient and its worldwide prevalence is 5%-12%. It also has many comorbidities with other disorders, and the genetic contribution seems the most significant cause. Objectives: The current study was conducted to investigate the association between norepinephrine transporter-3081 (A/T) polymorphisms and ADHD in Iranian population. Patients and Methods: Participants were chosen from children and adolescents diagnosed with ADHD referred to Imam Hoseyn Hospital. A child and adolescent psychiatrist confirmed the diagnosis using the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL) semi-structural interview. The control group was from pupils of schools in Tehran (capital city of Iran) who had no history or presence of psychiatric and medical complications. Also, a child and adolescent psychiatrist confirmed their health using the K-SADS-PL semi-structural interview. Genetic examinations were DNA distraction, Polymerase Chain Reaction (PCR), and Restricted Fragment Length Polymorphism (RFLP), which were conducted according to standard protocols. The statistical analysis was performed using chi-square and Fisher's exact test in SPSS version 21. Results: The percentages of ADHD subtypes for combined, inattentive, and hyperactive/impulsive were 72.2%, 17.2%, and 11.9%, respectively. There was no significant association between norepinephrine transporter polymorphism and ADHD (P = 0.81). Moreover, no significant relationship was found between gender [male (P = 0.92) and female (P = 0.63)] and polymorphism. No significant association was found between subtypes of ADHD [combined (P = 0.46), inattentive (P = 0.41), hyperactive/impulsive (P = 0.32)] and polymorphism SCL6A2. This lack of association can also be seen in gender in every subtype. Conclusions: The results of the study show no significant association between norepinephrine transporter polymorphism SCL6A2 and ADHD. PMID

  19. Differential Internalization Rates and Postendocytic Sorting of the Norepinephrine and Dopamine Transporters Are Controlled by Structural Elements in the N Termini.

    PubMed

    Vuorenpää, Anne; Jørgensen, Trine N; Newman, Amy H; Madsen, Kenneth L; Scheinin, Mika; Gether, Ulrik

    2016-03-11

    The norepinephrine transporter (NET) mediates reuptake of synaptically released norepinephrine in central and peripheral noradrenergic neurons. The molecular processes governing availability of NET in the plasma membrane are poorly understood. Here we use the fluorescent cocaine analogue JHC 1-64, as well as several other approaches, to investigate the trafficking itinerary of NET in live noradrenergic neurons. Confocal imaging revealed extensive constitutive internalization of JHC 1-64-labeled NET in the neuronal somata, proximal extensions and presynaptic boutons. Phorbol 12-myristate 13-acetate increased intracellular accumulation of JHC 1-64-labeled NET and caused a parallel reduction in uptake capacity. Internalized NET strongly colocalized with the "long loop" recycling marker Rab11, whereas less overlap was seen with the "short loop" recycling marker Rab4 and the late endosomal marker Rab7. Moreover, mitigating Rab11 function by overexpression of dominant negative Rab11 impaired NET function. Sorting of NET to the Rab11 recycling compartment was further supported by confocal imaging and reversible biotinylation experiments in transfected differentiated CATH.a cells. In contrast to NET, the dopamine transporter displayed markedly less constitutive internalization and limited sorting to the Rab11 recycling compartment in the differentiated CATH.a cells. Exchange of domains between the two homologous transporters revealed that this difference was determined by non-conserved structural elements in the intracellular N terminus. We conclude that NET displays a distinct trafficking itinerary characterized by continuous shuffling between the plasma membrane and the Rab11 recycling compartment and that the functional integrity of the Rab11 compartment is critical for maintaining proper presynaptic NET function. PMID:26786096

  20. Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice.

    PubMed

    Ansorge, Mark S; Morelli, Emanuela; Gingrich, Jay A

    2008-01-01

    Serotonin (5-HT) acts as a neurotransmitter, but also modulates brain maturation during early development. The demonstrated influence of genetic variants on brain function, personality traits, and susceptibility to neuropsychiatric disorders suggests a critical importance of developmental mechanisms. However, little is known about how and when developmentally perturbed 5-HT signaling affects circuitry and resulting behavior. The 5-HT transporter (5-HTT) is a key regulator of extracellular 5-HT levels and we used pharmacologic strategies to manipulate 5-HTT function during development and determine behavioral consequences. Transient exposure to the 5-HTT inhibitors fluoxetine, clomipramine, and citalopram from postnatal day 4 (P4) to P21 produced abnormal emotional behaviors in adult mice. Similar treatment with the norepinephrine transporter (NET) inhibitor, desipramine, did not adversely affect adult behavior, suggesting that 5-HT and norepinephrine (NE) do not share the same effects on brain development. Shifting our period of treatment/testing to P90/P185 failed to mimic the effect of earlier exposure, demonstrating that 5-HT effects on adult behavior are developmentally specific. We have hypothesized that early-life perturbations of 5-HT signaling affect corticolimbic circuits that do not reach maturity until the peri-adolescent period. In support of this idea, we found that abnormal behaviors resulting from postnatal fluoxetine exposure have a post-pubescent onset and persist long after reaching adult age. A better understanding of the underlying 5-HT sensitive circuits and how they are perturbed should lead to new insights into how various genetic polymorphisms confer their risk to carriers. Furthermore, these studies should help determine whether in utero exposure to 5-HTT blocking drugs poses a risk for behavioral abnormalities in later life. PMID:18171937

  1. Imaging the Norepinephrine Transporter in Neuroblastoma: A Comparison of [18F]-MFBG and 123I-MIBG

    PubMed Central

    Zhang, Hanwen; Huang, Ruimin; Cheung, Nai-Kong V.; Guo, Hongfen; Zanzonico, Pat B.; Thaler, Howard T.; Lewis, Jason S.; Blasberg, Ronald G.

    2014-01-01

    Purpose The norepinephrine transporter (NET) is a critical regulator of catecholamine uptake in normal physiology and is expressed in neuroendocrine tumors like neuroblastoma. Although the norepinephrine analog, meta-iodobenzylguanidine (MIBG), is an established substrate for NET, 123I/131I-MIBG has several clinical limitations for diagnostic imaging. In the current studies, we evaluated meta-[18F]-fluorobenzylguanidine ([18F]-MFBG) and compared it to 123I-MIBG for imaging NET-expressing neuroblastomas. Experimental Design NET expression levels in neuroblastoma cell lines were determined by Western blot and 123I-MIBG uptake assays. Five neuroblastoma cell lines and two xenografts (SK-N-BE(2)C and LAN1) expressing different levels of NET were used for comparative in vitro and in vivo uptake studies. Results The uptake of [18F]-MFBG in cells was specific and proportional to the expression level of NET. Although [18F]-MFBG had a 3-fold lower affinity for NET and approximately 2-fold lower cell uptake in vitro compared to that of 123I-MIBG, the in vivo imaging and tissue radioactivity concentration measurements demonstrated higher [18F]-MFBG xenograft uptake and tumor-to-normal organ ratios at 1 and 4 h post-injection. A comparison of 4 h [18F]-MFBG PET imaging with 24 h 123I-MIBG SPECT imaging showed a ~3-fold higher tumor uptake of [18F]-MFBG, but slightly lower tumor-to-background ratios in mice. Conclusions [18F]-MFBG is a promising radiopharmaceutical for specifically imaging NET-expressing neuroblastomas, with fast pharmacokinetics and whole-body clearance. [18F]-MFBG PET imaging shows higher sensitivity, better detection of small lesions with low NET expression, allows same day scintigraphy with a shorter image acquisition time, and has the potential for lower patient radiation exposure compared to 131I/123I-MIBG. PMID:24573553

  2. Analysis of Association between Norepinephrine Transporter Gene Polymorphisms and Personality Traits of NEO-FFI in a Japanese Population

    PubMed Central

    Narita, Shin; Nagahori, Kenta; Numajiri, Maki; Yoshihara, Eiji; Ohtani, Nobuyo; Ishigooka, Jun

    2015-01-01

    Objective Norepinephrine is an important chemical messenger that is involved in mood and stress in humans, and is reabsorbed by the norepinephrine transporter (NET). According to Cloninger's theory, the noradrenergic system mediates the personality trait of reward dependence. Thus far, although association studies on NET gene polymorphisms and Cloninger's personality traits have been reported, they yielded inconsistent results. Therefore, in the present study we investigated whether or not the 1287G/A, -182T/C and -3081A/T polymorphisms of the NET gene (SLC6A2) are associated with reward dependence-related traits, as assessed by the five-factor model. Methods After written informed consent was obtained from participants, the three NET gene polymorphisms were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), and personality was assessed by the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) in 270 Japanese university students. Results A significant relation was found between the -3081A/T functional promoter polymorphism and NEO-FFI scores: those with the T allele exhibited a lower extraversion (E) score than those without the T allele (Mann-Whitney U-test: z=-3.861, p<0.001). However, there was no correlation between the other NET gene polymorphisms and E score, and no association with other dimensions and these three polymorphisms. Conclusion We conclude that the -3081A/T functional polymorphism in the NET gene may affect the extraversion of reward dependence-related traits, as measured by NEO-FFI. However, we used only the shortened version of NEO-PI-R in this study. Further investigations are necessary using the full version of self-rating personality questionnaires. PMID:26207133

  3. Association between polymorphism of the norepinephrine transporter gene rs2242446 and rs5669 loci and depression disorders

    PubMed Central

    Pan, Yu; Cheng, Qi; Shan, Mo-Shui; Yan, Jin

    2015-01-01

    Objective: To explore the association between polymorphism of the norepinephrine transporter (NET) gene rs2242446 and rs5669 loci and depression in Chinese Han population. Methods: A case-control study was carried out, the gene types and allele distributions of NFT gene rs2242446 and rs5569 loci in 302 depression patients and 302 healthy controls were detected by Taqman SNP genotyping technology. Results: The gene types and allele frequency distributions of NFT gene rs2242446 and rs5569 loci had significant differences between case group and control group (rs2242446, x2=26.045, P<0.05, x2=8.827, P<0.05, rs5569, x2=42.47, P<0.05, x2=20.9, P<0.05). The CC genotype of NET gene rs2242446 locus and rs5569 loci was a protective factor of depression compared with the CT and TT genotypes. Conclusion: The NET genepoly morphism of rs2242446 and rs5569 loci was a ssociated with depression in Chinese Han population, in which the CC genotype of rs2242446 and rs5569 loci was a protective factor of depression. PMID:26770504

  4. Chronic serotonin-norepinephrine reuptake transporter inhibition modifies basal respiratory output in adult mouse in vitro and in vivo

    PubMed Central

    Warren, Kelly A.; Solomon, Irene C.

    2012-01-01

    Respiratory disturbances are a common feature of panic disorder and present as breathing irregularity, hyperventilation, and increased sensitivity to carbon dioxide. Common therapeutic interventions, such as tricyclic (TCA) and selective serotonin reuptake inhibitor (SSRI) antidepressants, have been shown to ameliorate not only the psychological components of panic disorder but also the respiratory disturbances. These drugs are also prescribed for generalized anxiety and depressive disorders, neither of which are characterized by respiratory disturbances, and previous studies have demonstrated that TCAs and SSRIs exert effects on basal respiratory activity in animal models without panic disorder symptoms. Whether serotonin-norepinephrine reuptake inhibitors (SNRIs) have similar effects on respiratory activity remains to be determined. Therefore, the current study was designed to investigate the effects of chronic administration of the SNRI antidepressant venlafaxine (VHCL) on basal respiratory output. For these experiments, we recorded phrenic nerve discharge in an in vitro arterially-perfused adult mouse preparation and diaphragm electromyogram (EMG) activity in an in vivo urethane-anesthetized adult mouse preparation. We found that following 28-d VHCL administration, basal respiratory burst frequency was markedly reduced due to an increase in expiratory duration (TE), and the inspiratory duty cycle (TI/Ttot) was significantly shortened. In addition, post-inspiratory and spurious expiratory discharges were seen in vitro. Based on our observations, we suggest that drugs capable of simultaneously blocking both 5-HT and NE reuptake transporters have the potential to influence the respiratory control network in patients using SNRI therapy. PMID:22871263

  5. Corticosterone administration upregulated expression of norepinephrine transporter and dopamine β-hydroxylase in rat locus coeruleus and its terminal regions

    PubMed Central

    Fan, Yan; Chen, Ping; Li, Ying; Cui, Kui; Noel, Daniel M.; Cummins, Elizabeth D.; Brown, Russell W.; Zhu, Meng-Yang

    2013-01-01

    Stress has been reported to activate the locus coeruleus (LC)–noradrenergic system. In the present study, corticosterone (CORT) was orally administrated to rats for 21 days to mimic stress status. In situ hybridization measurements showed that CORT ingestion significantly increased mRNA levels of norepinephrine transporter (NET) and dopamine β-hydroxylase (DBH) in the LC region. Immunofluorescence staining and western blotting revealed that CORT treatment also increased protein levels of NET and DBH in the LC, as well as NET protein levels in the hippocampus, the frontal cortex and the amygdala. However, CORT-induced increase of DBH protein levels only appeared in the hippocampus and the amygdala. Elevated NET and DBH expression in most of these areas (except for NET protein levels in the LC) was abolished by simultaneous treatment with combination of corticosteroid receptor antagonist mifepristone and spironolactone (s.c. for 21 days). Also, treatment with mifepristone alone prevented CORT-induced increases of NET expression and DBH protein levels in the LC. In addition, behavioral tasks showed that CORT ingestion facilitated escape in avoidance trials using an elevated T-maze, but interestingly, there was no significant effect on the escape trial. Corticosteroid receptor antagonists failed to counteract this response in CORT-treated rats. In the open-field task, CORT treatment resulted in less activity in a defined central zone compared to controls and corticosteroid receptor antagonist treatment alleviated this increase. In conclusion, the present study demonstrates that chronic exposure to CORT results in a phenotype that mimics stress-induced alteration of noradrenergic phenotypes, but the effects on behavior are task-dependent. As the sucrose consumption test strongly suggests CORT ingestion-induced depression-like behavior, further elucidation of underlying mechanisms may improve our understanding of the correlation between stress and the development of

  6. Effects of norepinephrine transporter gene variants on NET binding in ADHD and healthy controls investigated by PET

    PubMed Central

    Sigurdardottir, Helen L.; Kranz, Georg S.; Rami‐Mark, Christina; James, Gregory M.; Vanicek, Thomas; Gryglewski, Gregor; Kautzky, Alexander; Hienert, Marius; Traub‐Weidinger, Tatjana; Mitterhauser, Markus; Wadsak, Wolfgang; Hacker, Marcus; Rujescu, Dan; Kasper, Siegfried

    2016-01-01

    Abstract Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder with a strong genetic component. The norepinephrine transporter (NET) is a key target for ADHD treatment and the NET gene has been of high interest as a possible modulator of ADHD pathophysiology. Therefore, we conducted an imaging genetics study to examine possible effects of single nucleotide polymorphisms (SNPs) within the NET gene on NET nondisplaceable binding potential (BPND) in patients with ADHD and healthy controls (HCs). Twenty adult patients with ADHD and 20 HCs underwent (S,S)‐[18F]FMeNER‐D2 positron emission tomography (PET) and were genotyped on a MassARRAY MALDI‐TOF platform using the Sequenom iPLEX assay. Linear mixed models analyses revealed a genotype‐dependent difference in NET BPND between groups in the thalamus and cerebellum. In the thalamus, a functional promoter SNP (−3081 A/T) and a 5′‐untranslated region (5′UTR) SNP (−182 T/C), showed higher binding in ADHD patients compared to HCs depending on the major allele. Furthermore, we detected an effect of genotype in HCs, with major allele carriers having lower binding. In contrast, for two 3′UTR SNPs (*269 T/C, *417 A/T), ADHD subjects had lower binding in the cerebellum compared to HCs depending on the major allele. Additionally, symptoms of hyperactivity and impulsivity correlated with NET BPND in the cerebellum depending on genotype. Symptoms correlated positively with cerebellar NET BPND for the major allele, while symptoms correlated negatively to NET BPND in minor allele carriers. Our findings support the role of genetic influence of the NE system on NET binding to be pertubated in ADHD. Hum Brain Mapp 37:884–895, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID:26678348

  7. Effects of norepinephrine transporter gene variants on NET binding in ADHD and healthy controls investigated by PET.

    PubMed

    Sigurdardottir, Helen L; Kranz, Georg S; Rami-Mark, Christina; James, Gregory M; Vanicek, Thomas; Gryglewski, Gregor; Kautzky, Alexander; Hienert, Marius; Traub-Weidinger, Tatjana; Mitterhauser, Markus; Wadsak, Wolfgang; Hacker, Marcus; Rujescu, Dan; Kasper, Siegfried; Lanzenberger, Rupert

    2016-03-01

    Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder with a strong genetic component. The norepinephrine transporter (NET) is a key target for ADHD treatment and the NET gene has been of high interest as a possible modulator of ADHD pathophysiology. Therefore, we conducted an imaging genetics study to examine possible effects of single nucleotide polymorphisms (SNPs) within the NET gene on NET nondisplaceable binding potential (BPND ) in patients with ADHD and healthy controls (HCs). Twenty adult patients with ADHD and 20 HCs underwent (S,S)-[18F]FMeNER-D2 positron emission tomography (PET) and were genotyped on a MassARRAY MALDI-TOF platform using the Sequenom iPLEX assay. Linear mixed models analyses revealed a genotype-dependent difference in NET BPND between groups in the thalamus and cerebellum. In the thalamus, a functional promoter SNP (-3081 A/T) and a 5'-untranslated region (5'UTR) SNP (-182 T/C), showed higher binding in ADHD patients compared to HCs depending on the major allele. Furthermore, we detected an effect of genotype in HCs, with major allele carriers having lower binding. In contrast, for two 3'UTR SNPs (*269 T/C, *417 A/T), ADHD subjects had lower binding in the cerebellum compared to HCs depending on the major allele. Additionally, symptoms of hyperactivity and impulsivity correlated with NET BPND in the cerebellum depending on genotype. Symptoms correlated positively with cerebellar NET BPND for the major allele, while symptoms correlated negatively to NET BPND in minor allele carriers. Our findings support the role of genetic influence of the NE system on NET binding to be pertubated in ADHD. PMID:26678348

  8. Evaluation of [11C]MRB for assessment of occupancy of norepinephrine transporters: Studies with atomoxetine in non-human primates

    PubMed Central

    Gallezot, Jean-Dominique; Weinzimmer, David; Nabulsi, Nabeel; Lin, Shu-Fei; Fowles, Krista; Sandiego, Christine; McCarthy, Timothy J.; Maguire, R. Paul; Carson, Richard E.; Ding, Yu-Shin

    2013-01-01

    [11C]MRB is one of the most promising radioligands used to measure brain norepinephrine transporters (NET) with positron emission tomography (PET). The objective of this study was to evaluate the suitability of [11C]MRB for drug occupancy studies of NET using atomoxetine (ATX), a NET uptake inhibitor used in the treatment of depression and attention-deficit hyperactivity disorder (ADHD). A second goal of the study was identification of a suitable reference region. Ten PET studies were performed in three anesthetized rhesus monkeys following an infusion of ATX or placebo. [11C]MRB arterial input functions and ATX plasma levels were also measured. A dose-dependent reduction of [11C]MRB volume of distribution was observed after correction for [11C]MRB plasma free fraction. ATX IC50 was estimated to be 31±10 ng/mL plasma. This corresponds to an effective dose (ED50) of 0.13 mg/kg, which is much lower than the therapeutic dose of ATX in ADHD (1.0–1.5 mg/kg). [11C]MRB binding potential BPND in the thalamus was estimated to be 1.8±0.3. Defining a reference region for a NET radiotracer is challenging due to the widespread and relatively uniform distribution of NET in the brain. Three regions were evaluated for use as reference region: caudate, putamen and occipital cortex. Caudate was found to be the most suitable for preclinical drug occupancy studies in rhesus monkeys. The IC50 estimate obtained using MRTM2 BPND without arterial blood sampling was 21±3 ng/mL (using caudate as the reference region). This study demonstrated that [11C]MRB is suitable for drug occupancy studies of NET. PMID:20869448

  9. Imaging human brown adipose tissue under room temperature conditions with 11C-MRB, a selective norepinephrine transporter PET ligand

    PubMed Central

    Hwang, Janice J.; Yeckel, Catherine W.; Gallezot, Jean-Dominique; Aguiar, Renata Belfort-De; Ersahin, Devrim; Gao, Hong; Kapinos, Michael; Nabulsi, Nabeel; Huang, Yiyun; Cheng, David; Carson, Richard E.; Sherwin, Robert; Ding, Yu-Shin

    2015-01-01

    Introduction Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and is tightly regulated by the sympathetic nervous system (SNS). However, current BAT imaging modalities require cold stimulation and are often unreliable to detect BAT in the basal state, at room temperature (RT). We have shown previously that BAT can be detected in rodents under both RT and cold conditions with 11C-MRB ((S,S)-11C-O-methylreboxetine), a highly selective ligand for the norepinephrine transporter (NET). Here, we evaluate this novel approach for BAT detection in adult humans under RT conditions. Methods Ten healthy, Caucasian subjects (5 M: age 24.6±2.6, BMI 21.6±2.7 kg/m2; 5 F: age 25.4±2.1, BMI 22.1±1.0 kg/m2) underwent 11C-MRB PET-CT imaging for cervical/supraclavicular BAT under RT and cold-stimulated conditions (RPCM Cool vest; enthalpy 15°C) compared to 18F-FDG PET-CT imaging. Uptake of 11C-MRB, was quantified as the distribution volume ratio (DVR) using the occipital cortex as a low NET density reference region. Total body fat and lean body mass were assessed via bioelectrical impedance analysis. Results As expected, 18F-FDG uptake in BAT was difficult to identify at RT but easily detected with cold stimulation (p=0.01). In contrast, BAT 11C-MRB uptake (also normalized for muscle) was equally evident under both RT and cold conditions (BAT DVR: RT 1.0±0.3 vs. cold 1.1±0.3, p=0.31; BAT/muscle DVR: RT 2.3±0.7 vs. cold 2.5±0.5, p=0.61). Importantly, BAT DVR and BAT/muscle DVR of 11C-MRB at RT correlated positively with core body temperature (r=0.76, p=0.05 and r=0.92, p=0.004, respectively), a relationship not observed with 18F-FDG (p=0.63). Furthermore, there were gender differences in 11C-MRB uptake in response to cold (p=0.03), which reflected significant differences in the change in 11C-MRB as a function of both body composition and body temperature. Conclusions Unlike 18F-FDG, the uptake of 11C-MRB in BAT offers a unique opportunity to

  10. Corticotropin releasing factor up-regulates the expression and function of norepinephrine transporter in SK-N-BE (2) M17 cells.

    PubMed

    Huang, Jingjing; Tufan, Turan; Deng, Maoxian; Wright, Gary; Zhu, Meng-Yang

    2015-10-01

    Corticotropin releasing factor (CRF) has been implicated to act as a neurotransmitter or modulator in central nervous activation during stress. In this study, we examined the regulatory effect of CRF on the expression and function of the norepinephrine transporter (NET) in vitro. SK-N-BE (2) M17 cells were exposed to different concentrations of CRF for different periods. Results showed that exposure of cells to CRF significantly increased mRNA and protein levels of NET in a concentration- and time-dependent manner. The CRF-induced increase in NET expression was mimicked by agonists of either CRF receptor 1 or 2. Furthermore, similar CRF treatments induced a parallel increase in the uptake of [(3) H] norepinephrine. Both increased expression and function of NET caused by CRF were abolished by simultaneous administration of CRF receptor antagonists, indicating a mediation by CRF receptors. However, there was no additive effect for the combination of both receptor antagonists. Chromatin immunoprecipitation assays confirm an increased acetylation of histone H3 on the NET promoter following treatment with CRF. Taken together, this study demonstrates that CRF up-regulates the expression and function of NET in vitro. This regulation is mediated through CRF receptors and an epigenetic mechanism related to histone acetylation may be involved. This CRF-induced regulation on NET expression and function may play a role in development of stress-related depression and anxiety. This study demonstrated that corticotropin release factor (CRF) up-regulated the expression and function of norepinephrine transporter (NET) in a concentration- and time-dependent manner, through activation of CRF receptors and possible histone acetylation in NET promoter. The results indicate that their interaction may play an important role in stress-related physiological and pathological status. PMID:26212818

  11. (R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine ([125I]PYINXT) : a novel probe for norepinephrine transporters (NET)

    PubMed Central

    Lakshmi, B.; Kung, M-P.; Lieberman, B.; Zhao, J.; Waterhouse, R.; H.F.Kung

    2008-01-01

    Alterations in the serotonin and norepinephrine neuronal functions have been observed in patients with major depression. Several antidepressants bind to both serotonin transporters (SERT) and norepinephrine transporters (NET). The ability to image NET in the human brain would be a useful step toward understanding how alterations in NET relate to disease. In this study, we report the synthesis and characterization of a new series of derivatives of iodo-nisoxetine (INXT), a known radioiodinated probe. The most promising, (R)-N-methyl-3-(3-iodopyridin-2-yloxy)-3-phenylpropylamine (PYINXT) 9, displayed a high and saturable binding to NET with a Kd value of 0.53 ± 0.03 nM. Biodistribution studies of [125I]PYINXT in rats showed moderate initial brain uptake (0.54 %dose/organ at 2 min) with a relatively fast washout from the brain (0.16 %dose/organ at 2 hr) as compared to [125I]INXT, 7. The hypothalamus (a NET rich region) to striatum (a region devoid of NET) ratio was found to be 2.14 at 4 hr post i.v. injection. The preliminary results suggest that this improved iodinated ligand, when labeled with 123I, may be useful for mapping NET binding sites with SPECT in the living human brain. PMID:18158942

  12. Age-related changes in prefrontal norepinephrine transporter density: The basis for improved cognitive flexibility after low doses of atomoxetine in adolescent rats.

    PubMed

    Bradshaw, Sarah E; Agster, Kara L; Waterhouse, Barry D; McGaughy, Jill A

    2016-06-15

    Adolescence is a period of major behavioral and brain reorganization. As diagnoses and treatment of disorders like attention deficit hyperactivity disorder (ADHD) often occur during adolescence, it is important to understand how the prefrontal cortices change and how these changes may influence the response to drugs during development. The current study uses an adolescent rat model to study the effect of standard ADHD treatments, atomoxetine and methylphenidate on attentional set shifting and reversal learning. While both of these drugs act as norepinephrine reuptake inhibitors, higher doses of atomoxetine and all doses of methylphenidate also block dopamine transporters (DAT). Low doses of atomoxetine, were effective at remediating cognitive rigidity found in adolescents. In contrast, methylphenidate improved performance in rats unable to form an attentional set due to distractibility but was without effect in normal subjects. We also assessed the effects of GBR 12909, a selective DAT inhibitor, but found no effect of any dose on behavior. A second study in adolescent rats investigated changes in norepinephrine transporter (NET) and dopamine beta hydroxylase (DBH) density in five functionally distinct sub-regions of the prefrontal cortex: infralimbic, prelimbic, anterior cingulate, medial and lateral orbitofrontal cortices. These regions are implicated in impulsivity and distractibility. We found that NET, but not DBH, changed across adolescence in a regionally selective manner. The prelimbic cortex, which is critical to cognitive rigidity, and the lateral orbitofrontal cortex, critical to reversal learning and some forms of response inhibition, showed higher levels of NET at early than mid- to late adolescence. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID:26774596

  13. NASA's Subsonic Jet Transport Noise Reduction Research

    NASA Technical Reports Server (NTRS)

    Powell, Clemans A.; Preisser, John S.

    2000-01-01

    Although new jet transport airplanes in today s fleet are considerably quieter than the first jet transports introduced about 40 years ago, airport community noise continues to be an important environmental issue. NASA s Advanced Subsonic Transport (AST) Noise Reduction program was begun in 1994 as a seven-year effort to develop technology to reduce jet transport noise 10 dB relative to 1992 technology. This program provides for reductions in engine source noise, improvements in nacelle acoustic treatments, reductions in the noise generated by the airframe, and improvements in the way airplanes are operated in the airport environs. These noise reduction efforts will terminate at the end of 2001 and it appears that the objective will be met. However, because of an anticipated 3-8% growth in passenger and cargo operations well into the 21st Century and the slow introduction of new the noise reduction technology into the fleet, world aircraft noise impact will remain essentially constant until about 2020 to 2030 and thereafter begin to rise. Therefore NASA has begun planning with the Federal Aviation Administration, industry, universities and environmental interest groups in the USA for a new noise reduction initiative to provide technology for significant further reductions.

  14. Proteomic analysis of human norepinephrine transporter complexes reveals associations with protein phosphatase 2A anchoring subunit and 14-3-3 proteins

    SciTech Connect

    Sung, Uhna; Jennings, Jennifer L.; Link, Andrew J.; Blakely, Randy D.; E-mail: andy.blakely@vanderbilt.edu

    2005-08-05

    The norepinephrine transporter (NET) terminates noradrenergic signals by clearing released NE at synapses. NET regulation by receptors and intracellular signaling pathways is supported by a growing list of associated proteins including syntaxin1A, protein phosphatase 2A (PP2A) catalytic subunit (PP2A-C), PICK1, and Hic-5. In the present study, we sought evidence for additional partnerships by mass spectrometry-based analysis of proteins co-immunoprecipitated with human NET (hNET) stably expressed in a mouse noradrenergic neuroblastoma cell line. Our initial proteomic analyses reveal multiple peptides derived from hNET, peptides arising from the mouse PP2A anchoring subunit (PP2A-Ar) and peptides derived from 14-3-3 proteins. We verified physical association of NET with PP2A-Ar via co-immunoprecipitation studies using mouse vas deferens extracts and with 14-3-3 via a fusion pull-down approach, implicating specifically the hNET NH{sub 2}-terminus for interactions. The transporter complexes described likely support mechanisms regulating transporter activity, localization, and trafficking.

  15. Drag Reduction Tests on Supersonic Transport Design

    NASA Technical Reports Server (NTRS)

    1998-01-01

    Langley researchers recently completed supersonic tests in the Unitary Plan Wind Tunnel on a nonlinear design for a supersonic transport. Although the drag reduction measured during the tests was not as great as that predicted using computational methods, significant drag reductions were achieved. Future tests will be conducted at a higher Reynolds number, which will be more representative of flight conditions. These tests will be used to identify a supersonic transport configuration that provides maximum drag reduction. Reducing drag decreases operating cost by improving fuel consumption and lowering aircraft weight. As a result, this research has the potential to help make a future high-speed civil transport (HSCT) an affordable means of travel for the flying public.

  16. Knockout of the norepinephrine transporter and pharmacologically diverse antidepressants prevent behavioral and brain neurotrophin alterations in two chronic stress models of depression

    PubMed Central

    Haenisch, Britta; Bilkei-Gorzo, Andras; Caron, Marc G.; Bönisch, Heinz

    2009-01-01

    Diverse factors such as changes in neurotrophins and brain plasticity have been proposed to be involved in the actions of antidepressant drugs (ADs). However, in mouse models of depression based on chronic stress, it is still unclear whether simultaneous changes in behavior and neurotrophin expression occur and whether these changes can be corrected or prevented comparably by chronic administration of ADs or genetic manipulations that produce antidepressant-like effects such as the knockout (KO) of the norepinephrine transporter (NET) gene. Here we show that chronic restraint or social defeat stress induce comparable effects on behavior and changes in the expression of neurotrophins in depression-related brain regions. Chronic stress caused down-regulation of BDNF, NGF and NT-3 in hippocampus and cerebral cortex and up-regulation of these targets in striatal regions. In wild-type mice, these effects could be prevented by concomitant chronic administration of five pharmacologically diverse ADs. In contrast, NETKO mice were resistant to stress-induced depressive-like changes in behavior and brain neurotrophin expression. Thus, the resistance of the NETKO mice to the stress-induced depression-associated behaviors and biochemical changes highlight the importance of noradrenergic pathways in the maintenance of mood. In addition, these mice represent a useful model to study depression-resistant behaviors, and they might help to provide deeper insights into the identification of downstream targets involved in the mechanisms of antidepressants. PMID:19694905

  17. Effects of Persisting Emotional Impact from Child Abuse and Norepinephrine Transporter Genetic Variation on Antidepressant Efficacy in Major Depression: A Pilot Study

    PubMed Central

    Singh, Ajeet Bhagat; Bousman, Chad A.; Ng, Chee Hong; Byron, Keith; Berk, Michael

    2015-01-01

    Objective Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and anti-depressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials. Methods Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history. Results No subjects reporting abuse with high impact in adulthood (IES-15 ≥26, n=12) remitted; whereas 77% reporting low impact (IES-15 <26; n=26) remitted (p<0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85–514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error. Conclusion The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility. PMID:25912538

  18. NF-κB inhibition significantly upregulates the norepinephrine transporter system, causes apoptosis in pheochromocytoma cell lines and prevents metastasis in an animal model.

    PubMed

    Pacak, Karel; Sirova, Marta; Giubellino, Alessio; Lencesova, Lubomira; Csaderova, Lucia; Laukova, Marcela; Hudecova, Sona; Krizanova, Olga

    2012-11-15

    Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are specific types of neuroendocrine tumors that originate in the adrenal medulla or sympathetic/parasympathetic paraganglia, respectively. Although these tumors are intensively studied, a very effective treatment for metastatic PHEO or PGL has not yet been established. Preclinical evaluations of novel therapies for these tumors are very much required. Therefore, in this study we tested the effect of triptolide (TTL), a potent nuclear factor-kappaB (NF-κB) inhibitor, on the cell membrane norepinephrine transporter (NET) system, considered to be the gatekeeper for the radiotherapeutic agent 131I-metaiodobenzylguanidine (131I-MIBG). We measured changes in the mRNA and protein levels of NET and correlated them with proapoptotic factors and metastasis inhibition. The study was performed on three different stable PHEO cell lines. We found that blocking NF-κB with TTL or capsaicin increased both NET mRNA and protein levels. Involvement of NF-κB in the upregulation of NET was verified by mRNA silencing of this site and also by using NF-κB antipeptide. Moreover, in vivo treatment with TTL significantly reduced metastatic burden in an animal model of metastatic PHEO. The present study for the first time shows how NF-κB inhibitors could be successfully used in the treatment of metastatic PHEO/PGL by a significant upregulation of NET to increase the efficacy of 131I-MIBG and by the induction of apoptosis. PMID:22407736

  19. Effects of Electroacupuncture on Pain Threshold of Laboring Rats and the Expression of Norepinephrine Transporter and α2 Adrenergic Receptor in the Central Nervous System

    PubMed Central

    Lin, Shike; Feng, Yuanyuan; Zhang, Qi; Wang, Meili; Wang, Yu

    2016-01-01

    To observe the effects of electroacupuncture on pain threshold of laboring rats and the expression of norepinephrine transporter and α2 adrenergic receptor in the central nervous system to determine the mechanism of the analgesic effect of labor. 120 pregnant rats were divided into 6 groups: a control group, 4 electroacupuncture groups, and a meperidine group. After interventions, the warm water tail-flick test was used to observe pain threshold. NE levels in serum, NET, and α2AR mRNA and protein expression levels in the central nervous system were measured. No difference in pain threshold was observed between the 6 groups before intervention. After intervention, increased pain thresholds were observed in all groups except the control group with a higher threshold seen in the electroacupuncture groups. Serum NE levels decreased in the electroacupuncture and MP groups. Increases in NET and α2AR expression in the cerebral cortex and decreases in enlarged segments of the spinal cord were seen. Acupuncture increases uptake of NE via cerebral NET and decreases its uptake by spinal NET. The levels of α2AR are also increased and decreased, respectively, in both tissues. This results in a decrease in systemic NE levels and may be the mechanism for its analgesic effects. PMID:27547232

  20. Pharmacological and Behavioral Characterization of D-473, an Orally Active Triple Reuptake Inhibitor Targeting Dopamine, Serotonin and Norepinephrine Transporters

    PubMed Central

    Dutta, Aloke K.; Santra, Soumava; Sharma, Horrick; Voshavar, Chandrashekhar; Xu, Liping; Mabrouk, Omar; Antonio, Tamara; Reith, Maarten E. A.

    2014-01-01

    Major depressive disorder (MDD) is a debilitating disease affecting a wide cross section of people around the world. The current therapy for depression is less than adequate and there is a considerable unmet need for more efficacious treatment. Dopamine has been shown to play a significant role in depression including production of anhedonia which has been one of the untreated symptoms in MDD. It has been hypothesized that drugs acting at all three monoamine transporters including dopamine transporter should provide more efficacious antidepressants activity. This has led to the development of triple reuptake inhibitor D-473 which is a novel pyran based molecule and interacts with all three monoamine transporters. The monoamine uptake inhibition activity in the cloned human transporters expressed in HEK-293 cells (70.4, 9.18 and 39.7 for DAT, SERT and NET, respectively) indicates a serotonin preferring triple reuptake inhibition profile for this drug. The drug D-473 exhibited good brain penetration and produced efficacious activity in rat forced swim test under oral administration. The optimal efficacy dose did not produce any locomotor activation. Microdialysis experiment demonstrated that systemic administration of D-473 elevated extracellular level of the three monoamines DA, 5-HT, and NE efficaciously in the dorsal lateral striatum (DLS) and the medial prefrontal cortex (mPFC) area, indicating in vivo blockade of all three monoamine transporters by D-473. Thus, the current biological data from D-473 indicate potent antidepressant activity of the molecule. PMID:25427177

  1. Corticosterone administration up-regulated expression of norepinephrine transporter and dopamine β-hydroxylase in rat locus coeruleus and its terminal regions.

    PubMed

    Fan, Yan; Chen, Ping; Li, Ying; Cui, Kui; Noel, Daniel M; Cummins, Elizabeth D; Peterson, Daniel J; Brown, Russell W; Zhu, Meng-Yang

    2014-02-01

    Stress has been reported to activate the locus coeruleus (LC)-noradrenergic system. In this study, corticosterone (CORT) was orally administrated to rats for 21 days to mimic stress status. In situ hybridization measurements showed that CORT ingestion significantly increased mRNA levels of norepinephrine transporter (NET) and dopamine β-hydroxylase (DBH) in the LC region. Immunofluorescence staining and western blotting revealed that CORT treatment also increased protein levels of NET and DBH in the LC, as well as NET protein levels in the hippocampus, the frontal cortex and the amygdala. However, CORT-induced increase in DBH protein levels only appeared in the hippocampus and the amygdala. Elevated NET and DBH expression in most of these areas (except for NET protein levels in the LC) was abolished by simultaneous treatment with combination of corticosteroid receptor antagonist mifepristone and spironolactone (s.c. for 21 days). Also, treatment with mifepristone alone prevented CORT-induced increases of NET expression and DBH protein levels in the LC. In addition, behavioral tasks showed that CORT ingestion facilitated escape in avoidance trials using an elevated T-maze, but interestingly, there was no significant effect on the escape trial. Corticosteroid receptor antagonists failed to counteract this response in CORT-treated rats. In the open-field task, CORT treatment resulted in less activity in a defined central zone compared to controls and corticosteroid receptor antagonist treatment alleviated this increase. In conclusion, this study demonstrates that chronic exposure to CORT results in a phenotype that mimics stress-induced alteration of noradrenergic phenotypes, but the effects on behavior are task dependent. As the sucrose consumption test strongly suggests CORT ingestion-induced depression-like behavior, further elucidation of underlying mechanisms may improve our understanding of the correlation between stress and the development of depression. PMID

  2. The 1287 G/A polymorphism of the Norepinephrine Transporter gene (NET) is involved in Commission Errors in Korean children with Attention Deficit Hyperactivity Disorder

    PubMed Central

    2011-01-01

    Background Previous evidence supports the role of noradrenergic systems in ADHD, and norepinephrine transporter (NET) is critical in regulating the noradrenergic system. The present study aimed to investigate the association between NET gene polymorphism and the performance measures of the Continuous Performance Test (CPT) in Korean ADHD children. Methods Eighty-seven children (mean age = 9.23 ± 1.99 years) with ADHD were recruited from a university hospital. Genotypes of G1287A of the NET gene (SLC6A2) were analyzed. All participants completed the CPT, with performance measures of omission errors, commission errors, reaction time and reaction standardization computed. The relationship between G1287A polymorphisms and CPT performance measures was examined. Results There were 46 subjects with the G/G genotype, 35 subjects with the G/A genotype and 6 subjects with the A/A genotype. Among the three groups, there were no significant differences in the performance of CPTs. When dichotomized according to whether the subjects have the rare allele or not, subjects with the homozygous G/G genotype showed significantly lower commission errors compared to those without G/G genotypes (by independent T-test, t = -2.18, p = 0.026). Discussion Our study found a significant association between commission errors of the CPT and the G1287A genotype of the NET gene in Korean ADHD children. These findings suggest a protective role of the G/G genotype of the NET polymorphisms in the deficits of response inhibition in ADHD children. PMID:21569456

  3. No association of the norepinephrine transporter gene (SLC6A2) and cognitive and behavioural phenotypes of patients with autism spectrum disorder.

    PubMed

    Park, Subin; Park, Jong-Eun; Cho, Soo-Churl; Kim, Bung-Nyun; Shin, Min-Sup; Kim, Jae-Won; Cho, In Hee; Kim, Soon Ae; Park, Mira; Park, Tae-Won; Son, Jung-Woo; Chung, Un-Sun; Yoo, Hee Jeong

    2014-09-01

    We examined the association between the norepinephrine transporter (SLC6A2) gene and autism spectrum disorder (ASD) in a Korean population. In addition, we investigated which phenotypes of ASD are best attributed to the genotype of SLC6A2. A total of 184 subjects with ASD, their 156 unaffected siblings and both biological parents were recruited through university hospitals. We used the Autism Diagnostic Interview-Revised, the Aberrant Behaviour Checklist (ABC), the Child Behaviour Checklist (CBCL), the Stroop Colour-Word Interference Test and the Wisconsin Card Sorting Test (WCST) as quantitative measures of the ASD phenotypes. The associations between the quantitative measures and specific single-nucleotide polymorphisms (SNPs) were tested with linear regression analyses. We did not find any evidence of the over-transmission of either allele of the 10SLC6A2 SNPs in the DFAM test. At an empirical p value <0.05, findings that were consistent between the linear regression analyses and the QFAM tests were the positive associations between the A allele of rs36020 and attention problems on the CBCL and stereotypical behaviours on the ABC and between the C allele of rs1814270 and the number of trials required to complete the first WCST category. However, these associations did not remain after correction for multiple testing. The study results of this study do not support the association between the SLC6A2 and the diagnosis or phenotype of ASD. However, the study must be replicated in larger populations and with using more genetic markers. PMID:24381062

  4. The norepinephrine transporter (NET) radioligand (S,S)-[18F]FMeNER-D2 shows significant decreases in NET density in the human brain in Alzheimer's disease: a post-mortem autoradiographic study.

    PubMed

    Gulyás, Balázs; Brockschnieder, Damian; Nag, Sangram; Pavlova, Elena; Kása, Péter; Beliczai, Zsuzsa; Légrádi, Adám; Gulya, Károly; Thiele, Andrea; Dyrks, Thomas; Halldin, Christer

    2010-01-01

    Earlier post-mortem histological and autoradiographic studies have indicated a reduction of cell numbers in the locus coeruleus (LC) and a corresponding decrease in norepinephrine transporter (NET) in brains obtained from Alzheimer's disease (AD) patients as compared to age-matched healthy controls. In order to test the hypothesis that the regional decrease of NET is a disease specific biomarker in AD and as such, it can be used in PET imaging studies for diagnostic considerations, regional differences in the density of NET in various anatomical structures were measured in whole hemisphere human brain slices obtained from AD patients and age-matched control subjects in a series of autoradiographic experiments using the novel selective PET radioligand for NET (S,S)-[(18)F]FMeNER-D(2). (S,S)-[(18)F]FMeNER-D(2) appears to be a useful imaging biomarker for quantifying the density of NET in various brain structures, including the LC and the thalamus wherein the highest densities are found in physiological conditions. In AD significant decreases of NET densities can be demonstrated with the radioligand in both structures as compared to age-matched controls. The decreases in AD correlate with the progress of the disease as indicated by Braak grades. As the size of the LC is below the spatial resolution of the PET scanners, but the size of the thalamus can be detected with appropriate spatial accuracy in advanced scanners, the present findings confirm our earlier observations with PET that the in vivo imaging of NET with (S,S)-[(18)F]FMeNER-D(2) in the thalamus is viable. Nevertheless, further studies are warranted to assess the usefulness of such an imaging approach for the early detection of changes in thalamic NET densities as a disease-specific biomarker and the possible use of (S,S)-[(18)F]FMeNER-D(2) as a molecular imaging biomarker in AD. PMID:20211213

  5. Reduction in renal blood flow following administration of norepinephrine and phenylephrine in septic rats treated with Kir6.1 ATP-sensitive and KCa1.1 calcium-activated K+ channel blockers.

    PubMed

    da Rosa Maggi Sant'Helena, Bruna; Guarido, Karla L; de Souza, Priscila; Crestani, Sandra; da Silva-Santos, J Eduardo

    2015-10-15

    We evaluated the effects of K+ channel blockers in the vascular reactivity of in vitro perfused kidneys, as well as on the influence of vasoactive agents in the renal blood flow of rats subjected to the cecal ligation and puncture (CLP) model of sepsis. Both norepinephrine and phenylephrine had the ability to increase the vascular perfusion pressure reduced in kidneys of rats subjected to CLP at 18 h and 36 h before the experiments. The non-selective K+ channel blocker tetraethylammonium, but not the Kir6.1 blocker glibenclamide, normalized the effects of phenylephrine in kidneys from the CLP 18 h group. Systemic administration of tetraethylammonium, glibenclamide, or the KCa1.1 blocker iberiotoxin, did not change the renal blood flow in control or septic rats. Norepinephrine or phenylephrine also had no influence on the renal blood flow of septic animals, but its injection in rats from the CLP 18 h group previously treated with either glibenclamide or iberiotoxin resulted in an exacerbated reduction in the renal blood flow. These results suggest an abnormal functionality of K+ channels in the renal vascular bed in sepsis, and that the blockage of different subtypes of K+ channels may be deleterious for blood perfusion in kidneys, mainly when associated with vasoactive drugs. PMID:26277325

  6. Guam Transportation Petroleum-Use Reduction Plan

    SciTech Connect

    Johnson, C.

    2013-04-01

    The island of Guam has set a goal to reduce petroleum use 20% by 2020. Because transportation is responsible for one-third of on-island petroleum use, the Guam Energy Task Force (GETF), a collaboration between the U.S. Department of Energy and numerous Guam-based agencies and organizations, devised a specific plan by which to meet the 20% goal within the transportation sector. This report lays out GETF's plan.

  7. Occupancy of serotonin and norepinephrine transporter by milnacipran in patients with major depressive disorder: a positron emission tomography study with [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2).

    PubMed

    Nogami, Tsuyoshi; Takano, Harumasa; Arakawa, Ryosuke; Ichimiya, Tetsuya; Fujiwara, Hironobu; Kimura, Yasuyuki; Kodaka, Fumitoshi; Sasaki, Takeshi; Takahata, Keisuke; Suzuki, Masayuki; Nagashima, Tomohisa; Mori, Takaaki; Shimada, Hitoshi; Fukuda, Hajime; Sekine, Mizuho; Tateno, Amane; Takahashi, Hidehiko; Ito, Hiroshi; Okubo, Yoshiro; Suhara, Tetsuya

    2013-06-01

    Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported >80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2), in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED(50) was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients. PMID:23067569

  8. Light and electron microscopic analysis of enkephalin-like immunoreactivity in the basolateral amygdala, including evidence for convergence of enkephalin-containing axon terminals and norepinephrine transporter-containing axon terminals onto common targets.

    PubMed

    Zhang, Jingyi; McDonald, Alexander J

    2016-04-01

    Modulatory interactions of opioids and norepinephrine (NE) in the anterior subdivision of the basolateral nucleus of the amygdala (BLa) are critical for the consolidation of memories of emotionally arousing experiences. Although there have been several studies of the noradrenergic system in the amygdalar basolateral nuclear complex (BLC), little is known about the chemical neuroanatomy of opioid systems in this region. To address this knowledge gap the present study first examined the distribution of met-enkephalin-like immunoreactivity (ENK-ir) in the BLC at the light microscopic level, and then utilized dual-labeling immunocytochemistry combined with electron microscopy to investigate the extent of convergence of NE and ENK terminals onto common structures in the BLa. Antibodies to ENK and the norepinephrine transporter (NET) were used in these studies. Light microscopic examination revealed that a subpopulation of small nonpyramidal neurons expressed ENK-ir in all nuclei of the BLC. In addition, the somata of some pyramidal cells exhibited light to moderate ENK-ir. ENK+ axon terminals were also observed. Ultrastructural analysis confined to the BLa revealed that most ENK+ axon terminals formed asymmetrical synapses that mainly contacted spines and shafts of thin dendrites. ENK+ terminals forming symmetrical synapses mainly contacted dendritic shafts. Approximately 20% of NET+ terminals contacted a structure that was also contacted by an ENK+ terminal and 6% of NET+ terminals contacted an ENK+ terminal. These findings suggest that ENK and NE terminals in the BLa may interact by targeting common dendrites and by direct interactions between the two types of terminals. PMID:26835559

  9. TRANSPORT AND REDUCTION POSSIBILITIES DURING TPBAR EXTRACTION

    SciTech Connect

    Korinko, P

    2008-05-19

    In light of the discovery of the activated zinc 65 in the TEF process piping, a discussion of potential sources and mechanisms for the production of this species has been initiated. A suspected source is the presence of Cu as a contaminant in many of the alloy components that comprise the TPBARs and the presence of Zn as a contaminant in the aluminide coating. These two sources are expected to produce metallic transmutation products that could be mobile and be extracted from the metallic components of the TPBARs. Another potential source is the presence of ZnO that is present as part of the crud on the external surfaces of the TPBARs. In addition, it is conceivable to have ZnO within the TPBARs from transmutation products and subsequent oxidation reactions with water. This memo does not attempt to address all of the possible sources, nor does it derive the most likely scenarios as to how Zn or ZnO may be present in the TPBARs it merely posits that it is present as a transmutation product and if present, elementally, it may be mobile under high vacuum conditions at high temperatures as indicated by the pressure temperature curve shown in Fig. 1. Further, this document shows that it is thermodynamically feasible to reduce ZnO to Zn by solid state reactions of the ZnO with other metallic components in the TPBARs. However, for these reactions to occur, the ZnO must be in contact with the more active metal so that the chemical reactions can occur. The proposed reactions are based on equilibrium thermodynamics. For simplicity, they do not take into account the quantities of the various materials, the compositions, the effect of alloying, or other technical issues, they are intended only to provide feasibility for the reduction reactions. A more complete thermodynamic model can be developed, but it will require actual contents and be much more complicated with little value added.

  10. Discovery of a Potent, Dual Serotonin and Norepinephrine Reuptake Inhibitor

    PubMed Central

    2013-01-01

    The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug–drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions. PMID:24900709

  11. U.S. Virgin Islands Transportation Petroleum Reduction Plan

    SciTech Connect

    Johnson, C.

    2011-09-01

    This NREL technical report determines a way for USVI to meet its petroleum reduction goal in the transportation sector. It does so first by estimating current petroleum use and key statistics and characteristics of USVI transportation. It then breaks the goal down into subordinate goals and estimates the petroleum impacts of these goals with a wedge analysis. These goals focus on reducing vehicle miles, improving fuel economy, improving traffic flow, using electric vehicles, using biodiesel and renewable diesel, and using 10% ethanol in gasoline. The final section of the report suggests specific projects to achieve the goals, and ranks the projects according to cost, petroleum reduction, time frame, and popularity.

  12. Future developments in transport aircraft noise reduction technology

    SciTech Connect

    Pendley, R.E.

    1982-01-01

    During the past 13 years, important advances in the technology of aircraft noise control have resulted from industry and government research programs. Quieter commercial transport airplanes have entered the fleet and additional new designs now committed to production will begin service in a few years. This paper indicates the noise reductions that will be achieved by the quieter transports that will replace the older designs and remarks on the outlook for still quieter designs.

  13. Campus Sustainability: Climate Change, Transport and Paper Reduction

    ERIC Educational Resources Information Center

    Atherton, Alison; Giurco, Damien

    2011-01-01

    Purpose: This paper aims to detail the design of a campus climate change strategy, transport strategy and paper reduction strategy at the University of Technology, Sydney (Australia). Design/methodology/approach: The approach to strategy development used desktop research and staff/student consultation to inform the development of objectives,…

  14. In vitro binding assays using (3)H nisoxetine and (3)H WIN 35,428 reveal selective effects of gonadectomy and hormone replacement in adult male rats on norepinephrine but not dopamine transporter sites in the cerebral cortex.

    PubMed

    Meyers, B; Kritzer, M F

    2009-03-01

    The prefrontal cortices mediate cognitive functions that critically depend on local dopamine levels. In male rats, many prefrontal tasks where performance is disrupted by changes in dopamine signaling are also impaired by gonadectomy, a manipulation that increases cortical dopamine concentration, prefrontal dopamine axon density and possibly extracellular prefrontal dopamine levels as well. Because these actions could be responsible for the impairing effects of gonadectomy on prefrontal function, the question of how they might arise comes to the fore. Accordingly, the present studies asked whether dopamine levels might be increased via a hormone sensitivity of transporter-mediated dopamine uptake. Specifically, (3)H WIN 35,428 and (3)H nisoxetine, ligands selective for the dopamine (DAT)- and norepinephrine transporter (NET) respectively, were used in in vitro binding assays to ask whether gonadectomy altered transporter affinity (Kd) and/or binding site number (Bmax) in prefrontal cortex, sensorimotor cortex and/or caudate. Assays performed on tissues dissected from sham-operated, gonadectomized and gonadectomized rats supplemented with testosterone propionate or estradiol for 4 or 28 days revealed no significant group differences or obvious trends in Kd or Bmax for DAT binding or in measures of Bmax for NET binding. However, affinity constants for (3)H nisoxetine were found to be significantly higher in sensorimotor and/or prefrontal cortex of rats gonadectomized and gonadectomized and supplemented with estradiol for 4 or 28 days but similar to control in gonadectomized rats given testosterone. Because the NET contributes substantially to extracellular prefrontal dopamine clearance, these androgen-mediated effects could influence prefrontal dopamine levels and might thus be relevant for observed effects of gonadectomy on dopamine-dependent prefrontal behaviors. A hormone sensitivity of the NET could also have bearing on the prefrontal dopamine dysfunction seen in

  15. Nanoscale mechanisms for the reduction of heat transport in bismuth

    NASA Astrophysics Data System (ADS)

    Markov, Maxime; Sjakste, Jelena; Fugallo, Giorgia; Paulatto, Lorenzo; Lazzeri, Michele; Mauri, Francesco; Vast, Nathalie

    2016-02-01

    Hand-on routes to reduce lattice thermal conductivity (LTC) in bismuth have been explored by employing a combination of Boltzmann's transport equation and ab initio calculations of phonon-phonon interaction within the density functional perturbation theory. We have first obtained the temperature dependence of the bulk LTC in excellent agreement with available experiments. A very accurate microscopic description of heat transport has been achieved and the electronic contribution to thermal conductivity has been determined. By controlling the interplay between phonon-phonon interaction and phonon scattering by sample boundaries, we predict the effect of size reduction for various temperatures and nanostructure shapes. The largest heat transport reduction is obtained in polycrystals with grain sizes smaller than 100 nm.

  16. Reductive dissolution and metal transport in lake coeur d alenesediments

    SciTech Connect

    Sengor, Sevinc.S.; Spycher, Nicolas.F.; Ginn, Timothy.R.; Moberly, James; Peyton, B.; Sani, Rajesh.K.

    2007-04-27

    The benthic sediments in Lake Coeur d Alene, northern Idaho,have been contaminated by metals (primarily Zn, Pb, and Cu) from decadesof upstream mining activities. As part of ongoing research on thebiogeo-chemical cycling of metals in this area, a diffusivereactive-transport model has been developed to simulate metal transportin the lake sediments. The model includes 1-D inorganic diffusivetransport coupled to a biotic reaction network with multiple terminalelectron acceptors under redox disequilibrium conditions. Here, the modelis applied to evaluate the competing effects of heavy-metal mobilizationthrough biotic reductive dissolution of Fe(III) (hydr)oxides, andimmobilization as biogenic sulfide minerals. Results indicate that therelative rates of Fe and sulfate reduction could play an important rolein metal transport through the envi-ronment, and that the formation of(bi)sulfide complexes could significantly enhance metal solubility, aswell as desorption from Fe hydroxides.

  17. Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison.

    PubMed

    Sansone, Randy A; Sansone, Lori A

    2014-03-01

    The serotonin norepinephrine reuptake inhibitors are a family of antidepressants that inhibit the reuptake of both serotonin and norepinephrine. While these drugs are traditionally considered a group of inter-related antidepressants based upon reuptake inhibition, they generally display different chemical structures as well as different pharmacological properties. In this article, we discuss these and other differences among the serotonin norepinephrine reuptake inhibitors, including the year of approval by the United States Food and Drug Administration, generic availability, approved clinical indications, half-lives, metabolism and excretion, presence or not of active metabolites, dosing schedules, proportionate effects on serotonin and norepinephrine, and the timing of serotonin and norepinephrine reuptake (i.e., sequential or simultaneous). Again, while serotonin norepinephrine reuptake inhibitors are grouped as a family of antidepressants, they exhibit a surprising number of differences- differences that may ultimately relate to clinical nuances in patient care. PMID:24800132

  18. Control, Transport Reduction and Diagnostic use of Feedback

    NASA Astrophysics Data System (ADS)

    Sen, A. K.

    1999-11-01

    In the past we have reported on feedback suppression of a variety of micro-instabilities in the Columbia Linear Machine via an electron/ion beam suppressor. These include a curvature driven trapped particle mode, an E×B flute mode and an ITG mode; sometimes two of them simultaneously. We now report on reduction and scaling of transport under feedback. The anomalous particle transport due to an E×B centrifugally driven mode has been measured via cross-correlation of density and potential fluctuations. The transport is found to be reduced by up to a factor of three under feedback. By controlling the fluctuation amplitudes and consequently the transport via feedback, we find the scaling of diffusion coefficient to be linear with RMS fluctuation level. The scaling appears not to agree with any generic theory. Recently, we have performed a numerical experiment on feedback control of dissipative drift wave instability in collaboration with ETP, University of Marseille. The preliminary result is that even a highly chaotic state of the instability can be suppressed, if the feedback delay is less than the correlation time of fluctuations. We will explore the implication of these results for the remote prospect of reduction of micro-turbulence and associated transport. We are also persuing a variety of diagnostic uses of feedback. The primary goal is an experimental methodology for the determination of dynamic models of plasma turbulence, both for better transport understanding and more credible feedback controller designs. A specific motivation is to search for a low order dynamic model, suitable for the convenient study of both transport and feedback. First, we use time series analysis method for the determination of chaotic attractor dimension of plasma fluctuations. For E×B rotational flute modes it is found to be close to three, indicating that a model of three coupled modes may be adequate for transport prediction and feedback controller design. Secondly, we have

  19. Reduction of Convection in Closed Tube Vapor Transport Experiments

    NASA Technical Reports Server (NTRS)

    Naumann, R. J.; Tan, Sarwa Bakti; Shin, In-Seok; Kim, Joo Soo

    2002-01-01

    The primary objective of this effort was to develop a method for suppressing convective flows during the growth of mercurous chloride crystals by vapor transport in closed tubes to levels approaching those obtained in the microgravity environment. Mercurous chloride was chosen because it is a technologically interesting acoustical optical material whose optical properties are believed to be affected by convective flows. Since the Grashof number scales as the cube of the smallest dimension in the flow system, reduction of the size scale can be extremely effective in reducing unwanted convective flows. However, since materials of practical interest must be grown at least on the cm scale, reduction of the overall growth system is not feasible. But if the region just above the growing crystal could be restricted to a few mm, considerable reduction in flow velocity would result. By suspending an effusive barrier in the growth ampoule just above the growth interface, it should be possible to reduce the convective velocity in this vicinity to levels approaching flows in microgravity. If successful, this growth technique will offer a screening test for proposed space experiments that involve vapor transport to see if reduction of convection will result in improved material and will set a new standard against which the improvements obtained in microgravity may be judged. In addition, it may provide an improved method for preparing materials on Earth whose growth is affected adversely by convection. If the properties of this material can be improved there is a potential commercial interest from Brimrose Inc., who has agreed to fabricate and test devices from the crystals we have grown. This report describes the development of the growth facility, the purification processes developed for preparing the starting material, and the results from growth experiments with and without the effusive baffle. Mercurous chloride turned out to be a more difficult material to deal with than

  20. Random shearing by zonal flows and transport reduction

    SciTech Connect

    Kim, Eun-jin; Diamond, P.H.

    2004-12-01

    The physics of random shearing by zonal flows and the consequent reduction of scalar field transport are studied. In contrast to mean shear flows, zonal flows have a finite autocorrelation time and can exhibit complex spatial structure. A random zonal flow with a finite correlation time {tau}{sub ZF} decorrelates two nearby fluid elements less efficiently than a mean shear flow does. The decorrelation time is {tau}{sub D}=({tau}{sub {eta}}/{tau}{sub ZF}{omega}{sub rms}{sup 2}){sup 1sol2} ({tau}{sub {eta}} is the turbulent scattering time, and {omega}{sub rms} is the rms shear), leading to larger scalar field amplitude with a slightly different scaling ({proportional_to}{tau}{sub D}/{omega}{sub rms}), as compared to the case of coherent shearing. In the strong shear limit, the flux scales as {proportional_to}{omega}{sub rms}{sup -1}.

  1. Evaluation of viscous drag reduction schemes for subsonic transports

    NASA Technical Reports Server (NTRS)

    Marino, A.; Economos, C.; Howard, F. G.

    1975-01-01

    The results are described of a theoretical study of viscous drag reduction schemes for potential application to the fuselage of a long-haul subsonic transport aircraft. The schemes which were examined included tangential slot injection on the fuselage and various synergetic combinations of tangential slot injection and distributed suction applied to wing and fuselage surfaces. Both passive and mechanical (utilizing turbo-machinery) systems were examined. Overall performance of the selected systems was determined at a fixed subsonic cruise condition corresponding to a flight Mach number of free stream M = 0.8 and an altitude of 11,000 m. The nominal aircraft to which most of the performance data was referenced was a wide-body transport of the Boeing 747 category. Some of the performance results obtained with wing suction are referenced to a Lockheed C-141 Star Lifter wing section. Alternate designs investigated involved combinations of boundary layer suction on the wing surfaces and injection on the fuselage, and suction and injection combinations applied to the fuselage only.

  2. Structure-activity relationships of the cycloalkanol ethylamine scaffold: discovery of selective norepinephrine reuptake inhibitors.

    PubMed

    Mahaney, Paige E; Gavrin, Lori K; Trybulski, Eugene J; Stack, Gary P; Vu, T An; Cohn, Stephen T; Ye, Fei; Belardi, Justin K; Santilli, Arthur A; Sabatucci, Joseph P; Leiter, Jennifer; Johnston, Grace H; Bray, Jenifer A; Burroughs, Kevin D; Cosmi, Scott A; Leventhal, Liza; Koury, Elizabeth J; Zhang, Yingru; Mugford, Cheryl A; Ho, Douglas M; Rosenzweig-Lipson, Sharon J; Platt, Brian; Smith, Valerie A; Deecher, Darlene C

    2008-07-10

    Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction. PMID:18557608

  3. Genetic moderation of child maltreatment effects on depression and internalizing symptoms by serotonin transporter linked polymorphic region (5-HTTLPR), brain-derived neurotrophic factor (BDNF), norepinephrine transporter (NET), and corticotropin releasing hormone receptor 1 (CRHR1) genes in African American children.

    PubMed

    Cicchetti, Dante; Rogosch, Fred A

    2014-11-01

    Genetic moderation of the effects of child maltreatment on depression and internalizing symptoms was investigated in a sample of low-income maltreated and nonmaltreated African American children (N = 1,096). Lifetime child maltreatment experiences were independently coded from Child Protective Services records and maternal report. Child depression and internalizing problems were assessed in the context of a summer research camp by self-report on the Children's Depression Inventory and adult counselor report on the Teacher Report Form. DNA was obtained from buccal cell or saliva samples and genotyped for polymorphisms of the following genes: serotonin transporter linked polymorphic region (5-HTTLPR), brain-derived neurotrophic factor (BDNF), norepinephrine transporter, and corticotropin releasing hormone receptor 1. Analyses of covariance with age and gender as covariates were conducted, with maltreatment status and respective polymorphism as main effects and their Gene × Environment (G × E) interactions. Maltreatment consistently was associated with higher Children's Depression Inventory and Teacher Report Form symptoms. The results for child self-report symptoms indicated a G × E interaction for BDNF and maltreatment. In addition, BDNF and triallelic 5-HTTLPR interacted with child maltreatment in a G × G × E interaction. Analyses for counselor report of child anxiety/depression symptoms on the Teacher Report Form indicated moderation of child maltreatment effects by triallelic 5-HTTLPR. These effects were elaborated based on variation in developmental timing of maltreatment experiences. Norepinephrine transporter was found to further moderate the G × E interaction of 5-HTTLPR and maltreatment status, revealing a G × G × E interaction. This G × G × E was extended by consideration of variation in maltreatment subtype experiences. Finally, G × G × E effects were observed for the co-action of BDNF and the corticotropin releasing hormone receptor 1

  4. Perinatal reduction of functional serotonin transporters results in developmental delay.

    PubMed

    Kroeze, Yvet; Dirven, Bart; Janssen, Stefan; Kröhnke, Marijke; Barte, Ramona M; Middelman, Anthonieke; van Bokhoven, Hans; Zhou, Huiqing; Homberg, Judith R

    2016-10-01

    While there is strong evidence from rodent and human studies that a reduction in serotonin transporter (5-HTT) function in early-life can increase the risk for several neuropsychiatric disorders in adulthood, the effects of reduced 5-HTT function on behavior across developmental stages are underinvestigated. To elucidate how perinatal pharmacological and lifelong genetic inactivation of the 5-HTT affects behavior across development, we conducted a battery of behavioral tests in rats perinatally exposed to fluoxetine or vehicle and in 5-HTT(-/-) versus 5-HTT(+/+) rats. We measured motor-related behavior, olfactory function, grooming behavior, sensorimotor gating, object directed behavior and novel object recognition in the first three postnatal weeks and if possible the tests were repeated in adolescence and adulthood. We also measured developmental milestones such as eye opening, reflex development and body weight. We observed that both pharmacological and genetic inactivation of 5-HTT resulted in a developmental delay. Except for hypo-locomotion, most of the observed early-life effects were normalized later in life. In adolescence and adulthood we observed object directed behavior and decreased novel object recognition in the 5-HTT(-/-) rats, which might be related to the lifelong inactivation of 5-HTT. Together, these data provide an important contribution to the understanding of the effects of perinatal and lifelong 5-HTT inactivation on behavior across developmental stages. PMID:27208789

  5. The Involvement of Norepinephrine in Behaviors Related to Psychostimulant Addiction.

    PubMed

    Zaniewska, Magdalena; Filip, Małgorzata; Przegalinski, Edmund

    2015-01-01

    Although it is generally accepted that the abuse-related effects of amphetamines and cocaine result from the activation of the brain dopaminergic (DA) system, the psychostimulants also alter other neurotransmitter systems. In particular, they increase extracellular levels of norepinephrine (NE) and serotonin by inhibiting respective plasma membrane transporters and/or inducing release. The present review will discuss the preclinical findings on the effects of the NE system modulation (lesions, pharmacological and genetic approaches) on behaviors (locomotor hyperactivity, behavioral sensitization, modification of intracranial self-stimulation, conditioned place preference, drug self-administration, extinction/reinstatement of drug seeking behavior) related to the psychostimulant addiction. PMID:26411968

  6. The Involvement of Norepinephrine in Behaviors Related to Psychostimulant Addiction

    PubMed Central

    Zaniewska, Magdalena; Filip, Małgorzata; Przegaliński, Edmund

    2015-01-01

    Although it is generally accepted that the abuse-related effects of amphetamines and cocaine result from the activation of the brain dopaminergic (DA) system, the psychostimulants also alter other neurotransmitter systems. In particular, they increase extracellular levels of norepinephrine (NE) and serotonin by inhibiting respective plasma membrane transporters and/or inducing release. The present review will discuss the preclinical findings on the effects of the NE system modulation (lesions, pharmacological and genetic approaches) on behaviors (locomotor hyperactivity, behavioral sensitization, modification of intracranial self-stimulation, conditioned place preference, drug self-administration, extinction/reinstatement of drug seeking behavior) related to the psychostimulant addiction. PMID:26411968

  7. Serotonin and norepinephrine reuptake inhibition and eating behavior.

    PubMed

    Hainer, Vojtech; Kabrnova, Karolina; Aldhoon, Bashar; Kunesova, Marie; Wagenknecht, Martin

    2006-11-01

    Brain neurotransmitters, serotonin and norepinephrine, play an important role in the central nervous control of energy balance and are involved in symptomatology related to both obesity and depression. Therefore both serotonin and norepinephrine neural pathways have been paid a special attention as targets for the antiobesity drugs, antidepressants, and drugs used in the treatment of eating disorders. Selective serotonin reuptake inhibitors (SSRI) have been used in the treatment of depression and eating disorders but have failed to achieve sustained weight loss in the treatment of obesity. Sibutramine, a serotonin and norepinephrine reuptake inhibitor, which induces satiety and prevents decline in metabolic rate associated with a hypocaloric diet, is currently the sole centrally acting drug indicated for the long-term treatment of obesity. Depression, dietary disinhibition (evaluated by the Eating Inventory [EI]), and stress are associated with the accumulation of abdominal fat and the development of metabolic syndrome and related diseases. Subjects with abdominal obesity demonstrate neuroendocrine abnormalities which result in disturbances in hypothalamo-pituitary-adrenal (HPA) function. Treatment with SSRI might interrupt the vicious circle which leads to endocrine abnormalities and the accumulation of abdominal fat. Obesity treatment with sibutramine results, not only in significant weight loss, but also in reduction of abdominal fat and in the improvement of health risks associated with metabolic syndrome (lipid profile, blood glucose, insulin, HbA1c, and uric acid), as well as in the decline in disinhibition score of the EI. In a 1-year sibutramine trial, only a decrease in the disinhibition score remained a significant correlate of weight loss among the psychobehavioral and nutritional factors which were taken into account. PMID:17148744

  8. Effects of Norepinephrine Reuptake Inhibition on Postural Tachycardia Syndrome

    PubMed Central

    Green, Elizabeth A.; Raj, Vidya; Shibao, Cyndya A.; Biaggioni, Italo; Black, Bonnie K.; Dupont, William D.; Robertson, David; Raj, Satish R.

    2013-01-01

    Background Postural tachycardia syndrome (POTS) is a disorder of chronic orthostatic intolerance accompanied by excessive orthostatic tachycardia. Patients with POTS commonly have comorbid conditions such as attention deficit hyperactivity disorder, depression, or fibromyalgia that are treated with medications that inhibit the norepinephrine reuptake transporter (NRI). NRI medications can increase sympathetic nervous system tone, which may increase heart rate (HR) and worsen symptoms in POTS patients. We sought to determine whether NRI with atomoxetine increases standing tachycardia or worsens the symptom burden in POTS patients. Methods and Results Patients with POTS (n=27) underwent an acute drug trial of atomoxetine 40 mg and placebo on separate mornings in a randomized, crossover design. Blood pressure (BP), HR, and symptoms were assessed while seated and after standing prior to and hourly for 4 hours following study drug administration. Atomoxetine significantly increased standing HR compared with placebo (121±17 beats per minute versus 105±15 beats per minute; P=0.001) in POTS patients, with a trend toward higher standing systolic BP (P=0.072). Symptom scores worsened with atomoxetine compared to placebo (+4.2 au versus −3.5 au; P=0.028) from baseline to 2 hours after study drug administration. Conclusion Norepinephrine reuptake inhibition with atomoxetine acutely increased standing HR and symptom burden in patients with POTS. Clinical Trials Registration URL: http://clinicaltrials.gov. Unique identifier: NCT00262470. PMID:24002370

  9. Azepines and piperidines with dual norepinephrine dopamine uptake inhibition and antidepressant activity.

    PubMed

    Brown, Dean G; Bernstein, Peter R; Wu, Ye; Urbanek, Rebecca A; Becker, Christopher W; Throner, Scott R; Dembofsky, Bruce T; Steelman, Gary B; Lazor, Lois A; Scott, Clay W; Wood, Michael W; Wesolowski, Steven S; Nugiel, David A; Koch, Stephanie; Yu, Jian; Pivonka, Donald E; Li, Shuang; Thompson, Carol; Zacco, Anna; Elmore, Charles S; Schroeder, Patricia; Liu, JianWei; Hurley, Christopher A; Ward, Stuart; Hunt, Hazel J; Williams, Karen; McLaughlin, Joseph; Hoesch, Valerie; Sydserff, Simon; Maier, Donna; Aharony, David

    2013-01-10

    Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, 8b and 21a, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay. PMID:24900562

  10. Norepinephrine and impulsivity: Effects of acute yohimbine

    PubMed Central

    Swann, Alan C.; Lijffijt, Marijn; Lane, Scott D.; Cox, Blake; Steinberg, Joel L.; Moeller, F. Gerard

    2013-01-01

    Rationale Rapid-response impulsivity, characterized by inability to withhold response to a stimulus until it is adequately appraised, is associated with risky behavior and may be increased in a state-dependent manner by norepinephrine. Objective We assessed effects of yohimbine, which increases norepinephrine release by blocking alpha-2 noradrenergic receptors, on plasma catecholamine metabolites, blood pressure, subjective symptoms, and laboratory-measured rapid-response impulsivity. Methods Subjects were twenty-three healthy controls recruited from the community, with normal physical examination and ECG, and negative history for hypertension, cardiovascular illness, and Axis I or II disorder. Blood pressure, pulse, and behavioral measures were obtained before and periodically after 0.4 mg/kg oral yohimbine or placebo in a randomized, counterbalanced design. Metabolites of norepinephrine (3-methoxy-4-hydroxyphenylglycol, MHPG; vanillylmandelic acid, VMA) and dopamine (homovanillic acid, HVA) were measured by high pressure liquid chromatography with electrochemical detection. Rapid-response impulsivity was measured by commission errors and reaction times on the Immediate Memory Task (IMT), a continuous performance test designed to measure impulsivity and attention. Results Yohimbine increased plasma MHPG and VMA but not HVA. Yohimbine increased systolic and diastolic blood pressure and pulse rate. On the IMT, yohimbine increased impulsive errors and impulsive response bias and accelerated reaction times. Yohimbine-associated increase in plasma MHPG correlated with increased impulsive response rates. Time courses varied; effects on blood pressure generally preceded those on metabolites and test performance. Conclusions These effects are consistent with increased rapid-response impulsivity after pharmacological noradrenergic stimulation in healthy controls. Labile noradrenergic responses, or increased sensitivity to norepinephrine, may increase risk for impulsive

  11. MASS TRANSPORT EFFECTS ON THE KINETICS OF NITROBENZENE REDUCTION BY IRON METAL. (R827117)

    EPA Science Inventory

    To evaluate the importance of external mass transport on the overall rates of
    contaminant reduction by iron metal (Fe0), we have compared measured
    rates of surface reaction for nitrobenzene (ArNO2) to estimated rates
    of external mass transport...

  12. Transportation Energy Futures: Combining Strategies for Deep Reductions in Energy Consumption and GHG Emissions (Brochure)

    SciTech Connect

    Not Available

    2013-03-01

    This fact sheet summarizes actions in the areas of light-duty vehicle, non-light-duty vehicle, fuel, and transportation demand that show promise for deep reductions in energy use. Energy efficient transportation strategies have the potential to simultaneously reduce oil consumption and greenhouse gas (GHG) emissions. The Transportation Energy Futures (TEF) project examined how the combination of multiple strategies could achieve deep reductions in GHG emissions and petroleum use on the order of 80%. Led by NREL, in collaboration with Argonne National Laboratory, the project's primary goal was to help inform domestic decisions about transportation energy strategies, priorities, and investments, with an emphasis on underexplored opportunities. TEF findings reveal three strategies with the potential to displace most transportation-related petroleum use and GHG emissions: 1) Stabilizing energy use in the transportation sector through efficiency and demand-side approaches. 2) Using additional advanced biofuels. 3) Expanding electric drivetrain technologies.

  13. Norepinephrine-induced calcium signaling in astrocytes in the respiratory network of the ventrolateral medulla.

    PubMed

    Schnell, Christian; Negm, Mahmoud; Driehaus, Johannes; Scheller, Anja; Hülsmann, Swen

    2016-06-01

    The neuronal activity in the respiratory network of the ventrolateral medulla strongly depends on a variety of different neuromodulators. Since the respiratory activity generated by neurons in the pre-Bötzinger complex (preBötC) is stabilized by astrocytes, we investigated potential effects of the neuromodulator norepinephrine (NE) on the astrocytic calcium signaling in the ventral respiratory group. In acutely isolated brainstem slices from wild type mice (postnatal day 1-10) we performed calcium imaging experiments using Oregon Green 488 BAPTA-1 AM as a calcium indicator dye. Astrocytes in the preBötC, which were identified by their unique intracellular calcium rise after the reduction of the extracellular K(+) concentration, showed calcium rises in response to norepinephrine. These calcium signals persisted after blockade of neuronal activity by tetrodotoxin (TTX) indicating that they were independent of neuronal activity. Furthermore, application of the endoplasmic reticulum calcium pump blocker cyclopiazonic acid (CPA) diminished norepinephrine-induced calcium signals. This results could be confirmed using transgenic mice with astrocyte specific expression of GCaMP3. Thus, norepinephrine might, apart from acting directly on neurons, influence and modulate respiratory network activity via the modulation of astroglial calcium signaling. PMID:26514085

  14. Transportation Energy Futures Series. Effects of Travel Reduction and Efficient Driving on Transportation. Energy Use and Greenhouse Gas Emissions

    SciTech Connect

    Porter, C. D.; Brown, A.; DeFlorio, J.; McKenzie, E.; Tao, W.; Vimmerstedt, L.

    2013-03-01

    Since the 1970s, numerous transportation strategies have been formulated to change the behavior of drivers or travelers by reducing trips, shifting travel to more efficient modes, or improving the efficiency of existing modes. This report summarizes findings documented in existing literature to identify strategies with the greatest potential impact. The estimated effects of implementing the most significant and aggressive individual driver behavior modification strategies range from less than 1% to a few percent reduction in transportation energy use and GHG emissions. Combined strategies result in reductions of 7% to 15% by 2030. Pricing, ridesharing, eco-driving, and speed limit reduction/enforcement strategies are widely judged to have the greatest estimated potential effect, but lack the widespread public acceptance needed to accomplish maximum results. This is one of a series of reports produced as a result of the Transportation Energy Futures (TEF) project, a Department of Energy-sponsored multi-agency project initiated to pinpoint underexplored strategies for abating GHGs and reducing petroleum dependence related to transportation.

  15. Transportation Energy Futures Series: Effects of Travel Reduction and Efficient Driving on Transportation: Energy Use and Greenhouse Gas Emissions

    SciTech Connect

    Porter, C. D.; Brown, A.; DeFlorio, J.; McKenzie, E.; Tao, W.; Vimmerstedt, L.

    2013-03-01

    Since the 1970s, numerous transportation strategies have been formulated to change the behavior of drivers or travelers by reducing trips, shifting travel to more efficient modes, or improving the efficiency of existing modes. This report summarizes findings documented in existing literature to identify strategies with the greatest potential impact. The estimated effects of implementing the most significant and aggressive individual driver behavior modification strategies range from less than 1% to a few percent reduction in transportation energy use and GHG emissions. Combined strategies result in reductions of 7% to 15% by 2030. Pricing, ridesharing, eco-driving, and speed limit reduction/enforcement strategies are widely judged to have the greatest estimated potential effect, but lack the widespread public acceptance needed to accomplish maximum results. This is one of a series of reports produced as a result of the Transportation Energy Futures (TEF) project, a Department of Energy-sponsored multi-agency project initiated to pinpoint underexplored strategies for abating GHGs and reducing petroleum dependence related to transportation.

  16. Intrarenal and urinary oxygenation during norepinephrine resuscitation in ovine septic acute kidney injury.

    PubMed

    Lankadeva, Yugeesh R; Kosaka, Junko; Evans, Roger G; Bailey, Simon R; Bellomo, Rinaldo; May, Clive N

    2016-07-01

    Norepinephrine is the principal vasopressor used to restore blood pressure in sepsis, but its effects on intrarenal oxygenation are unknown. To clarify this, we examined renal cortical, medullary, and urinary oxygenation in ovine septic acute kidney injury and the response to resuscitation with norepinephrine. A renal artery flow probe and fiberoptic probes were placed in the cortex and medulla of sheep to measure tissue perfusion and oxygenation. A probe in the bladder catheter measured urinary oxygenation. Sepsis was induced in conscious sheep by infusion of Escherichia coli for 32 hours. At 24 to 30 hours of sepsis, either norepinephrine, to restore mean arterial pressure to preseptic levels or vehicle-saline was infused (8 sheep per group). Septic acute kidney injury was characterized by a reduction in blood pressure of ∼12 mm Hg, renal hyperperfusion, and oliguria. Sepsis reduced medullary perfusion (from an average of 1289 to 628 blood perfusion units), medullary oxygenation (from 32 to 16 mm Hg), and urinary oxygenation (from 36 to 24 mm Hg). Restoring blood pressure with norepinephrine further reduced medullary perfusion to an average of 331 blood perfusion units, medullary oxygenation to 8 mm Hg and urinary oxygenation to 18 mm Hg. Cortical perfusion and oxygenation were preserved. Thus, renal medullary hypoxia caused by intrarenal blood flow redistribution may contribute to the development of septic acute kidney injury, and resuscitation of blood pressure with norepinephrine exacerbates medullary hypoxia. The parallel changes in medullary and urinary oxygenation suggest that urinary oxygenation may be a useful real-time biomarker for risk of acute kidney injury. PMID:27165831

  17. Transformative Reduction of Transportation Greenhouse Gas Emissions. Opportunities for Change in Technologies and Systems

    SciTech Connect

    Vimmerstedt, Laura; Brown, Austin; Newes, Emily; Markel, Tony; Schroeder, Alex; Zhang, Yimin; Chipman, Peter; Johnson, Shawn

    2015-04-30

    The transportation sector is changing, influenced by concurrent, ongoing, dynamic trends that could dramatically affect the future energy landscape, including effects on the potential for greenhouse gas emissions reductions. Battery cost reductions and improved performance coupled with a growing number of electric vehicle model offerings are enabling greater battery electric vehicle market penetration, and advances in fuel cell technology and decreases in hydrogen production costs are leading to initial fuel cell vehicle offerings. Radically more efficient vehicles based on both conventional and new drivetrain technologies reduce greenhouse gas emissions per vehicle-mile. Net impacts also depend on the energy sources used for propulsion, and these are changing with increased use of renewable energy and unconventional fossil fuel resources. Connected and automated vehicles are emerging for personal and freight transportation systems and could increase use of low- or non-emitting technologies and systems; however, the net effects of automation on greenhouse gas emissions are uncertain. The longstanding trend of an annual increase in transportation demand has reversed for personal vehicle miles traveled in recent years, demonstrating the possibility of lower-travel future scenarios. Finally, advanced biofuel pathways have continued to develop, highlighting low-carbon and in some cases carbon-negative fuel pathways. We discuss the potential for transformative reductions in petroleum use and greenhouse gas emissions through these emerging transportation-sector technologies and trends and present a Clean Transportation Sector Initiative scenario for such reductions, which are summarized in Table ES-1.

  18. Anaerobic Fe(III) reduction by Shewanella putrefaciens: Analysis of the electron transport chain

    SciTech Connect

    Daad Saffarini

    2004-01-20

    The goals of the project were to isolate mutants that are deficient in metal reduction, identify components of the electron transport chain that are involved in this process, and purify some of these proteins for biochemical analyses. In the 3-year period since the start of the project, we have accomplished many of these goals. We have isolated several new S. oneidensis mutants that are deficient in metal reduction, and have initiated the development of vectors for the overexpression of cytochromes and other proteins in S. oneidensis. We have also overexpressed CymA, one of the c cytochromes that are involved in metal reduction.

  19. DEVELOPMENT AND EVALUATION OF A MATHEMATICAL MODEL FOR THE TRANSPORT AND OXIDATION-REDUCTION OF COEDTA

    EPA Science Inventory

    Oxidation-reduction reactions, catalyzed by iron and manganese oxides, influence the subsurface mobility of a variety of toxic metals. In the work reported here, we develop a new model for the transport of the redox-sensitive CoEDTA complex, and we test the model against publishe...

  20. Reductive dissolution and reactive solute transport in a sewage-contaminated glacial outwash aquifer

    USGS Publications Warehouse

    Lee, R.W.; Bennett, P.C.

    1998-01-01

    Contamination of shallow ground water by sewage effluent typically contains reduced chemical species that consume dissolved oxygen, developing either a low oxygen geochemical environment or an anaerobic geochemical environment. Based on the load of reduced chemical species discharged to shallow ground water and the amounts of reactants in the aquifer matrix, it should be possible to determine chemical processes in the aquifer and compare observed results to predicted ones. At the Otis Air Base research site (Cape Cod, Massachusetts) where sewage effluent has infiltrated the shallow aquifer since 1936, bacterially mediated processes such as nitrification, denitrification, manganese reduction, and iron reduction have been observed in the contaminant plume. In specific areas of the plume, dissolved manganese and iron have increased significantly where local geochemical conditions are favorable for reduction and transport of these constituents from the aquifer matrix. Dissolved manganese and iron concentrations ranged from 0.02 to 7.3 mg/L, and 0.001 to 13.0 mg/L, respectively, for 21 samples collected from 1988 to 1989. Reduction of manganese and iron is linked to microbial oxidation of sewage carbon, producing bicarbonate and the dissolved metal ions as by-products. Calculated production and flux of CO2 through the unsaturated zone from manganese reduction in the aquifer was 0.035 g/m2/d (12% of measured CO2 flux during winter). Manganese is limited in the aquifer, however. A one-dimensional, reaction-coupled transport model developed for the mildly reducing conditions in the sewage plume nearest the source beds showed that reduction, transport, and removal of manganese from the aquifer sediments should result in iron reduction where manganese has been depleted.

  1. Evaluation of simultaneous reduction and transport of selenium in saturated soil columns

    NASA Astrophysics Data System (ADS)

    Guo, Lei; Frankenberger, William T.; Jury, William A.

    1999-03-01

    Speciation plays an important role in determining the overall leachability of selenium in soil. In this study we present a mathematical model and results of miscible displacement experiments that were conducted to evaluate simultaneous reduction and transport of selenate in saturated soil columns. The experiments were carried out in organic amended (compost manure or gluten) or unamended soil, with O2-sparged or nonsparged influent solution. In all columns, reduction of selenate was fast enough to produce selenite flux in the effluent and elemental Se in the soil profile during a mean residence time of ˜30 hours. Reduction was accelerated in the presence of organic amendments and under low O2 concentrations, resulting in an increased retardation of selenium transport as a whole. The results of our experiments show that although selenate does not sorb to solid surfaces during transport, it reduces rapidly to forms that are strongly retarded. On the basis of simulation with the consecutive reaction and transport model using parameters derived from this study, selenium is expected to be retained near the soil surface, even under extreme leaching conditions.

  2. Ascorbate efflux as a new strategy for iron reduction and transport in plants.

    PubMed

    Grillet, Louis; Ouerdane, Laurent; Flis, Paulina; Hoang, Minh Thi Thanh; Isaure, Marie-Pierre; Lobinski, Ryszard; Curie, Catherine; Mari, Stéphane

    2014-01-31

    Iron (Fe) is essential for virtually all living organisms. The identification of the chemical forms of iron (the speciation) circulating in and between cells is crucial to further understand the mechanisms of iron delivery to its final targets. Here we analyzed how iron is transported to the seeds by the chemical identification of iron complexes that are delivered to embryos, followed by the biochemical characterization of the transport of these complexes by the embryo, using the pea (Pisum sativum) as a model species. We have found that iron circulates as ferric complexes with citrate and malate (Fe(III)3Cit2Mal2, Fe(III)3Cit3Mal1, Fe(III)Cit2). Because dicotyledonous plants only transport ferrous iron, we checked whether embryos were capable of reducing iron of these complexes. Indeed, embryos did express a constitutively high ferric reduction activity. Surprisingly, iron(III) reduction is not catalyzed by the expected membrane-bound ferric reductase. Instead, embryos efflux high amounts of ascorbate that chemically reduce iron(III) from citrate-malate complexes. In vitro transport experiments on isolated embryos using radiolabeled (55)Fe demonstrated that this ascorbate-mediated reduction is an obligatory step for the uptake of iron(II). Moreover, the ascorbate efflux activity was also measured in Arabidopsis embryos, suggesting that this new iron transport system may be generic to dicotyledonous plants. Finally, in embryos of the ascorbate-deficient mutants vtc2-4, vtc5-1, and vtc5-2, the reducing activity and the iron concentration were reduced significantly. Taken together, our results identified a new iron transport mechanism in plants that could play a major role to control iron loading in seeds. PMID:24347170

  3. Ascorbate Efflux as a New Strategy for Iron Reduction and Transport in Plants*

    PubMed Central

    Grillet, Louis; Ouerdane, Laurent; Flis, Paulina; Hoang, Minh Thi Thanh; Isaure, Marie-Pierre; Lobinski, Ryszard; Curie, Catherine; Mari, Stéphane

    2014-01-01

    Iron (Fe) is essential for virtually all living organisms. The identification of the chemical forms of iron (the speciation) circulating in and between cells is crucial to further understand the mechanisms of iron delivery to its final targets. Here we analyzed how iron is transported to the seeds by the chemical identification of iron complexes that are delivered to embryos, followed by the biochemical characterization of the transport of these complexes by the embryo, using the pea (Pisum sativum) as a model species. We have found that iron circulates as ferric complexes with citrate and malate (Fe(III)3Cit2Mal2, Fe(III)3Cit3Mal1, Fe(III)Cit2). Because dicotyledonous plants only transport ferrous iron, we checked whether embryos were capable of reducing iron of these complexes. Indeed, embryos did express a constitutively high ferric reduction activity. Surprisingly, iron(III) reduction is not catalyzed by the expected membrane-bound ferric reductase. Instead, embryos efflux high amounts of ascorbate that chemically reduce iron(III) from citrate-malate complexes. In vitro transport experiments on isolated embryos using radiolabeled 55Fe demonstrated that this ascorbate-mediated reduction is an obligatory step for the uptake of iron(II). Moreover, the ascorbate efflux activity was also measured in Arabidopsis embryos, suggesting that this new iron transport system may be generic to dicotyledonous plants. Finally, in embryos of the ascorbate-deficient mutants vtc2-4, vtc5-1, and vtc5-2, the reducing activity and the iron concentration were reduced significantly. Taken together, our results identified a new iron transport mechanism in plants that could play a major role to control iron loading in seeds. PMID:24347170

  4. Reduction of Fuel Consumption and Exhaust Pollutant Using Intelligent Transport Systems

    PubMed Central

    Nasir, Mostofa Kamal; Md Noor, Rafidah; Kalam, M. A.; Masum, B. M.

    2014-01-01

    Greenhouse gas emitted by the transport sector around the world is a serious issue of concern. To minimize such emission the automobile engineers have been working relentlessly. Researchers have been trying hard to switch fossil fuel to alternative fuels and attempting to various driving strategies to make traffic flow smooth and to reduce traffic congestion and emission of greenhouse gas. Automobile emits a massive amount of pollutants such as Carbon Monoxide (CO), hydrocarbons (HC), carbon dioxide (CO2), particulate matter (PM), and oxides of nitrogen (NOx). Intelligent transport system (ITS) technologies can be implemented to lower pollutant emissions and reduction of fuel consumption. This paper investigates the ITS techniques and technologies for the reduction of fuel consumption and minimization of the exhaust pollutant. It highlights the environmental impact of the ITS application to provide the state-of-art green solution. A case study also advocates that ITS technology reduces fuel consumption and exhaust pollutant in the urban environment. PMID:25032239

  5. Propagation behavior of permeability reduction in heterogeneous porous media due to particulate transport

    NASA Astrophysics Data System (ADS)

    Xu, Jianping

    2016-04-01

    In this letter we explore the propagation behavior of permeability reduction due to particulate transport in heterogeneous porous media. By simulating an advection-dispersion–based model we find that an attenuating sequence exists in terms of the propagation of particle concentration, permeability reduction and heterogeneity perturbation. The advancing speed of the fronts of the mentioned physical quantities attenuates successively from const to \\text{const}(1/n)1/t1-1/n to \\text{const}1/t (where n > 1 and t denotes time) regardless of the heterogeneity patterns. Then we move on to discuss the micro-dynamics of the propagation sequence, involving how it originates and how it connects with the macroscopic results. Moreover, exploiting the propagation mechanism enables us to know the condition under which we can apply the hypothesis of media homogeneity to describe the behavior of the particulate transport system in porous media.

  6. Solutions and reductions for radiative energy transport in laser-heated plasma

    SciTech Connect

    Broadbridge, P.; Ivanova, N. M.

    2015-01-15

    A full symmetry classification is given for models of energy transport in radiant plasma when the mass density is spatially variable and the diffusivity is nonlinear. A systematic search for conservation laws also leads to some potential symmetries and to an integrable nonlinear model. Classical point symmetries, potential symmetries, and nonclassical symmetries are used to effect variable reductions and exact solutions. The simplest time-dependent solution is shown to be stable and relevant to a closed system.

  7. Relationships of Whole Blood Serotonin and Plasma Norepinephrine within Families.

    ERIC Educational Resources Information Center

    Leventhal, Bennett L.; And Others

    1990-01-01

    This study of 47 families of autistic probands found that whole blood serotonin was positively correlated between autistic children and their mothers, fathers, and siblings, but plasma norepinephrine levels were not. (Author/JDD)

  8. Norepinephrine metabolism in neuronal cultures is increased by angiotensin II

    SciTech Connect

    Sumners, C.; Shalit, S.L.; Kalberg, C.J.; Raizada, M.K.

    1987-06-01

    In this study the authors have examined the actions of angiotensin II (ANG II) on catecholamine metabolism in neuronal brain cell cultures prepared from the hypothalamus and brain stem. Neuronal cultures prepared from the brains of 1-day-old Sprague-Dawley rats exhibit specific neuronal uptake mechanisms for both norepinephrine (NE) and dopamine (DA), and also monoamine oxidase (MAO) and catechol O-methyltransferase (COMT) activity. Separate neuronal uptake sites for NE and DA were identified by using specific neuronal uptake inhibitors for each amine. In previous studies, they determined that ANG II (10 nM-1 ..mu..M) stimulates increased neuronal (/sup 3/H)NE uptake by acting as specific receptors. They have confirmed these results here and in addition have shown that ANG II has not significant effects on neuronal (/sup 3/H)DA uptake. These results suggest that the actions of ANG II are restricted to the NE transporter in neuronal cultures. It is possible that ANG II stimulates the intraneuronal metabolism of at least part of the NE that is taken up, because the peptide stimulates MAO activity, an effect mediated by specific ANG II receptors. ANG II had no effect on COMT activity in neuronal cultures. Therefore, the use of neuronal cultures of hypothalamus and brain stem they have determined that ANG II can specifically alter NE metabolism in these areas, while apparently not altering DA metabolism.

  9. The Design, Synthesis and Structure-Activity Relationship of Mixed Serotonin, Norepinephrine and Dopamine Uptake Inhibitors

    NASA Astrophysics Data System (ADS)

    Chen, Zhengming; Yang, Ji; Skolnick, Phil

    The evolution of antidepressants over the past four decades has involved the replacement of drugs with a multiplicity of effects (e.g., TCAs) by those with selective actions (i.e., SSRIs). This strategy was employed to reduce the adverse effects of TCAs, largely by eliminating interactions with certain neurotransmitters or receptors. Although these more selective compounds may be better tolerated by patients, selective drugs, specifically SSRIs, are not superior to older drugs in treating depressed patients as measured by response and remission rates. It may be an advantage to increase synaptic levels of both serotonin and norepinephrine, as in the case of dual uptake inhibitors like duloxetine and venlafaxine. An important recent development has been the emergence of the triple-uptake inhibitors (TUIs/SNDRIs), which inhibit the uptake of the three neurotransmitters most closely linked to depression: serotonin, norepinephrine, and dopamine. Preclinical studies and clinical trials indicate that a drug inhibiting the reuptake of all three of these neurotransmitters could produce more rapid onset of action and greater efficacy than traditional antidepressants. This review will detail the medicinal chemistry involved in the design, synthesis and discovery of mixed serotonin, norepinephrine and dopamine transporter uptake inhibitors.

  10. Association of Posttraumatic Stress Disorder With Reduced In Vivo Norepinephrine Availability in the Locus Coeruleus

    PubMed Central

    Pietrzak, Robert H.; Gallezot, Jean-Dominique; Ding, Yu-Shin; Henry, Shannan; Potenza, Marc N.; Southwick, Steven M.; Krystal, John H.; Carson, Richard E.; Neumeister, Alexander

    2014-01-01

    IMPORTANCE Animal data suggest that chronic stress is associated with a reduction in norepinephrine transporter (NET) availability in the locus coeruleus. However, it is unclear whether such models are relevant to posttraumatic stress disorder (PTSD), which has been linked to noradrenergic dysfunction in humans. OBJECTIVES To use positron emission tomography and the radioligand [11C]methylreboxetine to examine in vivo NET availability in the locus coeruleus in the following 3 groups of individuals: healthy adults (HC group), adults exposed to trauma who did not develop PTSD (TC group), and adults exposed to trauma who developed PTSD (PTSD group) and to evaluate the relationship between NET availability in the locus coeruleus and a contemporary phenotypic model of PTSD symptoms. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional positron emission tomography study under resting conditions at academic and Veterans Affairs medical centers among 56 individuals in the following 3 study groups: HC (n = 18), TC (n = 16), and PTSD (n = 22). MAIN OUTCOMES AND MEASURES The [11C]methylreboxetine-binding potential of NET availability in the locus coeruleus and the severity of PTSD symptoms assessed using the Clinician-Administered PTSD Scale. RESULTS The PTSD group had significantly lower NET availability than the HC group (41% lower, Cohen d = 1.07). NET availability did not differ significantly between the TC and HC groups (31% difference, Cohen d = 0.79) or between the TC and PTSD groups (15% difference, Cohen d = 0.28). In the PTSD group, NET availability in the locus coeruleus was independently positively associated with the severity of anxious arousal (ie, hypervigilance) symptoms (r = 0.52) but not with any of the other PTSD symptom clusters. CONCLUSIONS AND RELEVANCE These results suggest that PTSD is associated with significantly reduced NET availability in the locus coeruleus and that greater NET availability in this brain region is associated with increased severity

  11. A bacterial glutathione transporter (Escherichia coli CydDC) exports reductant to the periplasm.

    PubMed

    Pittman, Marc S; Robinson, Hilary C; Poole, Robert K

    2005-09-16

    Glutathione (GSH), a major biological antioxidant, maintains redox balance in prokaryotes and eukaryotic cells and forms exportable conjugates with compounds of pharmacological and agronomic importance. However, no GSH transporter has been characterized in a prokaryote. We show here that a heterodimeric ATP-binding cassette-type transporter, CydDC, mediates GSH transport across the Escherichia coli cytoplasmic membrane. In everted membrane vesicles, GSH is imported via an ATP-driven, protonophore-insensitive, orthovanadate-sensitive mechanism, equating with export to the periplasm in intact cells. GSH transport and cytochrome bd quinol oxidase assembly are abolished in the cydD1 mutant. Glutathione disulfide (GSSG) was not transported in either Cyd(+) or Cyd(-) strains. Exogenous GSH restores defective swarming motility and benzylpenicillin sensitivity in a cydD mutant and also benzylpenicillin sensitivity in a gshA mutant defective in GSH synthesis. Overexpression of the cydDC operon in dsbD mutants defective in disulfide bond formation restores dithiothreitol tolerance and periplasmic cytochrome b assembly, revealing redundant pathways for reductant export to the periplasm. These results identify the first prokaryotic GSH transporter and indicate a key role for GSH in periplasmic redox homeostasis. PMID:16040611

  12. Risk reduction in road and rail LPG transportation by passive fire protection.

    PubMed

    Paltrinieri, Nicola; Landucci, Gabriele; Molag, Menso; Bonvicini, Sarah; Spadoni, Gigliola; Cozzani, Valerio

    2009-08-15

    The potential reduction of risk in LPG (Liquefied Petroleum Gas) road transport due to the adoption of passive fire protections was investigated. Experimental data available for small scale vessels fully engulfed by a fire were extended to real scale road and rail tankers through a finite elements model. The results of mathematical simulations of real scale fire engulfment scenarios that may follow accidents involving LPG tankers proved the effectiveness of the thermal protections in preventing the "fired" BLEVE (Boiling Liquid Expanding Vapour Explosion) scenario. The presence of a thermal coating greatly increases the "time to failure", providing a time lapse that in the European experience may be considered sufficient to allow the start of effective mitigation actions by fire brigades. The results obtained were used to calculate the expected reduction of individual and societal risk due to LPG transportation in real case scenarios. The analysis confirmed that the introduction of passive fire protections turns out in a significant reduction of risk, up to an order of magnitude in the case of individual risk and of about 50% if the expectation value is considered. Thus, the adoption of passive fire protections, not compulsory in European regulations, may be an effective technical measure for risk reduction, and may contribute to achieve the control of "major accidents hazards" cited by the European legislation. PMID:19188020

  13. Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β

    PubMed Central

    Xu, Jordan C.; Fomenko, Vira; Miyamoto, Takashi; Suberbielle, Elsa; Knox, Joseph A.; Ho, Kaitlyn; Kim, Daniel H.; Yu, Gui-Qiu

    2015-01-01

    Axonal transport deficits in Alzheimer’s disease (AD) are attributed to amyloid β (Aβ) peptides and pathological forms of the microtubule-associated protein tau. Genetic ablation of tau prevents neuronal overexcitation and axonal transport deficits caused by recombinant Aβ oligomers. Relevance of these findings to naturally secreted Aβ and mechanisms underlying tau’s enabling effect are unknown. Here we demonstrate deficits in anterograde axonal transport of mitochondria in primary neurons from transgenic mice expressing familial AD-linked forms of human amyloid precursor protein. We show that these deficits depend on Aβ1–42 production and are prevented by tau reduction. The copathogenic effect of tau did not depend on its microtubule binding, interactions with Fyn, or potential role in neuronal development. Inhibition of neuronal activity, N-methyl-d-aspartate receptor function, or glycogen synthase kinase 3β (GSK3β) activity or expression also abolished Aβ-induced transport deficits. Tau ablation prevented Aβ-induced GSK3β activation. Thus, tau allows Aβ oligomers to inhibit axonal transport through activation of GSK3β, possibly by facilitating aberrant neuronal activity. PMID:25963821

  14. Gas Transport Resistance in Polymer Electrolyte Thin Films on Oxygen Reduction Reaction Catalysts.

    PubMed

    Liu, Hang; Epting, William K; Litster, Shawn

    2015-09-15

    Significant reductions in expensive platinum catalyst loading for the oxygen reduction reaction are needed for commercially viable fuel cell electric vehicles as well as other important applications. In reducing loading, a resistance at the Pt surface in the presence of thin perfluorosulfonic acid (PFSA) electrolyte film, on the order of 10 nm thick, becomes a significant barrier to adequate performance. However, the resistance mechanism is unresolved and could be due to gas dissolution kinetics, increased diffusion resistance in thin films, or electrolyte anion interactions. A common hypothesis for the origin of the resistance is a highly reduced oxygen permeability in the thin polymer electrolyte films that coat the catalyst relative to bulk permeability that is caused by nanoscale confinement effects. Unfortunately, the prior work has not separated the thin-film gas transport resistance from that associated with PFSA interactions with a polarized catalyst surface. Here, we present the first characterization of the thin-film O2 transport resistance in the absence of a polarized catalyst, using a nanoporous substrate that geometrically mimics the active catalyst particles. Through a parametric study of varying PFSA film thickness, as thin as 50 nm, we observe no enhanced gas transport resistance in thin films as a result of either interfacial effects or structural changes in the PFSA. Our results suggest that other effects, such as anion poisoning at the Pt catalyst, could be the source of the additional resistance observed at low Pt loading. PMID:26299282

  15. Symmetry reductions of a nonlinear convection-dispersion model arising in contaminant transport theory

    NASA Astrophysics Data System (ADS)

    Ntsime, Basetsana P.; Moitsheki, Raseelo J.

    2016-06-01

    In this paper we consider a nonlinear convection-dispersion equation arising in contaminant transport. The water flow velocity is considered to be spatially-dependent and dispersion coefficient depends on concentration. A direct group classification resulted in a number of cases for which the governing equation admits Lie point symmetries. In each case the one dimensional optimal system of subalgebras is constructed. Reductions are performed. The reduced ordinary differential equations (ODEs) are nonlinear and difficult to solve exactly. On the other hand we consider the steady state problem and applied the method of canonical coordinates to determine exact solutions.

  16. An approximate framework for quantum transport calculation with model order reduction

    SciTech Connect

    Chen, Quan; Li, Jun; Yam, Chiyung; Zhang, Yu; Wong, Ngai; Chen, Guanhua

    2015-04-01

    A new approximate computational framework is proposed for computing the non-equilibrium charge density in the context of the non-equilibrium Green's function (NEGF) method for quantum mechanical transport problems. The framework consists of a new formulation, called the X-formulation, for single-energy density calculation based on the solution of sparse linear systems, and a projection-based nonlinear model order reduction (MOR) approach to address the large number of energy points required for large applied biases. The advantages of the new methods are confirmed by numerical experiments.

  17. Reactive Transport Modeling of Microbially-Mediated Chromate Reduction in 1-D Soil Columns

    NASA Astrophysics Data System (ADS)

    Qiu, H.; Viamajala, S.; Alam, M. M.; Peyton, B. M.; Petersen, J. N.; Yonge, D. R.

    2002-12-01

    Cr(VI) reduction tests were performed with the well known metal reducing bacterium Shewanella oneidensis MR-1 in liquid phase batch reactors and continuous flow soil columns under anaerobic conditions. In the batch tests, the cultures were grown with fumarate as the terminal electron acceptor and lactate as the electron donor in a simulated groundwater medium to determine yield coefficients and specific growth rates. The bench-scale soil column experiments were carried out with MR-1 to test the hypothesis that the kinetic parameters obtained in batch studies, combined with microbial attachment /detachment processes, will accurately predict reactive transport of Cr(VI) during bacterial Cr(VI) reduction in a soil matrix. Cr(VI)-free simulated groundwater media containing fumarate as the limiting substrate and lactate was supplied to a 2.1cm (ID) x 15 cm soil column inoculated with MR-1 for a duration of 9 residence times to allow for biomass to build-up in the column. Thereafter the column was supplied with both Cr(VI) and substrate. The concentrations of effluent substrate, biomass and Cr(VI) were monitored on a periodic basis and attached biomass in the column was measured in the termination of each column test. A reactive transport model was developed in which 6 governing equations deal with Cr(VI) bioreaction, fumarate (as electron donor) consumption, aqueous biomass growth and transport, solid biomass detachment and attachment kinetics, aqueous and solid phase enzyme reaction and transport, respectively. The model incorporating the enzyme reaction kinetics for Cr(VI) reduction, Monod kinetic expressions for substrate depletion, nonlinear attachment and detachment kinetics for aqueous and solid phase microorganism concentration, was solved by a fully implicit, finite-difference procedure using RT3D (A Modular Computer Code for Reactive Multi-species Transport in 3-Dimensional Groundwater Systems) platform in one dimension. Cr(VI)-free column data was used to

  18. Aeronautical fuel conservation possibilities for advanced subsonic transports. [application of aeronautical technology for drag and weight reduction

    NASA Technical Reports Server (NTRS)

    Braslow, A. L.; Whitehead, A. H., Jr.

    1973-01-01

    The anticipated growth of air transportation is in danger of being constrained by increased prices and insecure sources of petroleum-based fuel. Fuel-conservation possibilities attainable through the application of advances in aeronautical technology to aircraft design are identified with the intent of stimulating NASA R and T and systems-study activities in the various disciplinary areas. The material includes drag reduction; weight reduction; increased efficiency of main and auxiliary power systems; unconventional air transport of cargo; and operational changes.

  19. Thromboxane agonist (U46619) potentiates norepinephrine efflux from adrenergic nerves

    SciTech Connect

    Trachte, G.J.

    1986-05-01

    The effect of the synthetic thromboxane/prostaglandin (PG) H2 agonist U46619 on the electrically stimulated rabbit isolated vas deferens was examined to test for thromboxane influences on adrenergic nerves. U46619 effects on force generation, (/sup 3/H) norepinephrine release and norepinephrine-induced contractions were assessed to determine the mechanism of action. U46619 maximally enhanced adrenergic force generation 135 +/- 24% at a concentration of 100 nM. U46619 potentiated maximal contractile effects of exogenously administered norepinephrine 16 +/- 4% and augmented (/sup 3/H)norepinephrine release from electrically stimulated preparations 142 +/- 44%. A competitive thromboxane/PGH2 receptor antagonist, SQ29548, significantly shifted the concentration-response curve for U46619 to the right in a concentration-dependent manner and blocked U46619-induced tritium release. Thus, U46619 appears to potentiate neurotransmitter release by interacting with thromboxane/PGH2 receptors. Because SQ29548 did not prevent the potentiation of norepinephrine contractions by U46619, the postjunctional effect may be independent of thromboxane/PGH2 receptors. We interpret these results to be indicative of both pre- and postjunctional sites of action of U46619. The physiological importance of these thromboxane effects is unknown currently.

  20. In vitro vascular responsiveness to norepinephrine in experimental portal hypertension.

    PubMed

    Bomzon, A; Jacob, G; Lee, S S; Meddings, J

    1991-02-01

    It has been postulated that loss of response to norepinephrine accounts in part for the portal hypertension, systemic hypotension, and generalised vascular dilatation of chronic liver disease. The in vitro vascular responsiveness to norepinephrine was measured in aortic rings and portal veins excised from four different rat models of hepatic disease with and without portal hypertension, hepatocellular damage, and hyperbilirubinemia--the carbon tetrachloride (CCl4) cirrhotic rat with portal hypertension, the five-week chronic bile duct ligated and resected (CBDL) cirrhotic rat with portal hypertension and hyperbilirubinemia, the 10-day partial ligated portal vein (PVL) portal hypertensive rat without hepatocellular damage and hyperbilirubinemia, and the three-day bile duct ligated (ABDL) rat with acute hepatocellular damage and hyperbilirubinemia but without portal hypertension. Sham-treated or operated groups for each model were also prepared. Vascular reactivity of the aortic rings to norepinephrine was potentiated in the three portal hypertensive groups, and attenuated in the model of acute cholestasis. No consistent pattern of response to norepinephrine was evident in the portal veins. Based upon the presented in vitro data and the discussed limitations of an in vitro study, we conclude that it is unlikely that the loss of response to norepinephrine accounts for the portal hypertension, systemic hypotension, and generalised vascular dilatation of chronic liver disease. PMID:2040106

  1. Neuroimmunomodulatory interactions of norepinephrine and serotonin.

    PubMed

    Walker, R F; Codd, E E

    1985-11-01

    Monoamine neuroleptics alter rodents responses to immunization, suggesting that norepinephrine (NE) and serotonin (5HT) are neuroimmunomodulatory in these animals. Although endocrine factors participate in their mechanism(s) of action, recent studies suggest that NE and 5HT also interact more directly with immunocompetent cells. This review provides an overview of evidence for a direct regulatory link between the nervous and immune systems and further speculates on the process by which NE and 5HT realize in part, their neuroimmunomodulatory potential. Anatomical data show that noradrenergic fibers of the sympathetic nervous system innervate lymphoid organs providing a channel of communication between neurons and lymphocytes. Presumably neural signals transmitted by NE are received by platelets that in turn, transduce them via 5HT into immunomodulatory messages. It is proposed that NE alters the capacity of platelets to sequester and/or catabolize 5HT, thus regulating its physiologically active pool in the plasma. Macrophages possess a 5HT uptake system, the kinetic properties of which make them sensitive to changes in plasma levels of the amine. Thus, through its ability to regulate plasma levels of 5HT, an immunosuppressive amine with access to macrophages, the nervous system can influence cells involved in antigen recognition. Support for this hypothetical immunomodulatory mechanism is gleaned from clinical and experimental studies. For example, individuals suffering emotional trauma are more susceptible than others to developing physical illness. It is of interest that platelet 5HT pharmacodynamics are often abnormal in patients with psychological disorders characterized by catecholamine deficits. Similar platelet changes have been achieved experimentally by treating rats with catecholamine antimetabolites. Additional support for the hypothesis derives from aging research since 'monoamine imbalance' and immune dysfunction are co-characteristics of senescence. In

  2. Continuous infusion of tracer norepinephrine may miscalculate unidirectional nerve uptake of norepinephrine in humans

    SciTech Connect

    Henriksen, J.H.; Christensen, N.J.; Ring-Larsen, H. )

    1989-08-01

    In order to evaluate uptake kinetics of norepinephrine (NE) in different tissues, a catheterization study was performed in control subjects (n = 6) and patients with enhanced sympathetic nervous activity (cirrhosis, n = 12) during constant intravenous infusion of L(3H)norepinephrine ((3H)NE) for 75 minutes. In spite of a higher NE spillover from kidneys in patients compared with controls (82 vs. 49 ng/min, p less than 0.01), renal extraction ratios of (3H)NE were similar in the two groups (0.33 vs. 0.32, NS), and no significant change was observed during the time of infusion. In contrast, liver-intestine extraction ratios of (3H)NE decreased significantly and equally with infusion time in patients (from 0.57 to 0.44, p less than 0.01) and controls (from 0.59 to 0.46, p less than 0.01). This was observed despite the fact that spillover of NE from this vascular bed was observed only in patients with cirrhosis and not in controls (41 vs. -5 ng/min, p less than 0.02). In the lower limb, net release of NE was similar in patients and controls, and extraction ratios of (3H)NE decreased almost equally with infusion time (from 0.35 to 0.30, p less than 0.01 and from 0.40 to 0.24, p less than 0.1, respectively). Whole-body clearance of (3H)NE decreased over time in patients (-6%, p less than 0.01) and controls (-20%, p less than 0.01), but significant difference was not observed between the groups. We conclude that failure to attain a steady state with respect to (3H)NE removal was demonstrated in areas of large tissue volume relative to blood flow.

  3. Combined Norepinephrine/Serotonergic Reuptake Inhibition: Effects on Maternal Behavior, Aggression, and Oxytocin in the Rat

    PubMed Central

    Cox, Elizabeth Thomas; Jarrett, Thomas Merryfield; McMurray, Matthew Stephen; Greenhill, Kevin; Hofler, Vivian E.; Williams, Sarah Kaye; Joyner, Paul Wayland; Middleton, Christopher L.; Walker, Cheryl H.; Johns, Josephine M.

    2011-01-01

    Background: Few systematic studies exist on the effects of chronic reuptake of monoamine neurotransmitter systems during pregnancy on the regulation of maternal behavior (MB), although many drugs act primarily through one or more of these systems. Previous studies examining fluoxetine and amfonelic acid treatment during gestation on subsequent MB in rodents indicated significant alterations in postpartum maternal care, aggression, and oxytocin levels. In this study, we extended our studies to include chronic gestational treatment with desipramine or amitriptyline to examine differential effects of reuptake inhibition of norepinephrine and combined noradrenergic and serotonergic systems on MB, aggression, and oxytocin system changes. Methods: Pregnant Sprague-Dawley rats were treated throughout gestation with saline or one of three doses of either desipramine, which has a high affinity for the norepinephrine monoamine transporter, or amitriptyline, an agent with high affinity for both the norepinephrine and serotonin monoamine transporters. MB and postpartum aggression were assessed on postpartum days 1 and 6 respectively. Oxytocin levels were measured in relevant brain regions on postpartum day 7. Predictions were that amitriptyline would decrease MB and increase aggression relative to desipramine, particularly at higher doses. Amygdaloidal oxytocin was expected to decrease with increased aggression. Results: Amitriptyline and desipramine differentially reduced MB, and at higher doses reduced aggressive behavior. Hippocampal oxytocin levels were lower after treatment with either drug but were not correlated with specific behavioral effects. These results, in combination with previous findings following gestational treatment with other selective neurotransmitter reuptake inhibitors, highlight the diverse effects of multiple monoamine systems thought to be involved in maternal care. PMID:21713063

  4. Reaction-Based Reactive Transport Modeling of Fe(III) and U(V) Reduction

    SciTech Connect

    Burgos, William D.; Roden, Eric E.; Yeh, Gour-Tsyh

    2005-06-01

    Our new research project (started Fall 2004) was funded by a grant to The Pennsylvania State University, University of Central Florida, and The University of Alabama in the Integrative Studies Element of the NABIR Program (DE-FG04-ER63914/63915/63196). Our previous NABIR project (DE-FG02-01ER63180/63181/63182, funded within the Biotransformation Element) focused on (1) microbial reduction of Fe(III) and U(VI) individually, and concomitantly in natural sediments, (2) Fe(III) oxide surface chemistry, specifically with respect to reactions with Fe(II) and U(VI), (3) the influence of humic substances on Fe(III) and U(VI) bioreduction, and on U(VI) complexation, and (4) the development of reaction-based reactive transport biogeochemical models to numerically simulate our experimental results. The new project focuses on the development of a mechanistic understanding and quantitative models of coupled Fe(III)/U(VI) reduction in FRC Area 2 sediments. This work builds on our previous studies of microbial Fe(III) and U(VI) reduction, and is directly aligned with the Scheibe et al. NABIR FRC Field Project at Area 2.

  5. Experimental investigation of the ground transportation systems (GTS) project for heavy vehicle drag reduction

    SciTech Connect

    Croll, R.H.; Gutierrez, W.T.; Hassan, B.; Suazo, J.E.; Riggins, A.J.

    1995-12-31

    A wind tunnel experimental research program was conducted on a heavily instrumented Ground Transportation System (GTS) vehicle. The GTS baseline model represented a generic 1:8 scale Class-8 van-type tractor trailer geometry. Five base drag reduction add-on devices, instrumented with surface pressure ports, were also tested. These add-on devices included two ogive boattail shapes and three slant geometry devices. Six component force and moment data, surface pressure contours, and wake velocity surveys are presented for each configuration along with qualitative insights gained from flow visualization. This wind tunnel program was designed to complement a parallel research effort in computational fluid dynamics (CFD) which modeled many of these same vehicle geometries. The wind tunnel data are documented and archived in ASCII format on floppy discs and available to researchers interested in further analysis or comparison to other CFD solutions.

  6. The CydDC ABC transporter of Escherichia coli: new roles for a reductant efflux pump.

    PubMed

    Shepherd, Mark

    2015-10-01

    The CydDC complex of Escherichia coli is a heterodimeric ATP-binding cassette (ABC) transporter that exports cysteine and glutathione to the periplasm. These reductants are thought to modulate periplasmic redox poise, impacting upon the disulfide folding of periplasmic and secreted proteins involved in bacterial virulence. Diminished CydDC activity abolishes the assembly of functional bd-type respiratory oxidases and perturbs haem ligation during the assembly of c-type cytochromes. The focus herein is upon a newly-discovered interaction of the CydDC complex with a haem cofactor; haem has recently been shown to modulate CydDC activity and structural modelling reveals a potential haem-binding site on the periplasmic surface of the complex. These findings have important implications for future investigations into the potential roles for the CydDC-bound haem in redox sensing and tolerance to nitric oxide (NO). PMID:26517902

  7. Experimental study on noise reduction effect of a muffler inserted in liquid transporting pipeline

    NASA Astrophysics Data System (ADS)

    Du, T.; Xu, W. W.; Wu, D. Z.; Wang, L. Q.

    2013-12-01

    In order to reduce the noise of liquid transporting pipelines caused by the motion of the power unit, a kind of compact hydrodynamic muffler used in pipes with small diameters is proposed which achieves good vibration damping as well as hydrodynamic noise reduction. Based on the rubber damper tube, according to the structure characteristics, the muffler is composed of two main parts, the rubber damper tube and the inner noise reducing structure. Experiment on insertion loss of the muffler in stationary state is conducted. It is found that the rubber damper tube itself has a good performance at noise reducing at the frequency band considered here, total insertion loss values can reach 10 dB and the inner structures improve the performance of the muffler at low frequency band.

  8. Selective norepinephrine reuptake inhibition as a human model of orthostatic intolerance

    NASA Technical Reports Server (NTRS)

    Schroeder, Christoph; Tank, Jens; Boschmann, Michael; Diedrich, Andre; Sharma, Arya M.; Biaggioni, Italo; Luft, Friedrich C.; Jordan, Jens; Robertson, D. (Principal Investigator)

    2002-01-01

    BACKGROUND: Observations in patients with functional mutations of the norepinephrine transporter (NET) gene suggest that impaired norepinephrine uptake may contribute to idiopathic orthostatic intolerance. METHODS AND RESULTS: We studied the effect of the selective NET blocker reboxetine and placebo in a randomized, double-blind, crossover fashion on cardiovascular responses to cold pressor testing, handgrip testing, and a graded head-up tilt test (HUT) in 18 healthy subjects. In a subset, we determined isoproterenol and phenylephrine sensitivities. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. In the supine position, heart rate was 65+/-2 bpm with placebo and 71+/-3 bpm with reboxetine. At 75 degrees HUT, heart rate was 84+/-3 and 119+/-4 bpm with placebo and with reboxetine (P<0.0001). Mean arterial pressure was 85+/-2 with placebo and 91+/-2 mm Hg with reboxetine while supine (P<0.01) and 88+/-2 mm Hg and 90+/-3 mm Hg at 75 degrees HUT. Blood pressure responses to cold pressor and handgrip testing were attenuated with reboxetine. Reboxetine increased the sensitivity to the chronotropic effect of isoproterenol and the pressor effect of phenylephrine. Vasovagal reactions occurred in 9 subjects on placebo and in 1 subject on reboxetine. CONCLUSIONS: Selective NET blockade creates a phenotype that resembles idiopathic orthostatic intolerance. This observation supports the hypothesis that disordered norepinephrine uptake mechanisms can contribute to human cardiovascular disease. Our study also suggests that NET inhibition might be useful in preventing vasovagal reactions.

  9. Genetic influence on brain catecholamines: high brain norepinephrine in salt-sensitive rats

    SciTech Connect

    Iwai, J; Friedman, R; Tassinari, L

    1980-01-01

    Rats genetically sensitive to salt-induced hypertension evinced higher levels of plasma norepinephrine and epinephrine than rats genetically resistant to hypertension. The hypertension-sensitive rats showed higher hypothalamic norepinephrine and lower epinephrine than resistant rats. In response to a high salt diet, brain stem norepinephrine increased in sensitive rats while resistant rats exhibited a decrease on the same diet.

  10. Electrification of the transportation sector offers limited country-wide greenhouse gas reductions

    NASA Astrophysics Data System (ADS)

    Meinrenken, Christoph J.; Lackner, Klaus S.

    2014-03-01

    Compared with conventional propulsion, plugin and hybrid vehicles may offer reductions in greenhouse gas (GHG) emissions, regional air/noise pollution, petroleum dependence, and ownership cost. Comparing only plugins and hybrids amongst themselves, and focusing on GHG, relative merits of different options have been shown to be more nuanced, depending on grid-carbon-intensity, range and thus battery manufacturing and weight, and trip patterns. We present a life-cycle framework to compare GHG emissions for three drivetrains (plugin-electricity-only, gasoline-only-hybrid, and plugin-hybrid) across driving ranges and grid-carbon-intensities, for passenger cars, vans, buses, or trucks (well-to-wheel plus storage manufacturing). Parameter and model uncertainties are quantified via sensitivity analyses. We find that owing to the interplay of range, GHG/km, and portions of country-wide kms accessible to electrification, GHG reductions achievable from plugins (whether electricity-only or hybrids) are limited even when assuming low-carbon future grids. Furthermore, for policy makers considering GHG from electricity and transportation sectors combined, plugin technology may in fact increase GHG compared to gasoline-only-hybrids, regardless of grid-carbon-intensity.

  11. Systematic Dimensionality Reduction for Quantum Walks: Optimal Spatial Search and Transport on Non-Regular Graphs

    PubMed Central

    Novo, Leonardo; Chakraborty, Shantanav; Mohseni, Masoud; Neven, Hartmut; Omar, Yasser

    2015-01-01

    Continuous time quantum walks provide an important framework for designing new algorithms and modelling quantum transport and state transfer problems. Often, the graph representing the structure of a problem contains certain symmetries that confine the dynamics to a smaller subspace of the full Hilbert space. In this work, we use invariant subspace methods, that can be computed systematically using the Lanczos algorithm, to obtain the reduced set of states that encompass the dynamics of the problem at hand without the specific knowledge of underlying symmetries. First, we apply this method to obtain new instances of graphs where the spatial quantum search algorithm is optimal: complete graphs with broken links and complete bipartite graphs, in particular, the star graph. These examples show that regularity and high-connectivity are not needed to achieve optimal spatial search. We also show that this method considerably simplifies the calculation of quantum transport efficiencies. Furthermore, we observe improved efficiencies by removing a few links from highly symmetric graphs. Finally, we show that this reduction method also allows us to obtain an upper bound for the fidelity of a single qubit transfer on an XY spin network. PMID:26330082

  12. Systematic Dimensionality Reduction for Quantum Walks: Optimal Spatial Search and Transport on Non-Regular Graphs

    NASA Astrophysics Data System (ADS)

    Novo, Leonardo; Chakraborty, Shantanav; Mohseni, Masoud; Neven, Hartmut; Omar, Yasser

    2015-09-01

    Continuous time quantum walks provide an important framework for designing new algorithms and modelling quantum transport and state transfer problems. Often, the graph representing the structure of a problem contains certain symmetries that confine the dynamics to a smaller subspace of the full Hilbert space. In this work, we use invariant subspace methods, that can be computed systematically using the Lanczos algorithm, to obtain the reduced set of states that encompass the dynamics of the problem at hand without the specific knowledge of underlying symmetries. First, we apply this method to obtain new instances of graphs where the spatial quantum search algorithm is optimal: complete graphs with broken links and complete bipartite graphs, in particular, the star graph. These examples show that regularity and high-connectivity are not needed to achieve optimal spatial search. We also show that this method considerably simplifies the calculation of quantum transport efficiencies. Furthermore, we observe improved efficiencies by removing a few links from highly symmetric graphs. Finally, we show that this reduction method also allows us to obtain an upper bound for the fidelity of a single qubit transfer on an XY spin network.

  13. Reduction in Energy Consumption for Pretreatment Process and Transportation of Pulverized Wood Fuel

    NASA Astrophysics Data System (ADS)

    Nishi, Kenji; Sawai, Toru; Ohmasa, Mitsushi; Hirokawa, Noriyasu; Shibue, Tadashi; Kajimoto, Takeshi

    In recent years, much attention has been focused on the energy utilization of biomass to reduce the emission of greenhouse gas. Especially, woody biomass such as the forestry biomass derived from logging and thinning operations in forests is one of the most promising domestic resources in Japan. Woody biomass contributes not only to the improvement of energy self-sufficiency in Japan, but also to the environmental protection of Japanese forests. When the woody biomass is utilized, it is necessary to examine the energy consumption for collection of resources, pretreatment, transportation and after-treatment. In the present study, woody biomass is assumed to be utilized as pulverized wood fuel in local area. The pretreatment of pulverized wood fuel is consisted of three procedures; drying, semi-carbonizaion and fine comminution. The main purpose of the study is to investigate the comminution characteristic of the Japanese cedar thinning and the reduction in energy consumption for pretreatment process and transportation of pulverized wood fuel. The results obtained in the present study are as follows. (1) Comminution energy increases as the water content increases and the sieve of screen becomes small. The comminution energy of hammer mill is largely affected by the water content. Difference in comminution energy between the hammer and cutter mills is large. The ratio of comminution energy of the hammer mill to that of the cutter mill exceeds 10 for the water content of 40% and sieve of screen of 3mm. (2) To estimate the comminution energy of woody biomass, empirical equations of work index in Bond's Law are presented. In woody biomass region, the empirical equations of work index depend on the comminution method. In semi-carbonization and carbonization regions, the empirical equation of work index is presented regardless of comminution method and sieve of screen. The comminution energy can be estimated by using the present empirical equations within accuracy ±50

  14. Spatiotemporal norepinephrine mapping using a high-density CMOS microelectrode array.

    PubMed

    Wydallis, John B; Feeny, Rachel M; Wilson, William; Kern, Tucker; Chen, Tom; Tobet, Stuart; Reynolds, Melissa M; Henry, Charles S

    2015-10-21

    A high-density amperometric electrode array containing 8192 individually addressable platinum working electrodes with an integrated potentiostat fabricated using Complementary Metal Oxide Semiconductor (CMOS) processes is reported. The array was designed to enable electrochemical imaging of chemical gradients with high spatiotemporal resolution. Electrodes are arranged over a 2 mm × 2 mm surface area into 64 subarrays consisting of 128 individual Pt working electrodes as well as Pt pseudo-reference and auxiliary electrodes. Amperometric measurements of norepinephrine in tissue culture media were used to demonstrate the ability of the array to measure concentration gradients in complex media. Poly(dimethylsiloxane) microfluidics were incorporated to control the chemical concentrations in time and space, and the electrochemical response at each electrode was monitored to generate electrochemical heat maps, demonstrating the array's imaging capabilities. A temporal resolution of 10 ms can be achieved by simultaneously monitoring a single subarray of 128 electrodes. The entire 2 mm × 2 mm area can be electrochemically imaged in 64 seconds by cycling through all subarrays at a rate of 1 Hz per subarray. Monitoring diffusional transport of norepinephrine is used to demonstrate the spatiotemporal resolution capabilities of the system. PMID:26333296

  15. Norepinephrine Modulates Coding of Complex Vocalizations in the Songbird Auditory Cortex Independent of Local Neuroestrogen Synthesis.

    PubMed

    Ikeda, Maaya Z; Jeon, Sung David; Cowell, Rosemary A; Remage-Healey, Luke

    2015-06-24

    The catecholamine norepinephrine plays a significant role in auditory processing. Most studies to date have examined the effects of norepinephrine on the neuronal response to relatively simple stimuli, such as tones and calls. It is less clear how norepinephrine shapes the detection of complex syntactical sounds, as well as the coding properties of sensory neurons. Songbirds provide an opportunity to understand how auditory neurons encode complex, learned vocalizations, and the potential role of norepinephrine in modulating the neuronal computations for acoustic communication. Here, we infused norepinephrine into the zebra finch auditory cortex and performed extracellular recordings to study the modulation of song representations in single neurons. Consistent with its proposed role in enhancing signal detection, norepinephrine decreased spontaneous activity and firing during stimuli, yet it significantly enhanced the auditory signal-to-noise ratio. These effects were all mimicked by clonidine, an α-2 receptor agonist. Moreover, a pattern classifier analysis indicated that norepinephrine enhanced the ability of single neurons to accurately encode complex auditory stimuli. Because neuroestrogens are also known to enhance auditory processing in the songbird brain, we tested the hypothesis that norepinephrine actions depend on local estrogen synthesis. Neither norepinephrine nor adrenergic receptor antagonist infusion into the auditory cortex had detectable effects on local estradiol levels. Moreover, pretreatment with fadrozole, a specific aromatase inhibitor, did not block norepinephrine's neuromodulatory effects. Together, these findings indicate that norepinephrine enhances signal detection and information encoding for complex auditory stimuli by suppressing spontaneous "noise" activity and that these actions are independent of local neuroestrogen synthesis. PMID:26109659

  16. Sympathetic innervation, norepinephrine content, and norepinephrine turnover in orthotopic and spontaneous models of breast cancer.

    PubMed

    Szpunar, Mercedes J; Belcher, Elizabeth K; Dawes, Ryan P; Madden, Kelley S

    2016-03-01

    Activation of the sympathetic nervous system (SNS) drives breast cancer progression in preclinical breast cancer models, but it has yet to be established if neoplastic and stromal cells residing in the tumor are directly targeted by locally released norepinephrine (NE). In murine orthotopic and spontaneous mammary tumors, tyrosine hydroxylase (TH)+ sympathetic nerves were limited to the periphery of the tumor. No TH+ staining was detected deeper within these tumors, even in regions with a high density of blood vessels. NE concentration was much lower in tumors compared to the more densely innervated spleen, reflecting the relative paucity of tumor TH+ innervation. Tumor and spleen NE concentration decreased with increased tissue mass. In mice treated with the neurotoxin 6-hydroxydopamine (6-OHDA) to selectively destroy sympathetic nerves, tumor NE concentration was reduced approximately 50%, suggesting that the majority of tumor NE is derived from local sympathetic nerves. To evaluate NE utilization, NE turnover in orthotopic 4T1 mammary tumors was compared to spleen under baseline and stress conditions. In non-stressed mice, NE turnover was equivalent between tumor and spleen. In mice exposed to a stressor, tumor NE turnover was increased compared to spleen NE turnover, and compared to non-stressed tumor NE turnover. Together, these results demonstrate that NE in mammary tumors is derived from local sympathetic nerves that synthesize and metabolize NE. However, differences between spleen and tumor NE turnover with stressor exposure suggest that sympathetic NE release is regulated differently within the tumor microenvironment compared to the spleen. Local mammary tumor sympathetic innervation, despite its limited distribution, is responsive to stressor exposure and therefore can contribute to stress-induced tumor progression. PMID:26718447

  17. Analysis of acidity production during enhanced reductive dechlorination using a simplified reactive transport model

    NASA Astrophysics Data System (ADS)

    Brovelli, A.; Barry, D. A.; Robinson, C.; Gerhard, J. I.

    2012-07-01

    Build-up of fermentation products and hydrochloric acid at a contaminated site undergoing enhanced reductive dechlorination can result in groundwater acidification. Sub-optimal pH conditions can inhibit microbial activity and lead to reduced dechlorination rates. The extent of acidification likely to occur is site-specific and depends primarily on the extent of fermentation and dechlorination, the geochemical composition of soil and groundwater, and the pH-sensitivity of the active microbial populations. Here, the key chemical and physical mechanisms that control the extent of groundwater acidification in a contaminated site were examined, and the extent to which the remediation efficiency was affected by variations in groundwater pH was evaluated using a simplified process-based reactive-transport model. This model was applied successfully to a well-documented field site and was then employed in a sensitivity analysis to identify the processes likely to significantly influence acidity production and subsequent microbial inhibition. The accumulation of organic acids produced from the fermentation of the injected substrate was the main cause of the pH change. The concentration of dissolved sulphates controlled substrate utilisation efficiency because sulphate-reducing biomass competed with halo-respiring biomass for the fermentation products. It was shown further that increased groundwater velocity increases dilution and reduces the accumulation of acidic products. As a consequence, the flow rate corresponding to the highest remediation efficiency depends on the fermentation and dechlorination rates. The model enables investigation and forecasting of the extent and areal distribution of pH change, providing a means to optimise the application of reductive dechlorination for site remediation.

  18. Gold Nanoparticles-Based Barcode Analysis for Detection of Norepinephrine.

    PubMed

    An, Jeung Hee; Lee, Kwon-Jai; Choi, Jeong-Woo

    2016-02-01

    Nanotechnology-based bio-barcode amplification analysis offers an innovative approach for detecting neurotransmitters. We evaluated the efficacy of this method for detecting norepinephrine in normal and oxidative-stress damaged dopaminergic cells. Our approach use a combination of DNA barcodes and bead-based immunoassays for detecting neurotransmitters with surface-enhanced Raman spectroscopy (SERS), and provides polymerase chain reaction (PCR)-like sensitivity. This method relies on magnetic Dynabeads containing antibodies and nanoparticles that are loaded both with DNA barcords and with antibodies that can sandwich the target protein captured by the Dynabead-bound antibodies. The aggregate sandwich structures are magnetically separated from the solution and treated to remove the conjugated barcode DNA. The DNA barcodes are then identified by SERS and PCR analysis. The concentration of norepinephrine in dopaminergic cells can be readily detected using the bio-barcode assay, which is a rapid, high-throughput screening tool for detecting neurotransmitters. PMID:27305769

  19. The central nervous norepinephrine network links a diminished sense of emotional well-being to an increased body weight

    PubMed Central

    Melasch, J; Rullmann, M; Hilbert, A; Luthardt, J; Becker, GA; Patt, M; Villringer, A; Arelin, K; Meyer, PM; Lobsien, D; Ding, Y-S; Müller, K; Sabri, O; Hesse, S; Pleger, B

    2016-01-01

    OBJECTIVES The neurobiological mechanisms linking obesity to emotional distress remain largely undiscovered. METHODS In this pilot study, we combined positron emission tomography, using the norepinephrine transporter (NET) tracer [11C]-O-methylreboxetine, with functional connectivity magnetic resonance imaging, the Beck depression inventory (BDI), and the impact of weight on quality of life-Lite questionnaire (IWQOL–Lite), to investigate the role of norepinephrine in the severity of depression (BDI), as well as in the loss of emotional well-being with body weight (IWQOL–Lite). RESULTS In a small group of lean-to-morbidly obese individuals (n = 20), we show that an increased body mass index (BMI) is related to a lowered NET availability within the hypothalamus, known as the brain’s homeostatic control site. The hypothalamus displayed a strengthened connectivity in relation to the individual hypothalamic NET availability to the anterior insula/frontal operculum, as well as the medial orbitofrontal cortex, assumed to host the primary and secondary gustatory cortex, respectively (n = 19). The resting-state activity in these two regions was correlated positively to the BMI and IWQOL–Lite scores, but not to the BDI, suggesting that the higher the resting-state activity in these regions, and hence the higher the BMI, the stronger the negative impact of the body weight on the individual’s emotional well-being was. CONCLUSIONS This pilot study suggests that the loss in emotional well-being with weight is embedded within the central norepinephrine network. PMID:26620766

  20. [Anaerobic reduction of humus/Fe (III) and electron transport mechanism of Fontibacter sp. SgZ-2].

    PubMed

    Ma, Chen; Yang, Gui-qin; Lu, Qin; Zhou, Shun-gui

    2014-09-01

    Humus and Fe(III) respiration are important extracellular respiration metabolism. Electron transport pathway is the key issue of extracellular respiration. To understand the electron transport properties and the environmental behavior of a novel Fe(III)- reducing bacterium, Fontibacter sp. SgZ-2, capacities of anaerobic humus/Fe(III) reduction and electron transport mechanisms with four electron acceptors were investigated in this study. The results of anaerobic batch experiments indicated that strain SgZ-2 had the ability to reduce humus analog [ 9,10-anthraquinone-2,6-disulfonic acid (AQDS) and 9,10-anthraquinone-2-sulfonic acid (AQS)], humic acids (HA), soluble Fe(III) (Fe-EDTA and Fe-citrate) and Fe(III) oxides [hydrous ferric oxide (HFO)]. Fermentative sugars (glucose and sucrose) were the most effective electron donors in the humus/Fe(III) reduction by strain SgZ-2. Additionally, differences of electron carrier participating in the process of electron transport with different electron acceptors (i. e. , oxygen, AQS, Fe-EDTA and HFO) were investigated using respiratory inhibitors. The results suggested that similar respiratory chain components were involved in the reducing process of oxygen and Fe-EDTA, including dehydrogenase, quinones and cytochromes b-c. In comparison, only dehydrogenase was found to participate in the reduction of AQS and HFO. In conclusion, different electron transport pathways may be employed by strain SgZ-2 between insoluble and soluble electron acceptors or among soluble electron acceptors. Preliminary models of electron transport pathway with four electron acceptors were proposed for strain SgZ-2, and the study of electron transport mechanism was explored to the genus Fontibacter. All the results from this study are expected to help understand the electron transport properties and the environmental behavior of the genus Fontibacter. PMID:25518675

  1. Analysis of ballistic transport in nanoscale devices by using an accelerated finite element contact block reduction approach

    NASA Astrophysics Data System (ADS)

    Li, H.; Li, G.

    2014-08-01

    An accelerated Finite Element Contact Block Reduction (FECBR) approach is presented for computational analysis of ballistic transport in nanoscale electronic devices with arbitrary geometry and unstructured mesh. Finite element formulation is developed for the theoretical CBR/Poisson model. The FECBR approach is accelerated through eigen-pair reduction, lead mode space projection, and component mode synthesis techniques. The accelerated FECBR is applied to perform quantum mechanical ballistic transport analysis of a DG-MOSFET with taper-shaped extensions and a DG-MOSFET with Si/SiO2 interface roughness. The computed electrical transport properties of the devices obtained from the accelerated FECBR approach and associated computational cost as a function of system degrees of freedom are compared with those obtained from the original CBR and direct inversion methods. The performance of the accelerated FECBR in both its accuracy and efficiency is demonstrated.

  2. Analysis of ballistic transport in nanoscale devices by using an accelerated finite element contact block reduction approach

    SciTech Connect

    Li, H.; Li, G.

    2014-08-28

    An accelerated Finite Element Contact Block Reduction (FECBR) approach is presented for computational analysis of ballistic transport in nanoscale electronic devices with arbitrary geometry and unstructured mesh. Finite element formulation is developed for the theoretical CBR/Poisson model. The FECBR approach is accelerated through eigen-pair reduction, lead mode space projection, and component mode synthesis techniques. The accelerated FECBR is applied to perform quantum mechanical ballistic transport analysis of a DG-MOSFET with taper-shaped extensions and a DG-MOSFET with Si/SiO{sub 2} interface roughness. The computed electrical transport properties of the devices obtained from the accelerated FECBR approach and associated computational cost as a function of system degrees of freedom are compared with those obtained from the original CBR and direct inversion methods. The performance of the accelerated FECBR in both its accuracy and efficiency is demonstrated.

  3. Maternal obesity is associated with a reduction in placental taurine transporter activity

    PubMed Central

    Ditchfield, A M; Desforges, M; Mills, T A; Glazier, J D; Wareing, M; Mynett, K; Sibley, C P; Greenwood, S L

    2015-01-01

    Background/Objectives: Maternal obesity increases the risk of poor pregnancy outcome including stillbirth, pre-eclampsia, fetal growth restriction and fetal overgrowth. These pregnancy complications are associated with dysfunctional syncytiotrophoblast, the transporting epithelium of the human placenta. Taurine, a β-amino acid with antioxidant and cytoprotective properties, has a role in syncytiotrophoblast development and function and is required for fetal growth and organ development. Taurine is conditionally essential in pregnancy and fetal tissues depend on uptake of taurine from maternal blood. We tested the hypothesis that taurine uptake into placental syncytiotrophoblast by the taurine transporter protein (TauT) is lower in obese women (body mass index (BMI)⩾30 kg m−2) than in women of ideal weight (BMI 18.5–24.9 kg m−2) and explored potential regulatory factors. Subjects/Methods: Placentas were collected from term (37–42-week gestation), uncomplicated, singleton pregnancies from women with BMI 19–49 kg m−2. TauT activity was measured as the Na+-dependent uptake of 3H-taurine into placental villous fragments. TauT expression in membrane-enriched placental samples was investigated by western blot. In vitro studies using placental villous explants examined whether leptin or IL-6, adipokines/cytokines that are elevated in maternal obesity, regulates TauT activity. Results: Placental TauT activity was significantly lower in obese women (BMI⩾30) than women of ideal weight (P<0.03) and inversely related to maternal BMI (19–49 kg m−2; P<0.05; n=61). There was no difference in TauT expression between placentas of ideal weight and obese class III (BMI⩾40) subjects. Long-term exposure (48 h) of placental villous explants to leptin or IL-6 did not affect TauT activity. Conclusions: Placental TauT activity at term is negatively related to maternal BMI. We propose that the reduction in placental TauT activity in maternal obesity

  4. [Research on carbon reduction potential of electric vehicles for low-carbon transportation and its influencing factors].

    PubMed

    Shi, Xiao-Qing; Li, Xiao-Nuo; Yang, Jian-Xin

    2013-01-01

    Transportation is the key industry of urban energy consumption and carbon emissions. The transformation of conventional gasoline vehicles to new energy vehicles is an important initiative to realize the goal of developing low-carbon city through energy saving and emissions reduction, while electric vehicles (EV) will play an important role in this transition due to their advantage in energy saving and lower carbon emissions. After reviewing the existing researches on energy saving and emissions reduction of electric vehicles, this paper analyzed the factors affecting carbon emissions reduction. Combining with electric vehicles promotion program in Beijing, the paper analyzed carbon emissions and reduction potential of electric vehicles in six scenarios using the optimized energy consumption related carbon emissions model from the perspective of fuel life cycle. The scenarios included power energy structure, fuel type (energy consumption per 100 km), car type (CO2 emission factor of fuel), urban traffic conditions (speed), coal-power technologies and battery type (weight, energy efficiency). The results showed that the optimized model was able to estimate carbon emissions caused by fuel consumption more reasonably; electric vehicles had an obvious restrictive carbon reduction potential with the fluctuation of 57%-81.2% in the analysis of six influencing factors, while power energy structure and coal-power technologies play decisive roles in life-cycle carbon emissions of electric vehicles with the reduction potential of 78.1% and 81.2%, respectively. Finally, some optimized measures were proposed to reduce transport energy consumption and carbon emissions during electric vehicles promotion including improving energy structure and coal technology, popularizing energy saving technologies and electric vehicles, accelerating the battery R&D and so on. The research provides scientific basis and methods for the policy development for the transition of new energy vehicles

  5. Diffusion algorithms and data reduction routine for onsite launch predictions for the transport of Titan 3 C exhaust effluents

    NASA Technical Reports Server (NTRS)

    Stephens, J. B.; Hamilton, P. A.

    1974-01-01

    The NASA/MSFC multilayer diffusion algorithms have been specialized for the prediction of the surface impact for the dispersive transport of the exhaust effluents from the launch of a Titan 3 vehicle. This specialization permits these transport predictions to be made at the launch range in real time so that the effluent monitoring teams can optimize their monitoring grids. Basically, the data reduction routine requires just the meteorology profiles for the thermodynamics and kinematics of the atmosphere as an input. These profiles are graphed along with the resulting exhaust cloud rise history, the center line concentrations and dosages, and the hydrogen chloride isopleths.

  6. Norepinephrine release and reuptake by hypothalamic synaptosomes of spontaneously hypertensive rats

    SciTech Connect

    Hano, T.; Jeng, Y.; Rho, J.

    1989-03-01

    We compared the overflow of endogenous norepinephrine during electrical field stimulation, the norepinephrine content, and the rate of initial neuronal uptake of (3H)norepinephrine in synaptosomes isolated from hypothalamus and brainstem of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at 7 and 13 weeks of age. The synaptosomes of two rats, a SHR and a WKY rat control, were simultaneously processed and subjected to the same electrical field stimulation. The overflow of endogenous norepinephrine during electrical stimulation (2 Hz, 2 minutes) in the hypothalamic synaptosomes of 7-week-old SHR was significantly greater, whereas the overflow of 13-week-old SHR was equivalent to the age-matched WKY rat. The norepinephrine content of synaptosomes was about the same in SHR and age-matched controls. There was also significantly enhanced (3H)norepinephrine uptake in the hypothalamic synaptosomes of young SHR, but neither the hypothalamic nor the brainstem samples of 13-week-old SHR showed any significant difference in their rate of (3H)norepinephrine uptake. These data are similar to those we observed (unpublished observations) in perfused mesenteric artery system in which norepinephrine release was significantly elevated during periarterial nerve stimulation only in young SHR. Thus, these results suggest that a parallel enhancement of norepinephrine release in hypothalamus with that of peripheral nervous system may play an important role during development of hypertension in young SHR.

  7. Ischemic Necrosis of Upper Lip, and All Fingers and Toes After Norepinephrine Use.

    PubMed

    Shin, Jin Yong; Roh, Si-Gyun; Lee, Nae-Ho; Yang, Kyung-Moo

    2016-03-01

    A 68-year-old woman with necrosis of total finger, toe, and upper lip was requested by department of internal medicine. She was diagnosed with septic shock and treated with norepinephrine 10 days ago. Norepinephrine is an often-used medicine for normalizing blood pressure in septic shock patients. Norepinephrine stimulates adrenergic receptors, causing vasoconstriction and the rise of blood pressure. These peripheral vasoconstrictions sometimes lead to ischemic changes in end organs. In this case report, the authors describe ischemic necrosis of the upper lip and all fingers and toes after norepinephrine use in a patient in the intensive care unit. PMID:26854781

  8. Pressure dependence of the oxygen reduction reaction at the platinum microelectrode/nafion interface - Electrode kinetics and mass transport

    NASA Technical Reports Server (NTRS)

    Parthasarathy, Arvind; Srinivasan, Supramaniam; Appleby, A. J.; Martin, Charles R.

    1992-01-01

    The investigation of oxygen reduction kinetics at the platinum/Nafion interface is of great importance in the advancement of proton-exchange-membrane (PEM) fuel-cell technology. This study focuses on the dependence of the oxygen reduction kinetics on oxygen pressure. Conventional Tafel analysis of the data shows that the reaction order with respect to oxygen is unity at both high and low current densities. Chronoamperometric measurements of the transport parameters for oxygen in Nafion show that oxygen dissolution follows Henry's isotherm. The diffusion coefficient of oxygen is invariant with pressure; however, the diffusion coefficient for oxygen is lower when air is used as the equilibrating gas as compared to when oxygen is used for equilibration. These results are of value in understanding the influence of O2 partial pressure on the performance of PEM fuel cells and also in elucidating the mechanism of oxygen reduction at the platinum/Nafion interface.

  9. Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine

    SciTech Connect

    Fossa, Anthony A.; Wisialowski, Todd A.; Cremers, Thomas; Hart, Marieke van der; Tseng, Elaine; Deng, Shibing; Rollema, Hans; Wang, Ellen Q.

    2012-11-01

    Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure of arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure–response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment. -- Highlights: ► Acute RBX produces blood pressure increases acutely that decrease with chronic RBX ► Chronic RBX increases brain NE levels, a preclinical surrogate of improved efficacy ► Short-term screening of NRI often underestimates the chronic therapeutic index ► Chronic cardiovascular

  10. Norepinephrine release in the amygdala in response to footshock stimulation.

    PubMed

    Galvez, R; Mesches, M H; McGaugh, J L

    1996-11-01

    Extensive evidence suggests that many drugs and hormones influence memory storage by modulating training-induced release of norepinephrine (NE) within the amygdala. This experiment used in vivo microdialysis and high-performance liquid chromatography to examine norepinephrine NE release in the amygdala induced by footshock stimulation typically used in inhibitory avoidance training. Sprague-Dawley rats were implanted bilaterally with cannulae aimed at the amygdala. One to two weeks later, microdialysis probes were inserted (unilaterally) and the animals were placed in a box with a stainless-steel grid floor through which a single footshock (0.55 mA, 1.0 s) was administered either 45.5 (N = 5) or 180.5 (N = 4) min later. Samples were collected and analyzed at 15-min intervals. In both groups, the footshock stimulation increased NE levels to approximately 75% above basal levels in the first sample collected after the footshock and the levels returned to baseline within 30 min. The findings are consistent with pharmacological evidence suggesting that NE released by arousing stimulation is involved in regulating memory storage. PMID:8946419

  11. Norepinephrine at the nexus of arousal, motivation and relapse.

    PubMed

    España, Rodrigo A; Schmeichel, Brooke E; Berridge, Craig W

    2016-06-15

    Arousal plays a critical role in cognitive, affective and motivational processes. Consistent with this, the dysregulation of arousal-related neural systems is implicated in a variety of psychiatric disorders, including addiction. Noradrenergic systems exert potent arousal-enhancing actions that involve signaling at α1- and β-noradrenergic receptors within a distributed network of subcortical regions. The majority of research into noradrenergic modulation of arousal has focused on the nucleus locus coeruleus. Nevertheless, anatomical studies demonstrate that multiple noradrenergic nuclei innervate subcortical arousal-related regions, providing a substrate for differential regulation of arousal across these distinct noradrenergic nuclei. The arousal-promoting actions of psychostimulants and other drugs of abuse contribute to their widespread abuse. Moreover, relapse can be triggered by a variety of arousal-promoting events, including stress and re-exposure to drugs of abuse. Evidence has long-indicated that norepinephrine plays an important role in relapse. Recent observations suggest that noradrenergic signaling elicits affectively-neutral arousal that is sufficient to reinstate drug seeking. Collectively, these observations indicate that norepinephrine plays a key role in the interaction between arousal, motivation, and relapse. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID:26773688

  12. Myocardial imaging with a radioiodinated norepinephrine storage analog

    SciTech Connect

    Wieland, D.M.; Brown, L.E.; Rogers, W.L.; Worthington, K.C.; Wu, J.L.; Clinthorne, N.H.; Otto, C.A.; Swanson, D.P.; Beierwaltes, W.H.

    1981-01-01

    Meta-iodobenzylguanidine (M-IBG), an iodinated aromatic analog of the hypotensive drug guanethidine, localizes in the heart of the rat, dog, and rhesus monkey. A comparative study of tissue distribution in the dog has been performed with five myocardiophilic agents: thallium-201, I-125 16-iodohexadecanoic acid, H-3 norepinephrine, C-14 guanethidine and I-125 M-IBG. The last two compounds give heart concentrations and heart-to-blood concentration ratios similar to those of thallium-201. Planar and tomographic images of the hearts of the dog and rhesus monkey were obtained using I-131 or I-123 labeled M-IBG. Blocking studies with reserpine suggest that a major component of myocardial retention of M-IBG is sequestration within the norepinephrine storage vesicles of the adrenergic nerves. The localization of M-IBG in other organs with rich sympathetic innervation and the relative insensitivity of myocardial uptake to a wide range of loading doses lend additional support for a neuronal mode of retention.

  13. A technical review of urban land use - transportation models as tools for evaluating vehicle travel reduction strategies

    SciTech Connect

    Southworth, F.

    1995-07-01

    The continued growth of highway traffic in the United States has led to unwanted urban traffic congestion as well as to noticeable urban air quality problems. These problems include emissions covered by the 1990 Clean Air Act Amendments (CAAA) and 1991 Intermodal Surface Transportation Efficiency Act (ISTEA), as well as carbon dioxide and related {open_quotes}greenhouse gas{close_quotes} emissions. Urban travel also creates a major demand for imported oil. Therefore, for economic as well as environmental reasons, transportation planning agencies at both the state and metropolitan area level are focussing a good deal of attention on urban travel reduction policies. Much discussed policy instruments include those that encourage fewer trip starts, shorter trip distances, shifts to higher-occupancy vehicles or to nonvehicular modes, and shifts in the timing of trips from the more to the less congested periods of the day or week. Some analysts have concluded that in order to bring about sustainable reductions in urban traffic volumes, significant changes will be necessary in the way our households and businesses engage in daily travel. Such changes are likely to involve changes in the ways we organize and use traffic-generating and-attracting land within our urban areas. The purpose of this review is to evaluate the ability of current analytic methods and models to support both the evaluation and possibly the design of such vehicle travel reduction strategies, including those strategies involving the reorganization and use of urban land. The review is organized into three sections. Section 1 describes the nature of the problem we are trying to model, Section 2 reviews the state of the art in operational urban land use-transportation simulation models, and Section 3 provides a critical assessment of such models as useful urban transportation planning tools. A number of areas are identified where further model development or testing is required.

  14. Noise and Fuel Burn Reduction Potential of an Innovative Subsonic Transport Configuration

    NASA Technical Reports Server (NTRS)

    Guo, Yueping; Nickol, Craig L.; Thomas, Russell H.

    2014-01-01

    A study is presented for the noise and fuel burn reduction potential of an innovative double deck concept aircraft with two three-shaft direct-drive turbofan engines. The engines are mounted from the fuselage so that the engine inlet is over the main wing. It is shown that such an aircraft can achieve a cumulative Effective Perceived Noise Level (EPNL) about 28 dB below the current aircraft noise regulations of Stage 4. The combination of high bypass ratio engines and advanced wing design with laminar flow control technologies provide fuel burn reduction and low noise levels simultaneously. For example, the fuselage mounted engine position provides more than 4 EPNLdB of noise reduction by shielding the inlet radiated noise. To identify the potential effect of noise reduction technologies on this concept, parametric studies are presented to reveal the system level benefits of various emerging noise reduction concepts, for both engine and airframe noise reduction. These concepts are discussed both individually to show their respective incremental noise reduction potential and collectively to assess their aggregate effects on the total noise. Through these concepts approximately about 8 dB of additional noise reduction is possible, bringing the cumulative noise level of this aircraft to 36 EPNLdB below Stage 4, if the entire suite of noise reduction technologies would mature to practical application. In a final step, an estimate is made for this same aircraft concept but with higher bypass ratio, geared, turbofan engines. With this geared turbofan propulsion system, the noise is estimated to reach as low as 40-42 dB below Stage 4 with a fuel burn reduction of 43-47% below the 2005 best-in-class aircraft baseline. While just short of the NASA N+2 goals of 42 dB and 50% fuel burn reduction, for a 2025 in service timeframe, this assessment shows that this innovative concept warrants refined study. Furthermore, this design appears to be a viable potential future passenger

  15. Global threat reduction initiative efforts to address transportation challenges associated with the recovery of disused radioactive sealed sources - 10460

    SciTech Connect

    Whitworth, Julie; Abeyta, Cristy L; Griffin, Justin M; Matzke, James L; Pearson, Michael W; Cuthbertson, Abigail; Rawl, Richard; Singley, Paul

    2010-01-01

    Proper disposition of disused radioactive sources is essential for their safe and secure management and necessary to preclude their use in malicious activities. Without affordable, timely transportation options, disused sealed sources remain in storage at hundreds of sites throughout the country and around the world. While secure storage is a temporary measure, the longer sources remain disused or unwanted the chances increase that they will become unsecured or abandoned. The Global Threat Reduction Initiative's Off-Site Source Recovery Project (GTRIlOSRP), recovers thousands of disused and unwanted sealed sources annually as part of GTRl's larger mission to reduce and protect high risk nuclear and radiological materials located at civilian sites worldwide. Faced with decreasing availability of certified transportation containers to support movement of disused and unwanted neutron- and beta/gamma-emitting radioactive sealed sources, GTRIlOSRP has initiated actions to ensure the continued success of the project in timely recovery and management of sealed radioactive sources. Efforts described in this paper to enhance transportation capabilities include: {sm_bullet} Addition of authorized content to existing and planned Type B containers to support the movement of non-special form and other Type B-quantity sealed sources; {sm_bullet} Procurement of vendor services for the design, development, testing and certification of a new Type B container to support transportation of irradiators, teletherapy heads or sources removed from these devices using remote handling capabilities such as the IAEA portable hot cell facility; {sm_bullet} Expansion of shielded Type A container inventory for transportation of gamma-emitting sources in activity ranges requiring use of shielding for conformity with transportation requirements; {sm_bullet} Approval of the S300 Type A fissile container for transport of Pu-239 sealed sources internationally; {sm_bullet} Technology transfer of field

  16. Interfacial Reduction-Oxidation Mechanisms Governing Fate and Transport of Contaminants in the Vadose Zone

    SciTech Connect

    Deng, Baolin; Thornton, Edward C.; Cantrell, Kirk J.; Olsen, Khris B.; Amonette, James E.

    2003-06-01

    Immobilization of toxic and radioactive metals (e.g., Cr, Tc, and U) in the vadose zone by the In Situ Gaseous Reduction (ISGR) using hydrogen sulfide (H2S) is a promising technology for soil remediation. Earlier laboratory studies have shown that Cr(VI) in soil samples can be effectively immobilized by treatment with dilute gaseous H2S. A field test completed in 1999 at White Sand Missile Range, New Mexico, has shown a 70% immobilization of Cr(VI). The objective of this EMSP project is to characterize the interactions among H2S, the metal contaminants, and soil components. Understanding these interactions is needed to optimize the remediation system and to assess the long-term effectiveness of the technology. Proposed research tasks included: (A) Evaluation of the potential catalytic effect of mineral surfaces on the rate of Cr(VI) reduction by H2S and the rate of H2S oxidation by air; (B) Identification of the reactions of soil minerals with H2S and determination of associated reaction rates; (C) Evaluation of the role of soil water chemistry on the reduction of Cr(VI) by H2S; (D) Assessment of the reductive buffering capacity of H2S-reduced soil and the potential for emplacement of long-term vadose zone reactive barriers; and (E) Evaluation of the potential for immobilization of Tc and U in the vadose zone by reduction and an assessment of the potential for remobilization by subsequent reoxidation.

  17. Evidence for Noncanonical Neurotransmitter Activation: Norepinephrine as a Dopamine D2-Like Receptor Agonist.

    PubMed

    Sánchez-Soto, Marta; Bonifazi, Alessandro; Cai, Ning Sheng; Ellenberger, Michael P; Newman, Amy Hauck; Ferré, Sergi; Yano, Hideaki

    2016-04-01

    The Gαi/o-coupled dopamine D2-like receptor family comprises three subtypes: the D2 receptor (D2R), with short and long isoform variants (D2SR and D2LR), D3 receptor (D3R), and D4 receptor (D4R), with several polymorphic variants. The common overlap of norepinephrine innervation and D2-like receptor expression patterns prompts the question of a possible noncanonical action by norepinephrine. In fact, previous studies have suggested that norepinephrine can functionally interact with D4R. To our knowledge, significant interactions between norepinephrine and D2R or D3R receptors have not been demonstrated. By using radioligand binding and bioluminescent resonance energy transfer (BRET) assays in transfected cells, the present study attempted a careful comparison between dopamine and norepinephrine in their possible activation of all D2-like receptors, including the two D2R isoforms and the most common D4R polymorphic variants. Functional BRET assays included activation of G proteins with all Gαi/o subunits, adenylyl cyclase inhibition, and β arrestin recruitment. Norepinephrine acted as a potent agonist for all D2-like receptor subtypes, with the general rank order of potency of D3R > D4R ≥ D2SR ≥ D2L. However, for both dopamine and norepinephrine, differences depended on the Gαi/o protein subunit involved. The most striking differences were observed with Gαi2, where the rank order of potencies for both dopamine and norepinephrine were D4R > D2SR = D2LR > D3R. Furthermore the results do not support the existence of differences in the ability of dopamine and norepinephrine to activate different human D4R variants. The potency of norepinephrine for adrenergic α2A receptor was only about 20-fold higher compared with D3R and D4R across the three functional assays. PMID:26843180

  18. Evidence for Noncanonical Neurotransmitter Activation: Norepinephrine as a Dopamine D2-Like Receptor Agonist

    PubMed Central

    Sánchez-Soto, Marta; Bonifazi, Alessandro; Cai, Ning Sheng; Ellenberger, Michael P.; Newman, Amy Hauck

    2016-01-01

    The Gαi/o-coupled dopamine D2-like receptor family comprises three subtypes: the D2 receptor (D2R), with short and long isoform variants (D2SR and D2LR), D3 receptor (D3R), and D4 receptor (D4R), with several polymorphic variants. The common overlap of norepinephrine innervation and D2-like receptor expression patterns prompts the question of a possible noncanonical action by norepinephrine. In fact, previous studies have suggested that norepinephrine can functionally interact with D4R. To our knowledge, significant interactions between norepinephrine and D2R or D3R receptors have not been demonstrated. By using radioligand binding and bioluminescent resonance energy transfer (BRET) assays in transfected cells, the present study attempted a careful comparison between dopamine and norepinephrine in their possible activation of all D2-like receptors, including the two D2R isoforms and the most common D4R polymorphic variants. Functional BRET assays included activation of G proteins with all Gαi/o subunits, adenylyl cyclase inhibition, and β arrestin recruitment. Norepinephrine acted as a potent agonist for all D2-like receptor subtypes, with the general rank order of potency of D3R > D4R ≥ D2SR ≥ D2L. However, for both dopamine and norepinephrine, differences depended on the Gαi/o protein subunit involved. The most striking differences were observed with Gαi2, where the rank order of potencies for both dopamine and norepinephrine were D4R > D2SR = D2LR >> D3R. Furthermore the results do not support the existence of differences in the ability of dopamine and norepinephrine to activate different human D4R variants. The potency of norepinephrine for adrenergic α2A receptor was only about 20-fold higher compared with D3R and D4R across the three functional assays. PMID:26843180

  19. The Mammalian Neuroendocrine Hormone Norepinephrine Supplies Iron for Bacterial Growth in the Presence of Transferrin or Lactoferrin

    PubMed Central

    Freestone, Primrose P. E.; Lyte, Mark; Neal, Christopher P.; Maggs, Anthony F.; Haigh, Richard D.; Williams, Peter H.

    2000-01-01

    Norepinephrine stimulates the growth of a range of bacterial species in nutritionally poor SAPI minimal salts medium containing 30% serum. Addition of size-fractionated serum components to SAPI medium indicated that transferrin was required for norepinephrine stimulation of growth of Escherichia coli. Since bacteriostasis by serum is primarily due to the iron-withholding capacity of transferrin, we considered the possibility that norepinephrine can overcome this effect by supplying transferrin-bound iron for growth. Incubation with concentrations of norepinephrine that stimulated bacterial growth in serum-SAPI medium resulted in loss of bound iron from iron-saturated transferrin, as indicated by the appearance of monoferric and apo- isoforms upon electrophoresis in denaturing gels. Norepinephrine also caused the loss of iron from lactoferrin. The pharmacologically inactive metabolite norepinephrine 3-O-sulfate, by contrast, did not result in iron loss from transferrin or lactoferrin and did not stimulate bacterial growth in serum-SAPI medium. Norepinephrine formed stable complexes with transferrin, lactoferrin, and serum albumin. Norepinephrine-transferrin and norepinephrine-lactoferrin complexes, but not norepinephrine-apotransferrin or norepinephrine-albumin complexes, stimulated bacterial growth in serum-SAPI medium in the absence of additional norepinephrine. Norepinephrine-stimulated growth in medium containing 55Fe complexed with transferrin or lactoferrin resulted in uptake of radioactivity by bacterial cells. Moreover, norepinephrine-stimulated growth in medium containing [3H]norepinephrine indicated concomitant uptake of norepinephrine. In each case, addition of excess iron did not affect growth but significantly reduced levels of radioactivity (55Fe or 3H) associated with bacterial cells. A role for catecholamine-mediated iron supply in the pathophysiology of infectious diseases is proposed. PMID:11029429

  20. Arthroscopic Reduction and Transportal Screw Fixation of Acetabular Posterior Wall Fracture: Technical Note.

    PubMed

    Park, Jin Young; Chung, Woo Chull; Kim, Che Keun; Huh, Soon Ho; Kim, Se Jin; Jung, Bo Hyun

    2016-06-01

    Acetabular fractures can be treated with variable method. In this study, acetabular posterior wall fracture was treated with arthroscopic reduction and fixation using cannulated screw. The patient recovered immediately and had a satisfactory outcome. In some case of acetabular fracture could be good indication with additional advantages of joint debridement and loose body removal. So, we report our case with technical note. PMID:27536654

  1. Arthroscopic Reduction and Transportal Screw Fixation of Acetabular Posterior Wall Fracture: Technical Note

    PubMed Central

    Park, Jin young; Kim, Che Keun; Huh, Soon Ho; Kim, Se Jin; Jung, Bo Hyun

    2016-01-01

    Acetabular fractures can be treated with variable method. In this study, acetabular posterior wall fracture was treated with arthroscopic reduction and fixation using cannulated screw. The patient recovered immediately and had a satisfactory outcome. In some case of acetabular fracture could be good indication with additional advantages of joint debridement and loose body removal. So, we report our case with technical note. PMID:27536654

  2. Interfacial Reduction-Oxidation Mechanisms Governing Fate and Transport of Contaminants in the Vadose Zone

    SciTech Connect

    Principal Investigator: Baolin Deng, University of Missouri, Columbia, MO; Co-Principal Investigator: Silvia Sabine Jurisson, University of Missouri, Columbia, MO; Co-Principal Investigator: Edward C. Thornton, Pacific Northwest National Laboratory Richland, WA; Co-Principal Investigator: Jeff Terry, Illinois Institute of Technology, Chicago, IL

    2008-05-12

    There are many soil contamination sites at the Department of Energy (DOE) installations that contain radionuclides and toxic metals such as uranium (U), technetium (Tc), and chromium (Cr). Since these contaminants are the main 'risk drivers' at the Hanford site (WA) and some of them also pose significant risk at other DOE facilities (e.g., Oak Ridge Reservation - TN; Rocky Flats - CO), development of technologies for cost effective site remediation is needed. Current assessment indicates that complete removal of these contaminants for ex-situ disposal is infeasible, thus in-situ stabilization through reduction to insoluble species is considered one of the most important approaches for site remediation. In Situ Gaseous Reduction (ISGR) is a technology developed by Pacific Northwest National Laboratory (PNNL) for vadose zone soil remediation. The ISGR approach uses hydrogen sulfide (H{sub 2}S) for reductive immobilization of contaminants that show substantially lower mobility in their reduced forms (e.g., Tc, U, and Cr). The technology can be applied in two ways: (i) to immobilize or stabilize pre-existing contaminants in the vadose zone soils by direct H{sub 2}S treatment, or (ii) to create a permeable reactive barrier (PRB) that prevents the migration of contaminants. Direct treatment involves reduction of the contaminants by H{sub 2}S to less mobile species. Formation of a PRB is accomplished through reduction of ferric iron species in the vadose zone soils by H{sub 2}S to iron sulfides (e.g., FeS), which provides a means for capturing the contaminants entering the treated zone. Potential future releases may occur during tank closure activities. Thus, the placement of a permeable reactive barrier by ISGR treatment can be part of the leak mitigation program. Deployment of these ISGR approaches, however, requires a better understanding of the immobilization kinetics and mechanisms, and a better assessment of the long-term effectiveness of treatment. The primary

  3. Reduction of degradation in vapor phase transported InP/InGaAsP mushroom stripe lasers

    SciTech Connect

    Jung, H.; Burkhardt, E.G.; Pfister, W.

    1988-10-03

    The rapid degradation rate generally observed in InP/InGaAsP mushroom stripe lasers can be considerably decreased by regrowing the open sidewalls of the active stripe with low-doped InP in a second epitaxial step using the hydride vapor phase transport technique. This technique does not change the fundamental laser parameters like light-current and current-voltage characteristics. Because of this drastic reduction in degradation, the vapor phase epitaxy regrown InP/InGaAsP mushroom laser seems to be an interesting candidate for application in optical communication.

  4. Selective Serotonin–norepinephrine Reuptake Inhibitors-induced Takotsubo Cardiomyopathy

    PubMed Central

    Vasudev, Rahul; Rampal, Upamanyu; Patel, Hiten; Patel, Kunal; Bikkina, Mahesh; Shamoon, Fayez

    2016-01-01

    Context: Takotsubo translates to “octopus pot” in Japanese. Takotsubo cardiomyopathy (TTC) is characterized by a transient regional systolic dysfunction of the left ventricle. Catecholamine excess is the one most studied and favored theories explaining the pathophysiology of TTC. Case Report: We present the case of a 52-year-old Hispanic female admitted for venlafaxine-induced TTC with a review literature on all the cases of Serotonin–norepinephrine reuptake inhibitors (SNRI)-associated TTC published so far. Conclusion: SNRI inhibit the reuptake of catecholamines into the presynaptic neuron, resulting in a net gain in the concentration of epinephrine and serotonin in the neuronal synapses and causing iatrogenic catecholamine excess, ultimately leading to TTC. PMID:27583240

  5. The Effects of Locus Coeruleus and Norepinephrine in Methamphetamine Toxicity

    PubMed Central

    Ferrucci, Michela; Giorgi, Filippo S; Bartalucci, Alessia; Busceti, Carla L; Fornai, Francesco

    2013-01-01

    The activity of locus coeruleus (LC) neurons has been extensively investigated in a variety of behavioural states. In fact this norepinephrine (NE)-containing nucleus modulates many physiological and pathological conditions including the sleep-waking cycle, movement disorders, mood alterations, convulsive seizures, and the effects of drugs such as psychostimulants and opioids. This review focuses on the modulation exerted by central NE pathways on the behavioural and neurotoxic effects produced by the psychostimulant methamphetamine, essentially the modulation of the activity of mesencephalic dopamine (DA) neurons. In fact, although NE in itself mediates some behavioural effects induced by methamphetamine, NE modulation of DA release is pivotal for methamphetamine-induced behavioural states and neurotoxicity. These interactions are discussed on the basis of the state of the art of the functional neuroanatomy of central NE- and DA systems. Emphasis is given to those brain sites possessing a remarkable overlapping of both neurotransmitters. PMID:23814540

  6. Antihistamine effect on synaptosomal uptake of serotonin, norepinephrine and dopamine

    NASA Technical Reports Server (NTRS)

    Brown, P. A.; Vernikos, J.

    1980-01-01

    A study on the effects of five H1 and H2 antihistamines on the synaptosomal uptake of serotonin (5HT), norepinephrine (NE), and dopamine (DA) is presented. Brain homogenates from female rats were incubated in Krebs-Ringer phosphate buffer solution in the presence of one of three radioactive neurotransmitters, and one of the five antihistamines. Low concentrations of pyrilamine competitively inhibited 5HT uptake, had little effect on NE uptake, and no effect on DA uptake. Promethazine, diphenhydramine, metiamide, and cimetidine had no effect on 5HT or DA uptake at the same concentration. Diphenhydramine had a small inhibitory effect on NE uptake. It is concluded that pyrilamine is a selective and potent competitive inhibitor of 5HT uptake at concentrations between .05 and .5 micromolars.

  7. Aircraft surface coatings study: Energy efficient transport program. [sprayed and adhesive bonded coatings for drag reduction

    NASA Technical Reports Server (NTRS)

    1979-01-01

    Surface coating materials for application on transport type aircraft to reduce drag, were investigated. The investigation included two basic types of materials: spray on coatings and adhesively bonded films. A cost/benefits analysis was performed, and recommendations were made for future work toward the application of this technology.

  8. S-nitroso-l-cysteine releases norepinephrine in rat spinal synaptosomes.

    PubMed

    Li, X; Rose, G; Dongre, N; Pan, H L; Tobin, J R; Eisenach, J C

    2000-07-28

    Although nitric oxide (NO) participates in development of hypersensitivity states in the spinal cord thought to underlie chronic pain, it also participates in analgesia produced by various drugs. In rats with a hypersensitivity state following peripheral nerve injury, spinal administration of an NO donor or l-cysteine alone produced no effect, whereas their combination, which yields s-nitroso-l-cysteine (SNC) powerfully reduced hypersensitivity. In the current study, we examined the ability of SNC to stimulate release of a known spinal analgesic neurotransmitter, norepinephrine (NE), as a possible mechanism of analgesic action of NO in the spinal cord. SNC (but not the NO donor alone or decomposed SNC) produced a concentration-dependent release of NE from rat spinal cord synaptosomes. The d-isomer of SNC was less potent than the l-isomer, and the effect of SNC was partially blocked by l-, but not d-leucine, implicating an interaction with the l-amino acid transporter. SNC-induced NE release was partially Na(+) dependent, but largely Ca(2+) independent. NE uptake inhibitors partially antagonized the effect of SNC, but guanylate cyclase inhibitors were without effect. These data are therefore consistent with NO stimulating NE release in the spinal cord via reaction with thiol containing compounds, such as cysteine, entry into NE terminals via active transport, and production of both exocytotic and carrier mediated release. PMID:10924712

  9. Norepinephrine uptake by rat jejunum: Modulation by angiotensin II

    SciTech Connect

    Suvannapura, A.; Levens, N.R. )

    1988-02-01

    Angiotensin II (ANG II) is believed to stimulate sodium and water absorption from the small intestine by enhancing sympathetic nerve transmission. This study is designed to determine whether ANG II can enhance sympathetic neurotransmission within the small intestine by inhibition norepinephrine (NE) uptake. Intracellular NE accumulation by rat jejunum was concentration dependent and resolved into high- and low-affinity components. The high-affinity component (uptake 1) exhibited a Michaelis constant (K{sub m}) of 1.72 {mu}M and a maximum velocity (V{sub max}) of 1.19 nmol {center dot} g{sup {minus}1} {center dot} 10 min{sup {minus}1}. The low-affinity component (uptake 2) exhibited a K{sub m} of 111.1 {mu}M and a V{sub max} of 37.1 nmol {center dot} g{sup {minus}1} {center dot} 10 min{sup {minus}1}. Cocaine, an inhibitor of neuronal uptake, inhibited the intracellular accumulation of label by 80%. Treatment of animals with 6-hydroxydopamine, which depletes norepinephrine from sympathetic terminals, also attenuated NE uptake by 60%. Thus accumulation within sympathetic nerves constitutes the major form of ({sup 3}H)NE uptake into rat jejunum. ANG II inhibited intracellular ({sup 3}H)NE uptake in a concentration-dependent manner. At a dose of 1 mM, ANG II inhibited intracellular ({sup 3}H)NE accumulation by 60%. Cocaine failed to potentiate the inhibition of ({sup 3}H)NE uptake produced by ANG II. Thus ANG II appears to prevent ({sup 3}H)NE accumulation within rat jejunum by inhibiting neuronal uptake.

  10. Effects of graded LBNP on MSNA and interstitial norepinephrine

    NASA Technical Reports Server (NTRS)

    Khan, Mazhar H.; Sinoway, Lawrence I.; MacLean, David A.

    2002-01-01

    Exposure to lower body negative pressure (LBNP) leads to an increased activation of the sympathetic nervous system (SNS) and an increase in muscle sympathetic nerve activity (MSNA). In this study, we examined the relationship between MSNA and interstitial norepinephrine (NE(i)) concentrations during LBNP. Twelve healthy volunteers were studied (26 +/- 6 yr). Simultaneous MSNA and microdialysis data were collected in six of these subjects. Measurements of MSNA (microneurography) and NE(i) (microdialysis, vastus lateralis) were performed at rest and then during an incremental LBNP paradigm (-10, -30, and -50 mmHg). MSNA rose as a function of LBNP (P < 0.001, n = 12). The plasma norepinephrine (NE(p)) concentration was 0.9 +/- 0.1 nmol/l at rest (n = 12). NE(i) measured in six subjects rose from 5.2 +/- 0.8 nmol/l at rest to 17.0 +/- 1.7 nmol/l at -50 mmHg (P < 0.001). Of note, the rise in NE(p) with LBNP was considerably less compared with the changes in NE(i) (Delta21 +/- 6% vs. Delta197 +/- 52%, n = 6, P < 0.015). MSNA and NE(i) showed a significant linear relationship (r = 0.721, P < 0.004). Activation of the SNS increased MSNA and NE(i) levels. The magnitude of the NE(i) increase was far greater than that seen for NE(p) suggesting that NE movement into the circulation decreases with baroreceptor unloading.

  11. Fluctuation and transport reduction in a reversed field pinch by inductive poloidal current drive

    SciTech Connect

    Sarff, J.S.; Hokin, S.A.; Ji, H.; Prager, S.C.; Sovinec, C.R.

    1993-12-01

    An auxilliay poloidal inductive electric field applied to a reversed field pinch plasma reduces the current density gradient, slows the growth of m=1 tearing fluctations, suppresses their associated sawteeth, and doubles the energy confinement time. Small sawteeth occur in the improved state but with m=0 precursors. By requiring a change of toroidal flux embedding the plasma, inductive poloidal current profile drive is transient, but the improvement encourages the program of RFP transport suppression using current profile control.

  12. Potential emissions reduction in road transport sector using biofuel in developing countries

    NASA Astrophysics Data System (ADS)

    Liaquat, A. M.; Kalam, M. A.; Masjuki, H. H.; Jayed, M. H.

    2010-10-01

    Use of biofuels as transport fuel has high prospect in developing countries as most of them are facing severe energy insecurity and have strong agricultural sector to support production of biofuels from energy crops. Rapid urbanization and economic growth of developing countries have spurred air pollution especially in road transport sector. The increasing demand of petroleum based fuels and their combustion in internal combustion (IC) engines have adverse effect on air quality, human health and global warming. Air pollution causes respiratory problems, adverse effects on pulmonary function, leading to increased sickness absenteeism and induces high health care service costs, premature birth and even mortality. Production of biofuels promises substantial improvement in air quality through reducing emission from biofuel operated automotives. Some of the developing countries have started biofuel production and utilization as transport fuel in local market. This paper critically reviews the facts and prospects of biofuel production and utilization in developing countries to reduce environmental pollution and petro dependency. Expansion of biofuel industries in developing countries can create more jobs and increase productivity by non-crop marginal lands and wastelands for energy crops plantation. Contribution of India and China in biofuel industry in production and utilization can dramatically change worldwide biofuel market and leap forward in carbon cut as their automotive market is rapidly increasing with a souring proportional rise of GHG emissions.

  13. An open-label, randomized positron emission tomography (PET) study in healthy male volunteers consisiting of Part A and Part B. Part A: Clinical validation of norepinephrine transporter (NET) PET ligand, (S,S)-[11C]O-methylreboxetine ([11C]MRB) using different doses of oral atomoxetine as NET reuptake inhibitor. Part B: Evaluation of NET occupancy, as measured by [11C]MRB, with multiple dosing regimens of orally administered GSK372475.

    SciTech Connect

    Fowler, Joanna

    2007-08-31

    Results from human studies with the PET radiotracer (S,S)-[(11)C]O-methyl reboxetine ([(11)C](S,S)-MRB), a ligand targeting the norepinephrine transporter (NET), are reported. Quantification methods were determined from test/retest studies, and sensitivity to pharmacological blockade was tested with different doses of atomoxetine (ATX), a drug that binds to the NET with high affinity (K(i)=2-5 nM). METHODS: Twenty-four male subjects were divided into different groups for serial 90-min PET studies with [(11)C](S,S)-MRB to assess reproducibility and the effect of blocking with different doses of ATX (25, 50 and 100 mg, po). Region-of-interest uptake data and arterial plasma input were analyzed for the distribution volume (DV). Images were normalized to a template, and average parametric images for each group were formed. RESULTS: [(11)C](S,S)-MRB uptake was highest in the thalamus (THL) and the midbrain (MBR) [containing the locus coeruleus (LC)] and lowest for the caudate nucleus (CDT). The CDT, a region with low NET, showed the smallest change on ATX treatment and was used as a reference region for the DV ratio (DVR). The baseline average DVR was 1.48 for both the THL and MBR with lower values for other regions [cerebellum (CB), 1.09; cingulate gyrus (CNG) 1.07]. However, more accurate information about relative densities came from the blocking studies. MBR exhibited greater blocking than THL, indicating a transporter density approximately 40% greater than THL. No relationship was found between DVR change and plasma ATX level. Although the higher dose tended to induce a greater decrease than the lower dose for MBR (average decrease for 25 mg=24+/-7%; 100 mg=31+/-11%), these differences were not significant. The different blocking between MBR (average decrease=28+/- 10%) and THL (average decrease=17+/-10%) given the same baseline DVR indicates that the CDT is not a good measure for non-NET binding in both regions. Threshold analysis of the difference between the

  14. Escherichia coli O157:H7 gene expression in the presence of catecholamine norepinephrine.

    PubMed

    Dowd, Scot E

    2007-08-01

    Various forms of host stresses (e.g. physiological, psychological) are thought to influence susceptibility to pathogenic microorganisms. Catecholamines such as norepinephrine are released into the GI environment during acute stress and may influence the infective process of bacterial pathogens associated with the GI tract. To examine the effects of norepinephrine on expression of virulence factors in Escherichia coli O157:H7, the clinical-type isolate EDL933 (ATCC 43895) was grown in serum-Standard American Petroleum Institute media in the presence or absence of norepinephrine. After 5 h of exposure to norepinephrine, treatment and control cultures (not exposed to norepinephrine) were harvested, their RNA isolated, and gene expression evaluated. There was a dramatic increase in the expression of virulence factor transcripts including stx1, stx2, and eae. Also induced were transcripts involved in iron metabolism. Conversely, there was comparative repression of iron acquisition and phage shock protein-related transcripts in the presence of norepinephrine. Novel observations from these data suggested that exposure to norepinephrine induced glutamate decarboxylase acid resistance as well as an SOS response in E. coli O157:H7. The results corroborate many of the previous findings detailed in the literature and provide new observations that could expand the scope of microbial endocrinology. PMID:17573936

  15. Interfacial Reduction-Oxidation Mechanisms Governing Fate and Transport of Contaminants in the Vadose Zone

    SciTech Connect

    Baolin Deng; Edward Thornton; Kirk Cantrell; Khris Olsen; James Amonette

    2004-01-11

    Immobilization of toxic and radioactive metals in the vadose zone by In Situ Gaseous Reduction (ISGR) using hydrogen sulfide (H2S) is a promising technology for soil remediation. Earlier laboratory and field studies have shown that Cr(VI) can be effectively immobilized by treatment with dilute gaseous H2S. The objective of this project is to characterize the interactions among H2S, the metal contaminants, and soil components. Understanding these interactions is needed to assess the long-term effectiveness of the technology and to optimize the remediation system.

  16. Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study

    NASA Astrophysics Data System (ADS)

    Zheng, Guoxun; Xue, Weiwei; Wang, Panpan; Yang, Fengyuan; Li, Bo; Li, Xiaofeng; Li, Yinghong; Yao, Xiaojun; Zhu, Feng

    2016-05-01

    Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine’s enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy.

  17. Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study.

    PubMed

    Zheng, Guoxun; Xue, Weiwei; Wang, Panpan; Yang, Fengyuan; Li, Bo; Li, Xiaofeng; Li, Yinghong; Yao, Xiaojun; Zhu, Feng

    2016-01-01

    Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine's enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy. PMID:27230580

  18. Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study

    PubMed Central

    Zheng, Guoxun; Xue, Weiwei; Wang, Panpan; Yang, Fengyuan; Li, Bo; Li, Xiaofeng; Li, Yinghong; Yao, Xiaojun; Zhu, Feng

    2016-01-01

    Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine’s enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy. PMID:27230580

  19. Health Cobenefits and Transportation-Related Reductions in Greenhouse Gas Emissions in the San Francisco Bay Area

    PubMed Central

    Woodcock, James; Co, Sean; Ostro, Bart; Fanai, Amir; Fairley, David

    2013-01-01

    Objectives. We quantified health benefits of transportation strategies to reduce greenhouse gas emissions (GHGE). Methods. Statistics on travel patterns and injuries, physical activity, fine particulate matter, and GHGE in the San Francisco Bay Area, California, were input to a model that calculated the health impacts of walking and bicycling short distances usually traveled by car or driving low-emission automobiles. We measured the change in disease burden in disability-adjusted life years (DALYs) based on dose–response relationships and the distributions of physical activity, particulate matter, and traffic injuries. Results: Increasing median daily walking and bicycling from 4 to 22 minutes reduced the burden of cardiovascular disease and diabetes by 14% (32 466 DALYs), increased the traffic injury burden by 39% (5907 DALYS), and decreased GHGE by 14%. Low-carbon driving reduced GHGE by 33.5% and cardiorespiratory disease burden by less than 1%. Conclusions: Increased physical activity associated with active transport could generate a large net improvement in population health. Measures would be needed to minimize pedestrian and bicyclist injuries. Together, active transport and low-carbon driving could achieve GHGE reductions sufficient for California to meet legislative mandates. PMID:23409903

  20. Edge transport and turbulence reduction with lithium coated plasma facing components in the National Spherical Torus Experiment

    SciTech Connect

    Canik, J. M.; Maingi, R.; Kubota, S.; Ren, Y.; Bell, R. E.; Guttenfelder, W.; Kugel, H. W.; LeBlanc, B. P.; Callen, J. D.; Osborne, T. H.; Soukhanovskii, V. A.

    2011-05-15

    The coating of plasma facing components (PFCs) with lithium improves energy confinement and eliminates ELMs in the National Spherical Torus Experiment, the latter due to a relaxation of the density and pressure profiles that reduces the drive for peeling-ballooning modes. 2-D interpretive transport modeling of discharges without and with lithium shows that a reduction in the PFC recycling coefficient from R {approx} 0.98 to R {approx} 0.90 is required to match the drop in D{sub {alpha}} emission with lithium coatings. A broadening of the edge barrier region showing reduced transport coefficients is observed, with a {approx}75% drop of the D and {chi}{sub e} from 0.8 < {psi}{sub N} < 0.93 needed to match the profile relaxation with lithium coatings. Turbulence measurements using an edge reflectometry system as well as high-k microwave scattering show a decrease in density fluctuations with lithium coatings. These transport changes allow the realization of very wide pedestals, with a {approx}100% width increase relative to the reference discharges.

  1. Interfacial Reduction-Oxidation Mechanisms Governing Fate and Transport of Contaminants in the Vadose Zone

    SciTech Connect

    Thornton, Edward C.; Baolin Deng; Jurisson, Silvia Sabine; Terry, Jeff

    2006-06-01

    The mobility of many contaminants is redox sensitive and thus related to the reduction oxidation characteristics of the environment. Immobilization of certain contaminants (e.g., chromium, uranium, and technetium) can be achieved by reducing the contaminant. One remediation approach to achieving this is the application of diluted hydrogen sulfide gas mixtures, which may have particular value in vadose zone applications. Previous work has shown this approach to be viable for Cr(VI) remediation of soil waste sites. The primary objective of the current research is to assess the potential of in situ gaseous treatment to the immobilization of U(VI) and Tc(VII). This work also addresses basic science aspects of understanding the redox-related aspects of the mobility of these contaminants in the natural environment, thus providing a mechanistic-based understanding needed to successfully achieve remediation.

  2. Mass transport, corrosion, plugging, and their reduction in solar dish/Stirling heat pipe receivers

    SciTech Connect

    Adkins, D.R.; Andraka, C.E.; Bradshaw, R.W.; Goods, S.H.; Moreno, J.B.; Moss, T.A.

    1996-07-01

    Solar dish/Stirling systems using sodium heat pipe receivers are being developed by industry and government laboratories here and abroad. The unique demands of this application lead to heat pipe wicks with very large surface areas and complex three-dimensional flow patterns. These characteristics can enhance the mass transport and concentration of constituents of the wick material, resulting in wick corrosion and plugging. As the test times for heat pipe receivers lengthen, we are beginning to see these effects both indirectly, as they affect performance, and directly in post-test examinations. We are also beginning to develop corrective measures. In this paper, we report on our test experiences, our post-test examinations, and on our initial effort to ameliorate various problems.

  3. Reduction in tribological energy losses in the transportation and electric utilities sectors

    SciTech Connect

    Pinkus, O.; Wilcock, D.F.; Levinson, T.M.

    1985-09-01

    This report is part of a study of ways and means of advancing the national energy conservation effort, particularly with regard to oil, via progress in the technology of tribology. The report is confined to two economic sectors: transportation, where the scope embraces primarily the highway fleets, and electric utilities. Together these two sectors account for half of the US energy consumption. Goal of the study is to ascertain the energy sinks attributable to tribological components and processes and to recommend long-range research and development (R and D) programs aimed at reducing these losses. In addition to the obvious tribological machine components such as bearings, piston rings, transmissions and so on, the study also extends to processes which are linked to tribology indirectly such as wear of machine parts, coatings of blades, high temperature materials leading to higher cycle efficiencies, attenuation of vibration, and other cycle improvements.

  4. Reduction of spatial distribution of risk factors for transportation of contaminants released by coal mining activities.

    PubMed

    Karan, Shivesh Kishore; Samadder, Sukha Ranjan

    2016-09-15

    It is reported that water-energy nexus composes two of the biggest development and human health challenges. In the present study we presented a Risk Potential Index (RPI) model which encapsulates Source, Vector (Transport), and Target risks for forecasting surface water contamination. The main aim of the model is to identify critical surface water risk zones for an open cast mining environment, taking Jharia Coalfield, India as the study area. The model also helps in feasible sampling design. Based on spatial analysis various risk zones were successfully delineated. Monthly RPI distribution revealed that the risk of surface water contamination was highest during the monsoon months. Surface water samples were analysed to validate the model. A GIS based alternative management option was proposed to reduce surface water contamination risk and observed 96% and 86% decrease in the spatial distribution of very high risk areas for the months June and July respectively. PMID:27240204

  5. The locus coeruleus-norepinephrine network optimizes coupling of cerebral blood volume with oxygen demand.

    PubMed

    Bekar, Lane K; Wei, Helen S; Nedergaard, Maiken

    2012-12-01

    Given the brain's uniquely high cell density and tissue oxygen levels bordering on hypoxia, the ability to rapidly and precisely match blood flow to constantly changing patterns in neural activity is an essential feature of cerebrovascular regulation. Locus coeruleus-norepinephrine (LC-NE) projections innervate the cerebral vasculature and can mediate vasoconstriction. However, function of the LC-mediated constriction in blood-flow regulation has never been addressed. Here, using intrinsic optical imaging coupled with an anesthesia regimen that only minimally interferes with LC activity, we show that NE enhances spatial and temporal aspects of functional hyperemia in the mouse somatosensory cortex. Increasing NE levels in the cortex using an α(2)-adrenergic receptor antagonist paradoxically reduces the extent of functional hyperemia while enhancing the surround blood-flow reduction. However, the NE-mediated vasoconstriction optimizes spatial and temporal focusing of the hyperemic response resulting in a sixfold decrease in the disparity between blood volume and oxygen demand. In addition, NE-mediated vasoconstriction accelerated redistribution to subsequently active regions, enhancing temporal synchronization of blood delivery. These observations show an important role for NE in optimizing neurovascular coupling. As LC neuron loss is prominent in Alzheimer and Parkinson diseases, the diminished ability to couple blood volume to oxygen demand may contribute to their pathogenesis. PMID:22872230

  6. Comparison of the hypertrophic effect of phorbol ester, norepinephrine, angiotensin II and contraction on cultured cardiomyocytes

    SciTech Connect

    Allo, S.N.; Carl, L.L.; Morgan, H.E. )

    1991-03-15

    Phorbol 12-myristate 13-acetate (PMA), norepinephrine (NE), angiotensin II (AII) and contraction stimulate cardiomyocyte growth. Differences exist in the time course and extent of protein and RNA accumulation. Cells plated at 4 {times} 10{sup 6} cells/60mm dish and arrested with 50 mM KCl demonstrated no significant growth. Treatment with PMA stimulated growth to a maximum of 17% at 48 h. In contrast, maximal stimulation of growth was 36% at 48 h and 31% at 72 h for contracting and NE treated cells, respectively. Maximal stimulation of the capacity for protein synthesis was 32% for PMA treated cells at 24 h as compared to 59% and 77% for NE treated and contracting cells respectively at 72 h. In support of a primary role for altered capacity in the regulation of protein synthesis, there was a significant correlation between RNA and protein content independent of the stimulus used. AII increased RNA content by 28% at 48h, but had no effect on growth up to 72h. Treatment with staurosporine blocked the stimulation of growth, suggestive of a role for protein kinase C (PKC). However, the inhibition of contraction-induced growth was due in part to a reduction in the rate of contraction. It was concluded that: significant differences existed in the time course of growth stimulation and RNA accumulation, depending on the stimulus; and growth inhibition by staurosporine is suggestive of an important role of PKC in hypertrophic growth induced by these stimuli.

  7. Norepinephrine Activates Dopamine D4 Receptors in the Rat Lateral Habenula

    PubMed Central

    Root, David H.; Hoffman, Alexander F.; Good, Cameron H.; Zhang, Shiliang; Gigante, Eduardo

    2015-01-01

    The lateral habenula (LHb) is involved in reward and aversion and is reciprocally connected with dopamine (DA)-containing brain regions, including the ventral tegmental area (VTA). We used a multidisciplinary approach to examine the properties of DA afferents to the LHb in the rat. We find that >90% of VTA tyrosine hydroxylase (TH) neurons projecting to the LHb lack vesicular monoamine transporter 2 (VMAT2) mRNA, and there is little coexpression of TH and VMAT2 protein in this mesohabenular pathway. Consistent with this, electrical stimulation of LHb did not evoke DA-like signals, assessed with fast-scan cyclic voltammetry. However, electrophysiological currents that were inhibited by L741,742, a DA-D4-receptor antagonist, were observed in LHb neurons when DA uptake or degradation was blocked. To prevent DA activation of D4 receptors, we repeated this experiment in LHb slices from DA-depleted rats. However, this did not disrupt D4 receptor activation initiated by the dopamine transporter inhibitor, GBR12935. As the LHb is also targeted by noradrenergic afferents, we examined whether GBR12935 activation of DA-D4 receptors occurred in slices depleted of norepinephrine (NE). Unlike DA, NE depletion prevented the activation of DA-D4 receptors. Moreover, direct application of NE elicited currents in LHb neurons that were blocked by L741,742, and GBR12935 was found to be a more effective blocker of NE uptake than the NE-selective transport inhibitor nisoxetine. These findings demonstrate that NE is released in the rat LHb under basal conditions and that it activates DA-D4 receptors. Therefore, NE may be an important regulator of LHb function. PMID:25716845

  8. Dopamine and norepinephrine receptors participate in methylphenidate enhancement of in vivo hippocampal synaptic plasticity.

    PubMed

    Jenson, Daniel; Yang, Kechun; Acevedo-Rodriguez, Alexandra; Levine, Amber; Broussard, John I; Tang, Jianrong; Dani, John A

    2015-03-01

    Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g., Ritalin) has been used to treat ADHD for over 50 years. It is the most commonly prescribed treatment for ADHD, and in the past decade it was the drug most commonly prescribed to teenagers. In addition, MPH has become one of the most widely abused drugs on college campuses. In this study, we examined the effects of MPH on hippocampal synaptic plasticity, which serves as a measurable quantification of memory mechanisms. Field potentials were recorded with permanently implanted electrodes in freely-moving mice to quantify MPH modulation of perforant path synaptic transmission onto granule cells of the dentate gyrus. Our hypothesis was that MPH affects hippocampal synaptic plasticity underlying learning because MPH boosts catecholamine signaling by blocking the dopamine and norepinephrine transporters (DAT and NET respectively). In vitro hippocampal slice experiments indicated MPH enhances perforant path plasticity, and this MPH enhancement arose from action via D1-type dopamine receptors and β-type adrenergic receptors. Similarly, MPH boosted in vivo initiation of long-term potentiation (LTP). While there was an effect via both dopamine and adrenergic receptors in vivo, LTP induction was more dependent on the MPH-induced action via D1-type dopamine receptors. Under biologically reasonable experimental conditions, MPH enhances hippocampal synaptic plasticity via catecholamine receptors. PMID:25445492

  9. Chloride ion currents contribute functionally to norepinephrine-induced vascular contraction.

    PubMed

    Lamb, F S; Barna, T J

    1998-07-01

    Norepinephrine (NE) increases Cl- efflux from vascular smooth muscle (VSM) cells. An increase in Cl- conductance produces membrane depolarization. We hypothesized that if Cl- currents are important for agonist-induced depolarization, then interfering with cellular Cl- handling should alter contractility. Isometric contraction of rat aortic rings was studied in a bicarbonate buffer. Substitution of extracellular Cl- with 130 mM methanesulfonate (MS; 8 mM Cl-) did not cause contraction. NE- and serotonin-induced contractions were potentiated in this low-Cl- buffer, whereas responses to K+, BAY K 8644, or NE in the absence of Ca2+ were unaltered. Substitution of Cl- with I- or Br- suppressed responses to NE. Inhibition of Cl- transport with bumetanide (10(-5) M) or bicarbonate-free conditions (10 mM HEPES) inhibited NE- but not KCl-induced contraction. The Cl--channel blockers DIDS (10(-3) M), anthracene-9-carboxylic acid (10(-3) M), and niflumic acid (10(-5) M) all inhibited NE-induced contraction, whereas tamoxifen (10(-5) M) did not. Finally, disruption of sarcoplasmic reticular function with cyclopiazonic acid (10(-7) M) or ryanodine (10(-5) M) prevented the increase in the peak response to NE produced by low-Cl- buffer. We conclude that a Cl- current with a permeability sequence of I- > Br- > Cl- > MS is critical to agonist-induced contraction of VSM. PMID:9688908

  10. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety.

    PubMed

    Auclair, A L; Martel, J C; Assié, M B; Bardin, L; Heusler, P; Cussac, D; Marien, M; Newman-Tancredi, A; O'Connor, J A; Depoortère, R

    2013-07-01

    Levomilnacipran (LVM; F2695) is the more active enantiomer of the serotonin/norepinephrine (5-HT/NE) reuptake inhibitor (SNRI) milnacipran and is currently under development for the treatment of major depressive disorder. LVM was benchmarked against two other SNRIs, duloxetine and venlafaxine, in biochemical, neurochemical and pharmacological assays. LVM exhibited high affinity for human NE (Ki = 92.2 nM) and 5-HT (11.2 nM) transporters, and potently inhibited NE (IC50 = 10.5 nM) and 5-HT (19.0 nM) reuptake (human transporter) in vitro. LVM had 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition (i.e. NE/5-HT potency ratio: 0.6) and 17 and 27 times higher selectivity for NE reuptake inhibition compared with venlafaxine and duloxetine, respectively. LVM did not exhibit affinity for 23 off-target receptors. LVM (i.p.) increased cortical extracellular levels of 5-HT, and NE (minimal effective doses: MEDs = 20 and 10 mg/kg, respectively). In anti-depressive/anti-stress models, i.p. LVM diminished immobility time in the mouse forced swim (MED = 20 mg/kg) and tail suspension (MED = 2.5 mg/kg) tests, and reduced shock-induced ultrasonic vocalizations in rats (MED = 5 mg/kg). Duloxetine and venlafaxine were less potent (MEDs ≥ 10 mg/kg). At doses active in these three therapeutically-relevant models, LVM (i.p.) did not significantly affect spontaneous locomotor activity. In summary, LVM is a potent, selective inhibitor of NE and 5-HT transporters with preferential activity at the former. It is efficacious in models of anti-depressive/anti-stress activity, with minimal potential for locomotor side effects. PMID:23499664

  11. The antidepressant-like pharmacological profile of Yuanzhi-1, a novel serotonin, norepinephrine and dopamine reuptake inhibitor.

    PubMed

    Jin, Zeng-liang; Gao, Nana; Li, Xiao-rong; Tang, Yu; Xiong, Jie; Chen, Hong-xia; Xue, Rui; Li, Yun-Feng

    2015-04-01

    Triple reuptake inhibitors that block dopamine transporters (DATs), norepinephrine transporters (NETs), and serotonin transporters (SERTs) are being developed as a new class of antidepressants that might have better efficacy and fewer side effects than traditional antidepressants. In this study, we performed in vitro binding and uptake assays as well as in vivo behavioural tests to assess the pharmacological properties and antidepressant-like efficacy of Yuanzhi-1. In vitro, Yuanzhi-1 had a high affinity for SERTs, NETs, and DATs prepared from rat brain tissue (Ki=3.95, 4.52 and 0.87nM, respectively) and recombinant cells (Ki=2.87, 6.86 and 1.03nM, respectively). Moreover, Yuanzhi-1 potently inhibited the uptake of serotonin (5-hydroxytryptamine; 5-HT), norepinephrine (NE) and dopamine (DA) into rat brain synaptosomes (Ki=2.12, 4.85 and 1.08nM, respectively) and recombinant cells (Ki=1.65, 5.32 and 0.68nM, respectively). In vivo, Yuanzhi-1 decreased immobility in a dose-dependent manner, which was shown among rats via the forced-swim test (FST) and mice via the tail-suspension test (TST). The results observed in the behavioural tests did not appear to result from the stimulation of locomotor activity. Repeated Yuanzhi-1 treatment (2.5, 5 or 10mg/kg) significantly reversed depression-like behaviours in chronically stressed rats, including reduced sucrose preference, decreased locomotor activity, and prolonged time to begin eating. Furthermore, in vivo microdialysis studies showed that 5- and 10-mg/kg administrations of Yuanzhi-1 significantly increased the extracellular concentrations of 5-HT, NE and DA in the frontal cortices of freely moving rats. Therefore, Yuanzhi-1 might represent a novel triple reuptake inhibitor and possess antidepressant-like activity. PMID:25638027

  12. Norepinephrine represses the expression of toxA and the siderophore genes in Pseudomonas aeruginosa.

    PubMed

    Li, Wang; Lyte, Mark; Freestone, Primrose P; Ajmal, Aziba; Colmer-Hamood, Jane A; Hamood, Abdul N

    2009-10-01

    Among the different extracellular virulence factors produced by Pseudomonas aeruginosa are exotoxin A (ETA) and the pyoverdine and pyochelin siderophores. Production of ETA and the siderophores requires the function of the iron-starvation sigma factor PvdS, the transcriptional activator RegA, and the AraC-activator PchR. Iron represses the production of ETA and the siderophores by repressing the expression of pvdS, regA, and pchR. PvdS regulates the expression of the ETA gene, toxA, regA, and the pyoverdine synthesis genes. The catecholamine norepinephrine enhances the growth of pathogenic bacteria by transferring iron from host-binding proteins. In this study, we elucidated the mechanism by which norepinephrine and other catecholamines induce P. aeruginosa growth. We also investigated whether norepinephrine regulates the expression of toxA and the siderophore genes, and the mechanism of this regulation. Norepinephrine enhanced the growth of P. aeruginosa by supplying iron from transferrin. This provision of iron repressed the expression of toxA, the pyoverdine genes pvdD and pvdE, and their regulators, pvdS, regA, and pchR, suggesting that norepinephrine accomplishes this repression through PvdS and PchR. Additionally, norepinephrine bypassed PvdS and supported the growth of a pvdS deletion mutant, indicating that norepinephrine transfers iron to P. aeruginosa independent of pyoverdine. Thus, norepinephrine apparently influences the pathogenesis of P. aeruginosa by affecting its pattern of growth and the production of virulence factors. PMID:19686346

  13. Thermodynamic and achievable efficiencies for solar-driven electrochemical reduction of carbon dioxide to transportation fuels

    PubMed Central

    Singh, Meenesh R.; Clark, Ezra L.; Bell, Alexis T.

    2015-01-01

    Thermodynamic, achievable, and realistic efficiency limits of solar-driven electrochemical conversion of water and carbon dioxide to fuels are investigated as functions of light-absorber composition and configuration, and catalyst composition. The maximum thermodynamic efficiency at 1-sun illumination for adiabatic electrochemical synthesis of various solar fuels is in the range of 32–42%. Single-, double-, and triple-junction light absorbers are found to be optimal for electrochemical load ranges of 0–0.9 V, 0.9–1.95 V, and 1.95–3.5 V, respectively. Achievable solar-to-fuel (STF) efficiencies are determined using ideal double- and triple-junction light absorbers and the electrochemical load curves for CO2 reduction on silver and copper cathodes, and water oxidation kinetics over iridium oxide. The maximum achievable STF efficiencies for synthesis gas (H2 and CO) and Hythane (H2 and CH4) are 18.4% and 20.3%, respectively. Whereas the realistic STF efficiency of photoelectrochemical cells (PECs) can be as low as 0.8%, tandem PECs and photovoltaic (PV)-electrolyzers can operate at 7.2% under identical operating conditions. We show that the composition and energy content of solar fuels can also be adjusted by tuning the band-gaps of triple-junction light absorbers and/or the ratio of catalyst-to-PV area, and that the synthesis of liquid products and C2H4 have high profitability indices. PMID:26504215

  14. Thermodynamic and achievable efficiencies for solar-driven electrochemical reduction of carbon dioxide to transportation fuels

    NASA Astrophysics Data System (ADS)

    Singh, Meenesh R.; Clark, Ezra L.; Bell, Alexis T.

    2015-11-01

    Thermodynamic, achievable, and realistic efficiency limits of solar-driven electrochemical conversion of water and carbon dioxide to fuels are investigated as functions of light-absorber composition and configuration, and catalyst composition. The maximum thermodynamic efficiency at 1-sun illumination for adiabatic electrochemical synthesis of various solar fuels is in the range of 32-42%. Single-, double-, and triple-junction light absorbers are found to be optimal for electrochemical load ranges of 0-0.9 V, 0.9-1.95 V, and 1.95-3.5 V, respectively. Achievable solar-to-fuel (STF) efficiencies are determined using ideal double- and triple-junction light absorbers and the electrochemical load curves for CO2 reduction on silver and copper cathodes, and water oxidation kinetics over iridium oxide. The maximum achievable STF efficiencies for synthesis gas (H2 and CO) and Hythane (H2 and CH4) are 18.4% and 20.3%, respectively. Whereas the realistic STF efficiency of photoelectrochemical cells (PECs) can be as low as 0.8%, tandem PECs and photovoltaic (PV)-electrolyzers can operate at 7.2% under identical operating conditions. We show that the composition and energy content of solar fuels can also be adjusted by tuning the band-gaps of triple-junction light absorbers and/or the ratio of catalyst-to-PV area, and that the synthesis of liquid products and C2H4 have high profitability indices.

  15. Thermodynamic and achievable efficiencies for solar-driven electrochemical reduction of carbon dioxide to transportation fuels.

    PubMed

    Singh, Meenesh R; Clark, Ezra L; Bell, Alexis T

    2015-11-10

    Thermodynamic, achievable, and realistic efficiency limits of solar-driven electrochemical conversion of water and carbon dioxide to fuels are investigated as functions of light-absorber composition and configuration, and catalyst composition. The maximum thermodynamic efficiency at 1-sun illumination for adiabatic electrochemical synthesis of various solar fuels is in the range of 32-42%. Single-, double-, and triple-junction light absorbers are found to be optimal for electrochemical load ranges of 0-0.9 V, 0.9-1.95 V, and 1.95-3.5 V, respectively. Achievable solar-to-fuel (STF) efficiencies are determined using ideal double- and triple-junction light absorbers and the electrochemical load curves for CO2 reduction on silver and copper cathodes, and water oxidation kinetics over iridium oxide. The maximum achievable STF efficiencies for synthesis gas (H2 and CO) and Hythane (H2 and CH4) are 18.4% and 20.3%, respectively. Whereas the realistic STF efficiency of photoelectrochemical cells (PECs) can be as low as 0.8%, tandem PECs and photovoltaic (PV)-electrolyzers can operate at 7.2% under identical operating conditions. We show that the composition and energy content of solar fuels can also be adjusted by tuning the band-gaps of triple-junction light absorbers and/or the ratio of catalyst-to-PV area, and that the synthesis of liquid products and C2H4 have high profitability indices. PMID:26504215

  16. Resonant Pedestal Pressure Reduction Induced by a Thermal Transport Enhancement due to Stochastic Magnetic Boundary Layers in High Temperature Plasmas

    SciTech Connect

    Schmitz, O.; Evans, T.E.; Fenstermacher, M. E.; Unterberg, E. A.; Austin, M. E.; Bray, B. D.; Brooks, N. H.; Frerichs, H.; Groth, M.; Jakubowski, M. W.; Lasnier, C. J.; Lehnen, M.; Leonard, A. W.; Mordijck, S.; Moyer, R.A.; Osborne, T. H.; Reiter, D.; Samm, U.; Schaffer, M. J.; Unterberg, B.; West, W. P.

    2009-01-01

    Good alignment of the magnetic field line pitch angle with the mode structure of an external resonant magnetic perturbation (RMP) field is shown to induce modulation of the pedestal electron pressure p(e) in high confinement high rotation plasmas at the DIII-D tokamak with a shape similar to ITER, the next step tokamak experiment. This is caused by an edge safety factor q(95) resonant enhancement of the thermal transport, while in contrast, the RMP induced particle pump out does not show a significant resonance. The measured p(e) reduction correlates to an increase in the modeled stochastic layer width during pitch angle variations matching results from resistive low rotation plasmas at the TEXTOR tokamak. These findings suggest a field line pitch angle resonant formation of a stochastic magnetic edge layer as an explanation for the q(95) resonant character of type-I edge localized mode suppression by RMPs.

  17. Resonant Pedestal Pressure Reduction Induced by a Thermal Transport Enhancement due to Stochastic Magnetic Boundary Layers in High Temperature Plasmas

    SciTech Connect

    Schmitz, O.; Frerichs, H.; Lehnen, M.; Reiter, D.; Samm, U.; Unterberg, B.; Evans, T. E.; Austin, M. E.; Bray, B. D.; Brooks, N. H.; Leonard, A. W.; Osborne, T. H.; Schaffer, M. J.; West, W. P.; Fenstermacher, M. E.; Groth, M.; Lasnier, C. J.; Unterberg, E. A.; Jakubowski, M. W.; Mordijck, S.

    2009-10-16

    Good alignment of the magnetic field line pitch angle with the mode structure of an external resonant magnetic perturbation (RMP) field is shown to induce modulation of the pedestal electron pressure p{sub e} in high confinement high rotation plasmas at the DIII-D tokamak with a shape similar to ITER, the next step tokamak experiment. This is caused by an edge safety factor q{sub 95} resonant enhancement of the thermal transport, while in contrast, the RMP induced particle pump out does not show a significant resonance. The measured p{sub e} reduction correlates to an increase in the modeled stochastic layer width during pitch angle variations matching results from resistive low rotation plasmas at the TEXTOR tokamak. These findings suggest a field line pitch angle resonant formation of a stochastic magnetic edge layer as an explanation for the q{sub 95} resonant character of type-I edge localized mode suppression by RMPs.

  18. Good Night and Good Luck: Norepinephrine in Sleep Pharmacology

    PubMed Central

    Mitchell, Heather A.; Weinshenker, David

    2009-01-01

    Sleep is a crucial biological process is regulated through complex interactions between multiple brain regions and neuromodulators. As sleep disorders can have deleterious impacts on health and quality of life, a wide variety of pharmacotherapies have been developed to treat conditions of excessive wakefulness and excessive sleepiness. The neurotransmitter norepinephrine (NE), through its involvement in the ascending arousal system, impacts the efficacy of many wake- and sleep-promoting medications. Wake-promoting drugs such as amphetamine and modafinil increase extracellular levels of NE, enhancing transmission along the wake-promoting pathway. GABAergic sleep-promoting medications like benzodiazepines and benzodiazepine-like drugs that act more specifically on benzodiazepine receptors increase the activity of GABA, which inhibits NE and the wake-promoting pathway. Melatonin and related compounds increase sleep by suppressing the activity of the neurons in the brain’s circadian clock, and NE influences the synthesis of melatonin. Antihistamines block the wake-promoting effects of histamine, which shares reciprocal signaling with NE. Many antidepressants that affect the signaling of NE are also used for treatment of insomnia. Finally, adrenergic antagonists that are used to treat cardiovascular disorders have considerable sedative effects. Therefore, NE, long known for its role in maintaining general arousal, is also a crucial player in sleep pharmacology. The purpose of this review is to consider the role of NE in the actions of wake- and sleep-promoting drugs within the framework of the brain arousal systems. PMID:19833104

  19. Locus coeruleus, norepinephrine and Aβ peptides in Alzheimer's disease

    PubMed Central

    Ross, Jennifer A.; McGonigle, Paul; Van Bockstaele, Elisabeth J.

    2015-01-01

    Monoaminergic brainstem systems have widespread projections that participate in many central processes and, when dysregulated, contribute to a plethora of neuropsychiatric and neurodegenerative disorders. Synapses are the foundation of these neuronal circuits, and their local dysfunction results in global aberrations leading to pathophysiological disease states. This review focuses on the locus coeruleus (LC) norepinephrine (NE) brainstem system and its underappreciated role in Alzheimer's disease (AD). Amyloid beta (Aβ), a peptide that accumulates aberrantly in AD has recently been implicated as a modulator of neuronal excitability at the synapse. Evidence is presented showing that disruption of the LC-NE system at a synaptic and circuit level during early stages of AD, due to conditions such as chronic stress, can potentially lead to amyloid accumulation and contribute to the progression of this neurodegenerative disorder. Additional factors that impact neurodegeneration include neuroinflammation, and network de-synchronization. Consequently, targeting the LC-NE system may have significant therapeutic potential for AD, as it may facilitate modulation of Aβ production, curtail neuroinflammation, and prevent sleep and behavioral disturbances that often lead to negative patient outcomes. PMID:26618188

  20. Norepinephrine deficiency in Parkinson's disease: the case for noradrenergic enhancement.

    PubMed

    Espay, Alberto J; LeWitt, Peter A; Kaufmann, Horacio

    2014-12-01

    The dramatic response of most motor and some nonmotor symptoms to dopaminergic therapies has contributed to maintaining the long-established identity of Parkinson's disease (PD) as primarily a nigrostriatal dopamine (DA) deficiency syndrome. However, DA neurotransmission may be neither the first nor the major neurotransmitter casualty in the neurodegenerative sequence of PD. Growing evidence supports earlier norepinephrine (NE) deficiency resulting from selective degeneration of neurons of the locus coeruleus and sympathetic ganglia. Dopaminergic replacement therapy therefore would seem to neglect some of the motor, behavioral, cognitive, and autonomic impairments that are directly or indirectly associated with the marked deficiency of NE in the brain and elsewhere. Therapeutic strategies to enhance NE neurotransmission have undergone only limited pharmacological testing. Currently, these approaches include selective NE reuptake inhibition, presynaptic α2 -adrenergic receptor blockade, and an NE prodrug, the artificial amino acid L-threo-3,4-dihydroxyphenylserine. In addition to reducing the consequences of deficient noradrenergic signaling, enhancement strate gies have the potential for augmenting the effects of dopaminergic therapies in PD. Furthermore, early recognition of the various clinical manifestations associated with NE deficiency, which may precede development of motor symptoms, could provide a window of opportunity for neuroprotective interventions. PMID:25297066

  1. Norepinephrine storage, distribution, and release in diabetic cardiomyopathy

    SciTech Connect

    Ganguly, P.K.; Beamish, R.E.; Dhalla, K.S.; Innes, J.R.; Dhalla, N.S.

    1987-06-01

    The ability of hearts to store, distribute, and release norepinephrine (NE) was investigated in rats 8 wk after the induction of diabetes by an injection of streptozotocin. Chronic diabetes was associated with increased content and concentration of NE in heart and in other tissues such as kidney, brain, and spleen. Reserpine or tyramine treatment resulted in depletion of endogenous cardiac NE in control and diabetic rats. The depletion of NE stores at different times after a dose of reserpine was greater in diabetic hearts. On the other hand, NE stores in diabetic hearts were less sensitive than control hearts to low doses of tyramine but were more sensitive to high doses. The uptake of (/sup 3/H)NE was greater in diabetic hearts in isolated perfused preparations. In comparison with the control values, diabetic hearts showed a decrease in (/sup 3/H)NE in the granular fraction and an increase in the supernatant fraction. Diabetic hearts also showed an accelerated spontaneous release of (/sup 3/H)NE. The increased cardiac NE and the uptake and release of NE in diabetic animals were reversible upon treatment with insulin. These results are consistent with the view that sympathetic activity is increased in diabetic cardiomyopathy and indicate that cardiac NE in diabetic rats is maintained at a higher level partly due to an increased uptake of released NE by adrenergic nerve terminals.

  2. Beta blockers, norepinephrine, and cancer: an epidemiological viewpoint.

    PubMed

    Fitzgerald, Paul J

    2012-01-01

    There is growing evidence that the neurotransmitter norepinephrine (NE) and its sister molecule epinephrine (EPI) (adrenaline) affect some types of cancer. Several recent epidemiological studies have shown that chronic use of beta blocking drugs (which antagonize NE/EPI receptors) results in lower recurrence, progression, or mortality of breast cancer and malignant melanoma. Preclinical studies have shown that manipulation of the levels or receptors of NE and EPI with drugs affects experimentally induced cancers. Psychological stress may play an etiological role in some cases of cancer (which has been shown epidemiologically), and this could be partly mediated by NE and EPI released by the sympathetic nervous system as part of the body's "fight or flight" response. A less well-appreciated phenomenon is that the genetic tone of NE/EPI may play a role in cancer. NE and EPI may affect cancer by interacting with molecular pathways already implicated in abnormal cellular replication, such as the P38/MAPK pathway, or via oxidative stress. NE/EPI-based drugs other than beta blockers also may prevent or treat various types of cancer, as may cholinesterase inhibitors that inhibit the sympathetic nervous system, which could be tested epidemiologically. PMID:22807646

  3. Mutual modulation between norepinephrine and nitric oxide in haemocytes during the mollusc immune response

    PubMed Central

    Jiang, Qiufen; Zhou, Zhi; Wang, Lingling; Yang, Chuanyan; Wang, Jingjing; Wu, Tiantian; Song, Linsheng

    2014-01-01

    Nitric oxide (NO) is one of the most important immune molecules in innate immunity of invertebrates, and it can be regulated by norepinephrine in ascidian haemocytes. In the present study, the mutual modulation and underlying mechanism between norepinephrine and NO were explored in haemocytes of the scallop Chlamys farreri. After lipopolysaccharide stimulation, NO production increased to a significant level at 24 h, and norepinephrine concentration rose to remarkable levels at 3 h and 12~48 h. A significant decrease of NO production was observed in the haemocytes concomitantly stimulated with lipopolysaccharide and α-adrenoceptor agonist, while a dramatic increase of NO production was observed in the haemocytes incubated with lipopolysaccharide and β-adrenoceptor agonist. Meanwhile, the concentration of cyclic adenosine monophosphate (cAMP) decreased significantly in the haemocytes treated by lipopolysaccharide and α/β-adrenoceptor agonist, while the content of Ca2+ was elevated in those triggered by lipopolysaccharide and β-adrenoceptor agonist. When the haemocytes was incubated with NO donor, norepinephrine concentration was significantly enhanced during 1~24 h. Collectively, these results suggested that norepinephrine exerted varied effects on NO production at different immune stages via a novel α/β-adrenoceptor-cAMP/Ca2+ regulatory pattern, and NO might have a feedback effect on the synthesis of norepinephrine in the scallop haemocytes. PMID:25376551

  4. Norepinephrine turnover in brown adipose tissue is stimulated by a single meal

    SciTech Connect

    Glick, Z.; Raum, W.J.

    1986-07-01

    A single meal stimulates brown adipose tissue (BAT) thermogenesis in rats. In the present study the role of norepinephrine in this thermogenic response was assessed from the rate of its turnover in BAT after a single test meal. For comparison, norepinephrine turnover was determined in the heart and spleen. A total of 48 male Wistar rats (200 g) were trained to eat during two feeding sessions per day. On the experimental day, one group (n = 24) was meal deprived and the other (n = 24) was given a low-protein high-carbohydrate test meal for 2 h. The synthesis inhibition method with ..cap alpha..-methyl-p-tyrosine was employed to determine norepinephrine turnover from its concentration at four hourly time points after the meal. Tissue concentrations of norepinephrine were determined by radioimmunoassay. Norepinephrine concentration and turnover rate were increased more than threefold in BAT of the meal-fed compared with the meal-deprived rats. Neither were significantly altered by the meal in the heart or spleen. The data suggest that norepinephrine mediates a portion of the thermic effect of meals that originate in BAT.

  5. Inhibition of DNA methylation reverses norepinephrine-induced cardiac hypertrophy in rats

    PubMed Central

    Xiao, DaLiao; Dasgupta, Chiranjib; Chen, Man; Zhang, Kangling; Buchholz, John; Xu, Zhice; Zhang, Lubo

    2014-01-01

    Aims The mechanisms of heart failure remain largely elusive. The present study determined a causative role of DNA methylation in norepinephrine-induced heart hypertrophy and reduced cardiac contractility. Methods and results Male adult rats were subjected to norepinephrine infusion for 28 days, some of which were treated with 5-aza-2′-deoxycytidine for the last 6 days of norepinephrine treatment. At the end of the treatment, hearts were isolated and left ventricular morphology and function as well as molecular assessments was determined. Animals receiving chronic norepinephrine infusion showed a sustained increase in blood pressure, heightened global genomic DNA methylation and changes in the expression of subsets of proteins in the left ventricle, left ventricular hypertrophy, and impaired contractility with an increase in the susceptibility to ischaemic injury. Treatment of animals with 5-aza-2′-deoxycytidine for the last 6 days of norepinephrine infusion reversed norepinephrine-induced hypermethylation, corrected protein expression patterns, and rescued the phenotype of heart hypertrophy and failure. Conclusions The findings provide novel evidence of a causative role of increased DNA methylation in programming of heart hypertrophy and reduced cardiac contractility, and suggest potential therapeutic targets of demethylation in the treatment of failing heart and ischaemic heart disease. PMID:24272874

  6. Reduction of angular divergence of laser-driven ion beams during their acceleration and transport

    NASA Astrophysics Data System (ADS)

    Zakova, M.; Pšikal, Jan; Margarone, Daniele; Maggiore, Mario; Korn, G.

    2015-05-01

    Laser plasma physics is a field of big interest because of its implications in basic science, fast ignition, medicine (i.e. hadrontherapy), astrophysics, material science, particle acceleration etc. 100-MeV class protons accelerated from the interaction of a short laser pulse with a thin target have been demonstrated. With continuing development of laser technology, greater and greater energies are expected, therefore projects focusing on various applications are being formed, e.g. ELIMAIA (ELI Multidisciplinary Applications of laser-Ion Acceleration). One of the main characteristic and crucial disadvantage of ion beams accelerated by ultra-short intense laser pulses is their large divergence, not suitable for the most of applications. In this paper two ways how to decrease beam divergence are proposed. Firstly, impact of different design of targets on beam divergence is studied by using 2D Particlein-cell simulations (PIC). Namely, various types of targets include at foils, curved foil and foils with diverse microstructures. Obtained results show that well-designed microstructures, i.e. a hole in the center of the target, can produce proton beam with the lowest divergence. Moreover, the particle beam accelerated from a curved foil has lower divergence compared to the beam from a flat foil. Secondly, another proposed method for the divergence reduction is using of a magnetic solenoid. The trajectories of the laser accelerated particles passing through the solenoid are modeled in a simple Matlab program. Results from PIC simulations are used as input in the program. The divergence is controlled by optimizing the magnetic field inside the solenoid and installing an aperture in front of the device.

  7. The effectiveness of policy on consumer choices for private road passenger transport emissions reductions in six major economies

    NASA Astrophysics Data System (ADS)

    Mercure, J.-F.; Lam, A.

    2015-06-01

    The effectiveness of fiscal policy to influence vehicle purchases for emissions reductions in private passenger road transport depends on its ability to incentivise consumers to make choices oriented towards lower emissions vehicles. However, car purchase choices are known to be strongly socially determined, and this sector is highly diverse due to significant socio-economic differences between consumer groups. Here, we present a comprehensive dataset and analysis of the structure of the 2012 private passenger vehicle fleet-years in six major economies across the World (UK, USA, China, India, Japan and Brazil) in terms of price, engine size and emissions distributions. We argue that choices and aggregate elasticities of substitution can be predicted using this data, enabling us to evaluate the effectiveness of potential fiscal and technological change policies on fleet-year emissions reductions. We provide tools to do so based on the distributive structure of prices and emissions in segments of a diverse market, both for conventional as well as unconventional engine technologies. We find that markets differ significantly between nations, and that correlations between engine sizes, emissions and prices exist strongly in some markets and not strongly in others. We furthermore find that markets for unconventional engine technologies have patchy coverages of varying levels. These findings are interpreted in terms of policy strategy.

  8. The coprocessing of fossil fuels and biomass for CO{sub 2} emission reduction in the transportation sector

    SciTech Connect

    Steinberg, M.; Dong, Yuanji; Borgwardt, R.H.

    1993-10-01

    Research is underway to evaluate the Hydrocarb process for conversion of carbonaceous raw material to clean carbon and methanol products. These products are valuable in the market either as fuel or as chemical commodities. As fuel, methanol and carbon can be used economically, either independently or in slurry form, in efficient heat energies (turbines and internal combustion engines) for both mobile and stationary single and combined cycle power plants. When considering CO{sub 2} emission control in the utilization of fossil fuels, the copressing of those fossil fuels with biomass (which may include, wood, municipal solid waste and sewage sludge) is a viable mitigation approach. By coprocessing both types of feedstock to produce methanol and carbon while sequestering all or part of the carbon, a significant net CO{sub 2} reduction is achieved if the methanol is substituted for petroleum fuels in the transportation sector. The Hydrocarb process has the potential, if the R&D objectives are achieved, to produce alternative transportation fuel from indigenous resources at lower cost than any other biomass conversion process. These comparisons suggest the resulting fuel can significantly displace gasoline at a competitive price while mitigating CO{sub 2} emissions and reducing ozone and other toxics in urban atmospheres.

  9. Interstitial adenosine concentration during norepinephrine infusion in isolated guinea pig hearts

    PubMed Central

    GORMAN, MARK W.; WANGLER, ROGER D.; BASSINGTHWAIGHTE, JAMES B.; MOHRMAN, DAVID E.; WANG, C. Y.; SPARKS, HARVEY V.

    2010-01-01

    This study determined the effect of norepinephrine (NE) on cardiac interstitial fluid adenosine concentration ([ADO]isf). Isolated guinea pig hearts were perfused with a Krebs-Henseleit buffer solution. Radiolabeled albumin, sucrose, and adenosine were injected under control conditions and after 3 and 20 min of NE infusion to obtain multiple indicator dilution curves that were used to determine capillary transport parameters for adenosine. These parameters together with venous adenosine concentrations were used in a mathematical model to calculate [ADO]isf. Capillary transport parameters were not changed significantly by NE infusion. Because of uncertainty regarding two model parameters, two sets of [ADO]isf values were calculated. One set used best-fit values obtained from indicator dilution curves, and a second set used parameters chosen to provide the highest [ADO]isf values consistent with indicator dilution curves. Venous adenosine concentrations were 1.9 ± 0.4 nM under control conditions and 243 ± 110 and 45 ± 25 nM after 3 and 20 min of NE infusion, respectively. Calculated [ADO]isf was 2.6–9.4, 591–1,288, and 166–324 nM, respectively, under these same conditions. We conclude that NE infusion greatly increases [ADO]isf, and adenosine is responsible for most of the vasodilation at 3 min. The subsequent fall in venous concentration is due to a fall in [ADO]isf rather than to decreased capillary permeability. Vascular resistance remained low while [ADO]isf fell, which suggests that additional vasodilators are important during maintained NE infusion. PMID:1887934

  10. Reduction of Mn-oxides by ferrous iron in a flow system: column experiment and reactive transport modeling

    NASA Astrophysics Data System (ADS)

    Postma, D.; Appelo, C. A. J.

    2000-04-01

    The reduction of Mn-oxide by Fe2+ was studied in column experiments, using a column filled with natural Mn-oxide coated sand. Analysis of the Mn-oxide indicated the presence of both Mn(III) and Mn(IV) in the Mn-oxide. The initial exchange capacity of the column was determined by displacement of adsorbed Ca2+ with Mg2+. Subsequently a FeCl2 solution was injected into the column causing the reduction of the Mn-oxide and the precipitation of Fe(OH)3. Finally the exchange capacity of the column containing newly formed Fe(OH)3 was determined by injection of a KBr solution. During injection of the FeCl2 solution into the column, an ion distribution pattern was observed in the effluent that suggests the formation of separate reaction fronts for Mn(III)-oxide and Mn(IV)-oxide travelling at different velocities through the column. At the proximal reaction front, Fe2+ reacts with MnO2 producing Fe(OH)3, Mn2+ and H+. The protons are transported downstream and cause the disproportionation of MnOOH at a separate reaction front. Between the two Mn reaction fronts, the dissolution and precipitation of Fe(OH)3 and Al(OH)3 act as proton buffers. Reactive transport modeling, using the code PHREEQC 2.0, was done to quantify and analyze the reaction controls and the coupling between transport and chemical processes. A model containing only mineral equilibria constraints for birnessite, manganite, gibbsite, and ferrihydrite, was able to explain the overall reaction pattern with the sequential appearance of Mn2+, Al3+, Fe3+, and Fe2+ in the column outlet solution. However, the initial breakthrough of a peak of Ca2+ and the observed pH buffering indicated that exchange processes were of importance as well. The amount of potential exchangers, such as birnessite and ferrihydrite, did vary in the course of the experiment. A model containing surface complexation coupled to varying concentrations of birnessite and ferrihydrite and a constant charge exchanger in addition to mineral equilibria

  11. Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys.

    PubMed

    Negus, S S; Mello, N K; Blough, B E; Baumann, M H; Rothman, R B

    2007-02-01

    Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotonin-selective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin-selective [m-fluoroamphetamine (PAL-353), methamphetamine, m-methylamphetamine (PAL-314), 1-napthyl-2-aminopropane (PAL-287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine (0.4 mg/kg i.m.) in a two-key, food-reinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine versus serotonin release. In drug self-administration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food (1-g pellets) under a second-order fixed-ratio 2 (variable-ratio 16:S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/norepinephrine-selective releasers decreased cocaine self-administration with minimal effects on food-maintained responding, whereas the more serotonin-selective releasers produced nonselective reductions in both cocaine- and food-maintained responding. These results are consistent with the conclusion that dopamine/norepinephrine-selective releasers retain cocaine-like abuse

  12. Effects of desipramine on norepinephrine clearance in congestive heart failure

    SciTech Connect

    Clemson, B.; Baily, R.G.; Davis, D.; Zelis, R. )

    1990-08-01

    Elevated plasma norepinephrine (NE) in congestive heart failure (CHF) is caused by increased NE spillover and decreased NE clearance. To evaluate the effects of neuronal uptake blockade on NE clearance, we studied NE kinetics during steady-state infusions of (3H)NE, before and after oral desipramine (DMI, 50 mg) in 11 patients with CHF and 8 normal volunteers. Baseline plasma NE was greater in the CHF group (637 +/- 56 vs. 271 +/- 32 pg/ml; P less than 0.001), NE clearance was lower in CHF (1.31 +/- 0.21 vs. 1.94 +/- 0.17 l.min-1.m-2; P = 0.026), and NE spillover was greater in CHF (4.71 +/- 0.78 vs. 3.04 +/- 0.35 nmol.min-1.m-2, P = 0.054). After DMI, plasma NE rose significantly in CHF (778 +/- 67; P = 0.008), and NE clearance decreased further in CHF (0.97 +/- 0.16; P = 0.024), but neither changed in normal subjects. NE spillover did not change in either group. There appears to be an enhanced effect of DMI on NE clearance in CHF patients. Two general mechanisms may be responsible for this finding, an increased concentration of drug, possibly caused by a decreased volume of distribution, and an increased sensitivity of neuronal amine pumps to DMI. Both mechanisms may reflect a more general abnormality of clearance of drugs and hormones related to abnormalities of tissue perfusion in CHF.

  13. Copper-deficient mice have higher cardiac norepinephrine turnover

    SciTech Connect

    Gross, A.M.; Prohaska, J.R. )

    1989-02-01

    Male Swiss albino mice were studied at 6 weeks of age. Their dams were fed a copper-deficient diet (modified AIN-76A) starting 4 days after birth and given deionized water (-Cu) or water with CuSO{sub 4} added (+Cu) (20 {mu}g Cu/ml). When 3 weeks of age mice were weaned and housed in stainless steel cages on the respective treatment of their dams. Turnover of norepinephrine (NE) was studied in 8 experiments using 2 separate techniques. The first procedure used {alpha}-methyl-p-tyrosine methyl ester (300 mg/kg i.p.) to inhibit tyrosine hydroxlase activity. The loss of residual NE was determined by HPLC with electrochemical detection. Regression lines were constructed and fractional turnover (%/h) and calculated turnover (ng/g/h) were determined for heart, cerebellum and adrenal gland. In 4 experiments loss of NE in cerebellum of -Cu ad +Cu mice was equivalent. Loss of NE from adrenal gland could not be detected in the 8 h time course. Loss of NE, both fractional turnover and calculated turnover, from heart of -Cu mice was 4-5 fold higher compared to +Cu controls. A second method using m- hydroxybenzylhydrazine (NSD-1015) (100 mg/kg i.p.), which inhibits aromatic amino acid decarboxylase, confirmed the results. For all 4 experiments the cardiac accumulation of L-DOPA (measured by HPLC) was faster in -Cu mice compared to controls. The higher turnover rate of NE in heart and perhaps other sympathetic nerves may contribute to the higher urinary NE output observed previously.

  14. The stress hormone norepinephrine increases migration of prostate cancer cells in vitro and in vivo.

    PubMed

    Barbieri, Antonio; Bimonte, Sabrina; Palma, Giuseppe; Luciano, Antonio; Rea, Domenica; Giudice, Aldo; Scognamiglio, Giosuè; La Mantia, Elvira; Franco, Renato; Perdonà, Sisto; De Cobelli, Ottavio; Ferro, Matteo; Zappavigna, Silvia; Stiuso, Paola; Caraglia, Michele; Arra, Claudio

    2015-08-01

    The metastatic process is the most serious cause of cancer death. Norepinephrine, secreted in chronic stress conditions, stimulates the motility of breast and colon cells through β-adrenergic receptor. On these bases, we examined its possible role in metastasis formation and development in vitro and in vivo. Treatments with norepinephrine (β2-adrenoreceptor agonist) in mice xenografted with human DU145 prostate cancer cells increased the metastatic potential of these cells. Specifically, we showed that treatment of mice with norepinephrine induced a significant increase of the migratory activity of cancer cells in a concentration-dependent manner and that this process was blocked by propanolol (β-adrenergic antagonist). Mice treated with norepinephrine, displayed an increased number of metastatic foci of DU145 cells in inguinal lymph nodes and also showed an increased expression of MMP2 and MMP9 in tumor samples compared to controls. Moreover, we demonstrated that propanolol induced in norepinephrine treated DU145 cells a E-cadherin finger-like membrane protrusions driven by vimentin remodeling. Altogether these data suggest that β2-AR plays an important role in prostate cancer metastasis formation and that the treatment with antagonist propanolol, could represents an interesting tool to control this process in cells overexpressing β2AR. PMID:26058426

  15. Adrenergic support during anesthesia in experimental endotoxin shock: norepinephrine versus dobutamine.

    PubMed

    Van der Linden, P; Gilbart, E; Engelman, E; de Rood, M; Vincent, J L

    1991-02-01

    The effects of norepinephrine and dobutamine were compared during endotoxin shock in dogs anesthetized either with enflurane (E: 1.5%, N = 12) or with i.v. ketamine (K: 5 mg.kg-1 + 0.2 mg.kg-1.min-1, N = 12). An i.v. bolus of 1.5 mg.kg-1 E. coli endotoxin was followed by saline infusion to restore left-sided filling pressures at baseline. With E, heart rate, mean arterial pressure and stroke index decreased (P less than 0.01). The decrease in oxygen delivery (DO2) and in oxygen consumption (VO2) was associated with an increase in blood lactate. In contrast, K anesthesia was associated with remarkable hemodynamic stability. DO2 was well maintained, VO2 decreased (P less than 0.01) and blood lactate did not change. Under E anesthesia, mean arterial pressure increased more with norepinephrine and heart rate increased more with dobutamine. Under K anesthesia, cardiac index, stroke index and left ventricular stroke work index increased similarly with both agents. In both groups DO2 and VO2 increased markedly. The amount of fluid infused was higher with dobutamine than with norepinephrine. Thus, enflurane but not ketamine had depressant cardiovascular effects at the doses used in this model. With both anesthetics, norepinephrine and dobutamine could effectively improve cardiac function. Dobutamine could therefore represent a valuable alternative to norepinephrine for cardiovascular support during anesthesia in septic shock. PMID:2024562

  16. Cortical serotonin and norepinephrine denervation in parkinsonism: Preferential loss of the beaded serotonin innervation

    PubMed Central

    Nayyar, Tultul; Bubser, Michael; Ferguson, Marcus C.; Neely, M. Diana; Goodwin, J. Shawn; Montine, Thomas J.; Deutch, Ariel Y.; Ansah, Twum A.

    2009-01-01

    Parkinson’s Disease (PD) is marked by prominent motor symptoms that reflect striatal dopamine insufficiency. However, non-motor symptoms, including depression, are common in PD. These changes have been suggested to reflect pathological involvement of non-dopaminergic systems. We examined regional changes in serotonin and norepinephrine systems in mice treated with two different 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment paradigms and that survived for 3 or 16 weeks after the last MPTP injection. MPTP caused a decrease in striatal dopamine concentration, the magnitude of which depended on the treatment regimen and survival interval after MPTP treatment. There was significant involvement of other subcortical areas receiving a dopamine innervation, but no consistent changes in serotonin or norepinephrine levels in subcortical sites. In contrast, we observed an enduring decrease in serotonin and norepinephrine concentrations in both the somatosensory and medial prefrontal (PFC) cortex. Immunohistochemical studies also revealed a decrease in the density of PFC norepinephrine and serotonin axons. The decrease in the cortical serotonergic innervation preferentially involved the thick beaded but not smooth fine serotonin axons. Similar changes in the serotonin innervation of postmortem samples of the prefrontal cortex from idiopathic PD cases were seen. Our findings point to a major loss of the serotonin and norepinephrine innervations of the cortex in MPTP-induced parkinsonism, and suggest that loss of the beaded cortical serotonin innervation is associated with a predisposition to the development of depression in PD. PMID:19659923

  17. Correction: Decrease in thermal conductivity in polymeric P3HT nanowires by size-reduction induced by crystal orientation: new approaches towards thermal transport engineering of organic materials.

    PubMed

    Muñoz Rojo, Miguel; Martín, Jaime; Grauby, Stéphane; Borca-Tasciuc, Theodorian; Dilhaire, Stefan; Martin-Gonzalez, Marisol

    2015-03-01

    Correction for 'Decrease in thermal conductivity in polymeric P3HT nanowires by size-reduction induced by crystal orientation: new approaches towards thermal transport engineering of organic materials' by Miguel Muñoz Rojo et al., Nanoscale, 2014, 6, 7858-7865. PMID:25668105

  18. Amelioration of deficit syndrome of schizophrenia by norepinephrine reuptake inhibitor

    PubMed Central

    Shoja Shafti, Saeed; Jafarabad, Mohammad Sadeghe; Azizi, Reza

    2015-01-01

    Objective: Negative symptoms are a significant barrier to successful functional outcome and recovery in individuals with schizophrenia and their management is not unproblematic. Reboxetine is a norepinephrine reuptake inhibitor (NRI). Previous studies regarding the useful effects of reboxetine on deficit symptoms of schizophrenia have resulted in inconsistent results. The present study therefore evaluated the effectiveness of reboxetine as an adjunctive treatment in a group of schizophrenic patients with prominent negative symptoms. Method: A total of 50 male inpatients meeting diagnosis of schizophrenia entered into a 12-week parallel group, double-blind study for random assignment to reboxetine (n = 25 patients) or placebo (n = 25 patients). The inclusion criterion, in addition to the diagnosis of schizophrenia, was the existence of obvious negative symptoms for a duration of at least 2 years. The Scale for Assessment of Negative Symptoms (SANS) was used as the primary outcome measure. The Scale for Assessment of Positive Symptoms (SAPS), Simpson Angus Scale (SAS), Hamilton Rating Scale for Depression (HAM-D) and Mini-Mental Status Examination (MMSE) were used for comparison of the intervening parameters in this study. Results: According to the findings, 76% of patients in the target group showed some positive response to reboxetine compared with 24% in the control group (p < 0.01). The mean total score of SANS in the reboxetine group decreased significantly from 79.94 ± 1.20 to 74.23 ± 4.07 (p < 0.0001) at the end of the study; such an improvement was not significant in the placebo group with a decrease from 80.42 ± 2.46 to 79.08 ± 5.83 (p < 0.29). Changes of SAPS were insignificant in both groups. Effect size analysis for changes of SANS at the end of assessment indicated a large improvement with reboxetine (Cohen’s d = 2.91). Conclusion: Reboxetine, as an adjuvant to haloperidol, may have a helpful effect on the deficit syndrome of schizophrenia. PMID

  19. Norepinephrine and Epinephrine Enhanced the Infectivity of Enterovirus 71

    PubMed Central

    Liao, Yu-Ting; Wang, Shih-Min; Wang, Jen-Ren; Yu, Chun-Keung; Liu, Ching-Chuan

    2015-01-01

    Background Enterovirus 71 (EV71) infections may be associated with neurological complications, including brainstem encephalitis (BE). Severe EV71 BE may be complicated with autonomic nervous system (ANS) dysregulation and/or pulmonary edema (PE). ANS dysregulation is related to the overactivation of the sympathetic nervous system, which results from catecholamine release. Objective The aims of this study were to explore the effects of catecholamines on severe EV71 infection and to investigate the changes in the percentages of EV71-infected cells, virus titer, and cytokine production on the involvement of catecholamines. Study Design Plasma levels of norepinephrine (NE) and epinephrine (EP) in EV71-infected patients were measured using an enzyme-linked immunoassay. The expression of adrenergic receptors (ADRs) on RD, A549, SK-N-SH, THP-1, Jurkat and human peripheral blood mononuclear cells (hPBMCs) were detected using flow cytometry. The percentages of EV71-infected cells, virus titer, and cytokine production were investigated after treatment with NE and EP. Results The plasma levels of NE and EP were significantly higher in EV71-infected patients with ANS dysregulation and PE than in controls. Both α1A- and β2-ADRs were expressed on A549, RD, SK-N-SH, HL-60, THP-1, Jurkat cells and hPBMCs. NE treatment elevated the percentages of EV71-infected cells to 62.9% and 22.7% in THP-1 and Jurkat cells, respectively. Via treatment with EP, the percentages of EV71-infected cells were increased to 64.6% and 26.9% in THP-1 and Jurkat cells. The percentage of EV71-infected cells increased upon NE or EP treatment while the α- and β-blockers reduced the percentages of EV71-infected cells with NE or EP treatment. At least two-fold increase in virus titer was observed in EV71-infected A549, SK-N-SH and hPBMCs after treatment with NE or EP. IL-6 production was enhanced in EV71-infected hPBMCs at a concentration of 102 pg/mL NE. Conclusion The plasma levels of NE and EP elevated

  20. Norepinephrine triggers Ca2+-dependent exocytosis of 5-hydroxytryptamine from rat pinealocytes in culture.

    PubMed

    Yamada, Hiroshi; Hayashi, Mitsuko; Uehara, Shunsuke; Kinoshita, Mika; Muroyama, Akiko; Watanabe, Masami; Takei, Koji; Moriyama, Yoshinori

    2002-05-01

    5-hydroxytryptamine (5-HT) is a precursor and a putative modulator for melatonin synthesis in mammalian pinealocytes. 5-HT is present in organelles distinct from l-glutamate-containing synaptic-like microvesicles as well as in the cytoplasm of pinealocytes, and is secreted upon stimulation by norepinephrine (NE) to enhance serotonin N-acetyltransferase activity via the 5-HT2 receptor. However, the mechanism underlying the secretion of 5-HT from pinealocytes is unknown. In this study, we show that NE-evoked release of 5-HT is largely dependent on Ca2+ in rat pinealocytes in culture. Omission of Ca2+ from the medium and incubation of pineal cells with EGTA-tetraacetoxymethyl-ester inhibited by 59 and 97% the NE-evoked 5-HT release, respectively. Phenylephrine also triggered the Ca2+-dependent release of 5-HT, which was blocked by phentolamine, an alpha antagonist, but not by propranolol, a beta antagonist. Botulinum neurotoxin type E cleaved 25 kDa synaptosomal-associated protein and inhibited by 50% of the NE-evoked 5-HT release. Bafilomycin A1, an inhibitor of vacuolar H+-ATPase, and reserpine and tetrabenazine, inhibitors of vesicular monoamine transporter, all decreased the storage of vesicular 5-HT followed by inhibition of the NE-evoked 5-HT release. Agents that trigger L-glutamte exocytosis such as acetylcholine did not trigger any Ca2+-dependent 5-HT release. Vice versa neither NE nor phenylephrine caused synaptic-like microvesicle-mediated l-glutamate exocytosis. These results indicated that upon stimulation of a adrenoceptors pinealocytes secrete 5-HT through a Ca2+-dependent exocytotic mechanism, which is distinct from the exocytosis of synaptic-like microvesicles. PMID:12065661

  1. Selective Serotonin-norepinephrine Re-uptake Inhibition Limits Renovas-cular-hypertension Induced Cognitive Impairment, Endothelial Dysfunction, and Oxidative Stress Injury.

    PubMed

    Singh, Prabhat; Sharma, Bhupesh

    2016-01-01

    Hypertension has been reported to induce cognitive decline and dementia of vascular origin. Serotonin- norepinephrine reuptake transporters take part in the control of inflammation, cognitive functions, motivational acts and deterioration of neurons. This study was carried out to examine the effect of venlafaxine; a specific serotonin-norepinephrine reuptake inhibitor (SNRI), in two-kidney-one-clip-2K1C (renovascular hypertension) provoked vascular dementia (VaD) in albino rats. 2K1C technique was performed to provoke renovascular-hypertension in adult male albino Wistar rats. Learning and memory were assessed by using the elevated plus maze and Morris water maze. Mean arterial blood pressure- MABP, as well as endothelial function, were assessed by means of BIOPAC system. Serum nitrosative stress (nitrite/ nitrate), aortic superoxide anion, brain oxidative stress, inflammation, cholinergic dysfunction and brain damage (2,3,5-triphenylterazolium chloride staining) were also assessed. 2K1C has increased MABP, endothelial dysfunction as well as learning and memory impairments. 2K1C method has increased serum nitrosative stress (reduced nitrite/nitrate level), oxidative stress (increased brain thiobarbituric acid reactive species and aortic superoxide anion content along with decreased levels of brain superoxide dismutase, glutathione, and catalase), brain inflammation (increased myeloperoxidase), cholinergic dysfunction (increased acetylcholinesterase activity) and brain damage. Treatment with venlafaxine considerably attenuated renovascular-hypertension induced cognition impairment, endothelial dysfunction, serum nitrosative stress, brain and aortic oxidative stress, cholinergic function, inflammation as well as cerebral damage. The finding of this study indicates that specific modulation of the serotonin-norepinephrine transporter perhaps regarded as potential interventions for the management of renovascular hypertension provoked VaD. PMID:26915517

  2. Prejunctional inhibition of norepinephrine release caused by acetylcholine in the human saphenous vein

    SciTech Connect

    Rorie, D.K.; Rusch, N.J.; Shepherd, J.T.; Vanhoutte, P.M.; Tyce, G.M.

    1981-08-01

    We performed experiments to determine whether or not acetylcholine exerts a prejunctional inhibitory effect on adrenergic neurotransmission in the human blood vessel wall. Rings of human greater saphenous veins were prepared 2 to 15 hours after death and mounted for isometric tension recording in organ chambers filled with Krebs-Ringer solution. Acetylcholine depressed contractile responses to electric activation of the sympathetic nerve endings significantly more than those to exogenous norepinephrine; the relaxations caused by the cholinergic transmitter were antagonized by atropine. Helical strips were incubated with (/sub 3/H)norepinephrine and mounted for superfusion. Electric stimulation augmented the fractional release of labeled norepinephrine. Acetylcholine caused a depression of the evoked /sub 3/H release which was antagonized by atropine but not by hexamethonium. These experiments demonstrate that, as in animal cutaneous veins, there are prejunctional inhibitory muscarinic receptors on the adrenergic nerve endings in the human saphenous vein. By contrast, the human vein also contains postjunctional inhibitory muscarinic receptors.

  3. Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine.

    PubMed

    Janowsky, Aaron; Tosh, Dilip K; Eshleman, Amy J; Jacobson, Kenneth A

    2016-04-01

    Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760% of control) or inhibited [(125)I] methyl (1R,2S,3S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (RTI-55) binding at the human dopamine (DA) transporter (DAT) and inhibited DA uptake. Several nucleosides also enhanced [(3)H]mazindol [(±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol] binding to the DAT. The combination of binding enhancement and functional inhibition suggests possible allosteric interaction with the tropanes. The structure-activity relationship of this novel class of DAT ligands was explored: small N(6)-substition (methyl or ethyl) was favored, while the N1 of the adenine ring was essential. Effective terminal aryl groups include thien-2-yl (compounds 9 and 16), with EC50 values of 35.1 and 9.1 nM, respectively, in [(125)I]RTI-55 binding enhancement, and 3,4-difluorophenyl as in the most potent DA uptake inhibitor (compound 6) with an IC50 value of 92 nM (3-fold more potent than cocaine), but not nitrogen heterocycles. Several compounds inhibited or enhanced binding at the norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited function in the micromolar range; truncation at the 4'-position in compound 23 allowed for weak inhibition of the SERT. We have not yet eliminated adenosine receptor affinity from this class of DAT modulators, but we identified modifications that remove DAT inhibition as an off-target effect of potent adenosine receptor agonists. Thus, we have identified a new class of allosteric DAT ligands, rigidified adenosine derivatives, and explored their initial structural requirements. They display a very atypical pharmacological profile, i.e., either enhancement by increasing affinity or inhibition of radioligand binding at the DAT, and in some cases the NET and SERT, and inhibition of neurotransmitter

  4. Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine

    PubMed Central

    Tosh, Dilip K.; Eshleman, Amy J.; Jacobson, Kenneth A.

    2016-01-01

    Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760% of control) or inhibited [125I] methyl (1R,2S,3S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (RTI-55) binding at the human dopamine (DA) transporter (DAT) and inhibited DA uptake. Several nucleosides also enhanced [3H]mazindol [(±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol] binding to the DAT. The combination of binding enhancement and functional inhibition suggests possible allosteric interaction with the tropanes. The structure-activity relationship of this novel class of DAT ligands was explored: small N6-substition (methyl or ethyl) was favored, while the N1 of the adenine ring was essential. Effective terminal aryl groups include thien-2-yl (compounds 9 and 16), with EC50 values of 35.1 and 9.1 nM, respectively, in [125I]RTI-55 binding enhancement, and 3,4-difluorophenyl as in the most potent DA uptake inhibitor (compound 6) with an IC50 value of 92 nM (3-fold more potent than cocaine), but not nitrogen heterocycles. Several compounds inhibited or enhanced binding at the norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited function in the micromolar range; truncation at the 4′-position in compound 23 allowed for weak inhibition of the SERT. We have not yet eliminated adenosine receptor affinity from this class of DAT modulators, but we identified modifications that remove DAT inhibition as an off-target effect of potent adenosine receptor agonists. Thus, we have identified a new class of allosteric DAT ligands, rigidified adenosine derivatives, and explored their initial structural requirements. They display a very atypical pharmacological profile, i.e., either enhancement by increasing affinity or inhibition of radioligand binding at the DAT, and in some cases the NET and SERT, and inhibition of neurotransmitter uptake

  5. Reduced naphthylphthalamic acid binding in the tir3 mutant of Arabidopsis is associated with a reduction in polar auxin transport and diverse morphological defects

    NASA Technical Reports Server (NTRS)

    Ruegger, M.; Dewey, E.; Hobbie, L.; Brown, D.; Bernasconi, P.; Turner, J.; Muday, G.; Estelle, M.

    1997-01-01

    Polar auxin transport plays a key role in the regulation of plant growth and development. To identify genes involved in this process, we have developed a genetic procedure to screen for mutants of Arabidopsis that are altered in their response to auxin transport inhibitors. We recovered a total of 16 independent mutants that defined seven genes, called TRANSPORT INHIBITOR RESPONSE (TIR) genes. Recessive mutations in one of these genes, TIR3, result in altered responses to transport inhibitors, a reduction in polar auxin transport, and a variety of morphological defects that can be ascribed to changes in indole-3-acetic acid distribution. Most dramatically, tir3 seedlings are strongly deficient in lateral root production, a process that is known to depend on polar auxin transport from the shoot into the root. In addition, tir3 plants display a reduction in apical dominance as well as decreased elongation of siliques, pedicels, roots, and the inflorescence. Biochemical studies indicate that tir3 plants have a reduced number of N-1-naphthylphthalamic (NPA) binding sites, suggesting that the TIR3 gene is required for expression, localization, or stabilization of the NPA binding protein (NBP). Alternatively, the TIR3 gene may encode the NBP. Because the tir3 mutants have a substantial defect in NPA binding, their phenotype provides genetic evidence for a role for the NBP in plant growth and development.

  6. Reduced naphthylphthalamic acid binding in the tir3 mutant of Arabidopsis is associated with a reduction in polar auxin transport and diverse morphological defects.

    PubMed Central

    Ruegger, M; Dewey, E; Hobbie, L; Brown, D; Bernasconi, P; Turner, J; Muday, G; Estelle, M

    1997-01-01

    Polar auxin transport plays a key role in the regulation of plant growth and development. To identify genes involved in this process, we have developed a genetic procedure to screen for mutants of Arabidopsis that are altered in their response to auxin transport inhibitors. We recovered a total of 16 independent mutants that defined seven genes, called TRANSPORT INHIBITOR RESPONSE (TIR) genes. Recessive mutations in one of these genes, TIR3, result in altered responses to transport inhibitors, a reduction in polar auxin transport, and a variety of morphological defects that can be ascribed to changes in indole-3-acetic acid distribution. Most dramatically, tir3 seedlings are strongly deficient in lateral root production, a process that is known to depend on polar auxin transport from the shoot into the root. In addition, tir3 plants display a reduction in apical dominance as well as decreased elongation of siliques, pedicels, roots, and the inflorescence. Biochemical studies indicate that tir3 plants have a reduced number of N-1-naphthylphthalamic (NPA) binding sites, suggesting that the TIR3 gene is required for expression, localization, or stabilization of the NPA binding protein (NBP). Alternatively, the TIR3 gene may encode the NBP. Because the tir3 mutants have a substantial defect in NPA binding, their phenotype provides genetic evidence for a role for the NBP in plant growth and development. PMID:9165751

  7. β3-adrenoceptors inhibit stimulated norepinephrine release in spontaneously hypertensive rats

    PubMed Central

    Berg, Torill

    2014-01-01

    Here, the influence of β3-adrenoceptors on catecholamine release in normotensive and spontaneously hypertensive rats was analyzed. Blood pressure was recorded through a femoral artery catheter, and cardiac output by ascending aorta flow. Time from onset of flow to maximum rise in flow indicated inotropy. Total peripheral vascular resistance (TPR) was calculated. Norepinephrine release was stimulated with tyramine, which allowed presynaptic release-control to be reflected as changes in the plasma norepinephrine concentration. β3-adrenoceptor agonist (BRL37344) reduced baseline vascular resistance, the tyramine-stimulated norepinephrine overflow and the positive inotropic response to tyramine in hypertensive but not normotensive rats. β3-adrenoceptor antagonist (SR59230A) reduced tyramine-stimulated norepinephrine release in both strains and the secretion of epinephrine in hypertensive rats. SR59230A reduced tyramine-induced tachycardia in normotensive rats, and prevented down-regulation of the tyramine-induced rise in resistance in hypertensive rats. It was concluded that the contradicting results obtained by agonist vs. antagonist, could be explained by their interaction with two different β-adrenoceptors: The BRL37344-dependent inhibition of stimulated norepinephrine release and positive inotropic response to tyramine was compatible with stimulation of β3-adrenoceptor coupling to inhibitory G-protein. This was observed only in hypertensive rats during stimulated, high levels of circulating catecholamines. The effect of BRL37344 on baseline vascular resistance was compatible with activation of β3-adrenoceptor coupling to endothelial nitric oxide synthase. The inhibitory effect of SR59230A on tyramine-stimulated norepinephrine release in both strains, the increased TPR-response to tyramine in hypertensive rats and tachycardia in normotensive rats may result from inhibition of the low-affinity-state β1-adrenoceptor, also known as the putative β4-adrenoceptor

  8. Transportation.

    ERIC Educational Resources Information Center

    Crank, Ron

    This instructional unit is one of 10 developed by students on various energy-related areas that deals specifically with transportation and energy use. Its objective is for the student to be able to discuss the implication of energy usage as it applies to the area of transportation. Some topics covered are efficiencies of various transportation…

  9. Genetic and chemical reductions in protein phosphatase activity alter auxin transport, gravity response, and lateral root growth

    NASA Technical Reports Server (NTRS)

    Rashotte, A. M.; DeLong, A.; Muday, G. K.; Brown, C. S. (Principal Investigator)

    2001-01-01

    Auxin transport is required for important growth and developmental processes in plants, including gravity response and lateral root growth. Several lines of evidence suggest that reversible protein phosphorylation regulates auxin transport. Arabidopsis rcn1 mutant seedlings exhibit reduced protein phosphatase 2A activity and defects in differential cell elongation. Here we report that reduced phosphatase activity alters auxin transport and dependent physiological processes in the seedling root. Root basipetal transport was increased in rcn1 or phosphatase inhibitor-treated seedlings but showed normal sensitivity to the auxin transport inhibitor naphthylphthalamic acid (NPA). Phosphatase inhibition reduced root gravity response and delayed the establishment of differential auxin-induced gene expression across a gravity-stimulated root tip. An NPA treatment that reduced basipetal transport in rcn1 and cantharidin-treated wild-type plants also restored a normal gravity response and asymmetric auxin-induced gene expression, indicating that increased basipetal auxin transport impedes gravitropism. Increased auxin transport in rcn1 or phosphatase inhibitor-treated seedlings did not require the AGR1/EIR1/PIN2/WAV6 or AUX1 gene products. In contrast to basipetal transport, root acropetal transport was normal in phosphatase-inhibited seedlings in the absence of NPA, although it showed reduced NPA sensitivity. Lateral root growth also exhibited reduced NPA sensitivity in rcn1 seedlings, consistent with acropetal transport controlling lateral root growth. These results support the role of protein phosphorylation in regulating auxin transport and suggest that the acropetal and basipetal auxin transport streams are differentially regulated.

  10. Safflower extracts functionally regulate monoamine transporters.

    PubMed

    Zhao, Gang; Zheng, Xiang-Wei; Gai, Yue; Chu, Wen-Jing; Qin, Guo-Wei; Guo, Li-He

    2009-07-01

    Safflower (HH), the dry flower of Carthamus tinctorius L., has long been used to empirically treat neuropsychological disorders such as stroke and major depression in traditional Chinese medicine, and recently been proven effective for regulating levels of dopamine and serotonin in new-born rat brain. The present study assessed whether HH would be bioactive for functionally regulating monoamine transporters using in vitro drug-screening cell lines. Our current results showed that all solvent-extracted HH fractions, in different degrees, markedly increased both dopamine uptake by Chinese hamster ovary (CHO) cells stably expressing dopamine transporter (DAT) and norepinephrine uptake by CHO cells expressing norepinephrine transporter (NET), and also showed that chloroform (HC), ethyl acetate (HE), and n-butyl alcohol extract strikingly depressed serotonin uptake by CHO cells expressing serotonin transporter (SERT); wherein, the potencies of ethanol extract, HC, HE, and aqueous extract to up-regulate dopamine/norepinephrine uptake and potency of HE to inhibit serotonin uptake were relatively stronger. Further investigation revealed that the enhancement of dopamine/norepinephrine uptake by HC and HE was dependent of DAT/NET activity, and the HE-induced inhibition of serotonin uptake was typical of competition. Thus, HH extracts are novel monoamine transporter modulators functioning as DAT/NET activators and/or SERT inhibitors, and would likely improve neuropsychological disorders through regulating monoamine-transporter activity. PMID:19527825

  11. A HTAP Multi-Model Assessment of the Influence of Regional Anthropogenic Emission Reductions on Aerosol Direct Radiative Forcing and the Role of Intercontinental Transport

    NASA Technical Reports Server (NTRS)

    Yu, Hongbin; Chin, Mian; West, J. Jason; Atherton, Cynthia S.; Bellouin, Nicolas; Bergmann, Dan; Bey, Isabelle; Bian, Huisheng; Diehl, Thomas; Forberth, Gerd; Hess, Peter; Schulz, Michael; Shindell, Drew; Takemura, Toshihiko; Tan, Qian

    2012-01-01

    In this study, we assess changes of aerosol optical depth (AOD) and direct radiative forcing (DRF) in response to the reduction of anthropogenic emissions in four major pollution regions in the northern hemisphere by using results from 10 global chemical transport models in the framework of the Hemispheric Transport of Air Pollution (HTAP). The multi-model results show that on average, a 20% reduction of anthropogenic emissions in North America, Europe, East Asia and South Asia lowers the global mean AOD and DRF by about 9%, 4%, and 10% for sulfate, organic matter, and black carbon aerosol, respectively. The impacts of the regional emission reductions on AOD and DRF extend well beyond the source regions because of intercontinental transport. On an annual basis, intercontinental transport accounts for 10-30% of the overall AOD and DRF in a receptor region, with domestic emissions accounting for the remainder, depending on regions and species. While South Asia is most influenced by import of sulfate aerosol from Europe, North America is most influenced by import of black carbon from East Asia. Results show a large spread among models, highlighting the need to improve aerosol processes in models and evaluate and constrain models with observations.

  12. Effects of vasopressinergic receptor agonists on sublingual microcirculation in norepinephrine-dependent septic shock

    PubMed Central

    2011-01-01

    Introduction The present study was designed to determine the effects of continuously infused norepinephrine (NE) plus (1) terlipressin (TP) or (2) arginine vasopressin (AVP) or (3) placebo on sublingual microcirculation in septic shock patients. The primary study end point was a difference of ≥ 20% in the microvascular flow index of small vessels among groups. Methods The design of the study was a prospective, randomized, double-blind clinical trial. NE was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg after establishment of normovolemia in 60 septic shock patients. Thereafter patients (n = 20 per group) were randomized to receive continuous infusions of either TP (1 μg/kg/hour), AVP (0.04 U/minute) or placebo (isotonic saline). In all groups, open-label NE was adjusted to maintain MAP within threshold values if needed. The sublingual microcirculatory blood flow of small vessels was assessed by sidestream dark-field imaging. All measurements, including data from right heart catheterization and norepinephrine requirements, were obtained at baseline and 6 hours after randomization. Results TP and AVP decreased NE requirements at the end of the 6-hour study period. The data are medians (25th and 75th interquartile ranges (IQRs)): 0.57 μg/kg/minute (0.29 to 1.04) vs. 0.16 μg/kg/minute (0.03 to 0.37) for TP and 0.40 μg/kg/minute (0.20 to 1.05) vs. 0.23 μg/kg/minute (0.03 to 0.77) for AVP, with statistical significance of P < 0.05 vs. baseline and vs. placebo. There were no differences in sublingual microcirculatory variables, systemic hemodynamics, oxygen transport and acid-base homeostasis among the three study groups during the entire observation period. The proportions of perfused vessels increased in relation to baseline within all study groups, and there were no significant differences between groups. The specific data were as follows (median (IQR)): 9.7% (2.6 to 19.8) for TP, 8.9% (0.0 to 17.8) for AVP, and 6.9% (3.5 to 10.1) for

  13. Diffusion algorithms and data reduction routine for onsite real-time launch predictions for the transport of Delta-Thor exhaust effluents

    NASA Technical Reports Server (NTRS)

    Stephens, J. B.

    1976-01-01

    The National Aeronautics and Space Administration/Marshall Space Flight Center multilayer diffusion algorithms have been specialized for the prediction of the surface impact for the dispersive transport of the exhaust effluents from the launch of a Delta-Thor vehicle. This specialization permits these transport predictions to be made at the launch range in real time so that the effluent monitoring teams can optimize their monitoring grids. Basically, the data reduction routine requires only the meteorology profiles for the thermodynamics and kinematics of the atmosphere as an input. These profiles are graphed along with the resulting exhaust cloud rise history, the centerline concentrations and dosages, and the hydrogen chloride isopleths.

  14. Perilipin regulates the thermogenic actions of norepinephrine in brown adipose tissue

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In response to cold, norepinephrine (NE)-induced triacylglycerol hydrolysis (lipolysis) in adipocytes of brown adipose tissue (BAT) provides fatty acid substrates to mitochondria for heat generation (adaptive thermogenesis). NE-induced lipolysis is mediated by protein kinase A (PKA)-dependent phosp...

  15. Norepinephrine Drives Persistent Activity in Prefrontal Cortex via Synergistic α1 and α2 Adrenoceptors

    PubMed Central

    Jego, Sonia; Adamantidis, Antoine; Séguéla, Philippe

    2013-01-01

    Optimal norepinephrine levels in the prefrontal cortex (PFC) increase delay-related firing and enhance working memory, whereas stress-related or pathologically high levels of norepinephrine are believed to inhibit working memory via α1 adrenoceptors. However, it has been shown that activation of Gq-coupled and phospholipase C-linked receptors can induce persistent firing, a cellular correlate of working memory, in cortical pyramidal neurons. Therefore, despite its importance in stress and cognition, the exact role of norepinephrine in modulating PFC activity remains elusive. Using electrophysiology and optogenetics, we report here that norepinephrine induces persistent firing in pyramidal neurons of the PFC independent of recurrent fast synaptic excitation. This persistent excitatory effect involves presynaptic α1 adrenoceptors facilitating glutamate release and subsequent activation of postsynaptic mGluR5 receptors, and is enhanced by postsynaptic α2 adrenoceptors inhibiting HCN channel activity. Activation of α2 adrenoceptors or inhibition of HCN channels also enhances cholinergic persistent responses in pyramidal neurons, providing a mechanism of crosstalk between noradrenergic and cholinergic inputs. The present study describes a novel cellular basis for the noradrenergic control of cortical information processing and supports a synergistic combination of intrinsic and network mechanisms for the expression of mnemonic properties in pyramidal neurons. PMID:23785477

  16. Intrahippocampal Infusions of Anisomycin Produce Amnesia: Contribution of Increased Release of Norepinephrine, Dopamine, and Acetylcholine

    ERIC Educational Resources Information Center

    Qi, Zhenghan; Gold, Paul E.

    2009-01-01

    Intra-amygdala injections of anisomycin produce large increases in the release of norepinephrine (NE), dopamine (DA), and serotonin in the amygdala. Pretreatment with intra-amygdala injections of the beta-adrenergic receptor antagonist propranolol attenuates anisomycin-induced amnesia without reversing the inhibition of protein synthesis, and…

  17. Norepinephrine Triggers Metaplasticity of LTP by Increasing Translation of Specific mRNAs

    ERIC Educational Resources Information Center

    Maity, Sabyasachi; Rah, Sean; Sonenberg, Nahum; Gkogkas, Christos G.; Nguyen, Peter V.

    2015-01-01

    Norepinephrine (NE) is a key modulator of synaptic plasticity in the hippocampus, a brain structure crucially involved in memory formation. NE boosts synaptic plasticity mostly through initiation of signaling cascades downstream from beta (ß)-adrenergic receptors (ß-ARs). Previous studies demonstrated that a ß-adrenergic receptor agonist,…

  18. NOREPINEPHRINE AND EPIDERMAL GROWTH FACTOR: DYNAMICS OF THEIR INTERACTION IN THE STIMULATION OF HEPATOCYTE DNA SYNTHESIS

    EPA Science Inventory

    Primary cultures of adult rat hepatocytes are stimulated to enter DNA synthesis by norepinephrine (NE). This stimulation is maximal if the hepatocytes are incubated with NE for more than 12 hr, beginning no later than 2-4 hr after the cells are first plated. After 24 hr in cultur...

  19. Escherichia coli O157:H7 gene expression in the presence of the catecholamine norepinephrine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To examine the effects of the catecholamine norepinephrine (NE) on the expression of virulence factors in Escherichia coli O157:H7, the clinical-type isolate EDL933 (ATCC 43895) was grown in the presence or absence of NE. An in-vitro culture system made up of low initial innocula and a serum-SAPI ba...

  20. Low dose naltrexone administration in morphine dependent rats attenuates withdrawal-induced norepinephrine efflux in forebrain

    PubMed Central

    Van Bockstaele, Elisabeth J.; Qian, Yaping; Sterling, Robert C.; Page, Michelle E.

    2009-01-01

    The administration of low dose opioid antagonists has been explored as a potential means of detoxification in opiate dependence. Previous results from our laboratory have shown that concurrent administration of low dose naltrexone in the drinking water of rats implanted with subcutaneous morphine pellets attenuates behavioral and biochemical signs of withdrawal in brainstem noradrenergic nuclei. Noradrenergic projections originating from the nucleus tractus solitarius (NTS) and the locus coeruleus (LC) have previously been shown to be important neural substrates involved in the somatic expression of opiate withdrawal. The hypothesis that low dose naltrexone treatment attenuates noradrenergic hyperactivity typically associated with opiate withdrawal was examined in the present study by assessing norepinephrine tissue content and norepinephrine efflux using in vivo microdialysis coupled to high performance liquid chromatography (HPLC) with electrochemical detection (ED). The frontal cortex (FC), amygdala, bed nucleus of the stria terminalis (BNST) and cerebellum were analyzed for tissue content of norepinephrine following withdrawal in morphine dependent rats. Naltrexone precipitated withdrawal elicited a significant decrease in tissue content of norepinephrine in the BNST and amygdala. This decrease was significantly attenuated in the BNST of rats that received low dose naltrexone pretreatment compared to controls. No significant difference was observed in the other brain regions examined. In a separate group of rats, norepinephrine efflux was assessed with in vivo microdialysis in the BNST or the FC of morphine dependent rats or placebo treated rats subjected to naltrexone-precipitated withdrawal that received either naltrexone in their drinking water (5 mg/L) or unadulterated water. Following baseline dialysate collection, withdrawal was precipitated by injection of naltrexone and sample collection continued for an additional four hours. At the end of the

  1. Antidepressants that inhibit both serotonin and norepinephrine reuptake impair long-term potentiation in hippocampus

    PubMed Central

    Cooke, Jennifer D.; Cavender, Hannah M.; Lima, Hope K.; Grover, Lawrence M.

    2014-01-01

    Rationale Monoamine reuptake inhibitors can stimulate expression of brain-derived neurotrophic factor (BDNF) and alter long-term potentiation (LTP), a widely used model for the synaptic mechanisms that underlie memory formation. BDNF expression is up-regulated during LTP, and BDNF in turn positively modulates LTP. Previously, we found that treatment with venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), but not citalopram, a selective serotonin reuptake inhibitor (SSRI) reduced LTP in hippocampal area CA1 without changing hippocampal BDNF protein expression. Objectives We tested the hypothesis that combined serotonin and norepinephrine reuptake inhibition is necessary for LTP impairment, and we reexamined the potential role of BNDF by testing for region-specific changes in areas CA1, CA3 and dentate gyrus. We also tested whether early events in the LTP signaling pathway were altered to impair LTP. Methods Animals were treated for 21 days with venlafaxine, imipramine, fluoxetine, or maprotiline. In vitro hippocampal slices were used for electrophysiological measurements. Protein expression was measured by enzyme-linked immunosorbent assay (ELISA) and western blotting. Results LTP was impaired only following treatment with combined serotonin and norepinephrine reuptake inhibitors (venlafaxine, imipramine) but not with selective serotonin (fluoxetine) or norepinephrine (maprotiline) reuptake inhibitors. BDNF protein expression was not altered by venlafaxine or imipramine treatment, nor were postsynaptic depolarization during LTP inducing stimulation or synaptic membrane NMDA receptor subunit expression affected. Conclusions LTP is impaired by chronic treatment with antidepressant that inhibit both serotonin and norepinephrine reuptake; this impairment results from changes that are downstream of postsynaptic depolarization and calcium-influx. PMID:24781518

  2. Muscarinic inhibition of cardiac norepinephrine and neuropeptide Y release during ischemia and reperfusion.

    PubMed

    Haunstetter, A; Haass, M; Yi, X; Krüger, C; Kübler, W

    1994-12-01

    It was the aim of the present study to characterize the modulatory effect of muscarinic agonists on the overflow of norepinephrine and neuropeptide Y (NPY) from the in situ perfused guinea pig heart, induced by electrical stimulation of the left stellate ganglion (6 Hz, 5 V, 1 min). The muscarinic agonists oxotremorine (0.01-1 microM) and carbachol (0.1-10 microM) reduced norepinephrine and NPY overflow in a concentration-dependent manner to approximately 30% of control. The inhibitory effect of carbachol was antagonized by the unspecific muscarinic antagonist atropine (1 microM) but not by the nicotinic antagonist hexamethonium (100 microM). The M2-specific antagonist AF-DX-116BS was 25 times more potent than the M1-specific antagonist pirenzepine in antagonizing the inhibitory effect of carbachol [50% inhibitory concentration (IC50) = 0.2 microM for AF-DX-116BS; IC50 = 5.0 microM for pirenzepine]. These findings indicate that presynaptic muscarinic inhibition of stimulated norepinephrine and NPY release from the guinea pig heart is mediated mainly by activation of M2 receptors. As early as 2 min after stop-flow ischemia, the inhibitory effect of carbachol (10 microM) on the stimulation-evoked overflow of norepinephrine and NPY was lost. On reperfusion with oxygenated buffer after 10 min of stop-flow ischemia the inhibitory effect of carbachol (10 microM) on stimulation-induced norepinephrine and NPY overflow recovered within 3 min. PMID:7810765

  3. Host stress hormone norepinephrine stimulates pneumococcal growth, biofilm formation and virulence gene expression

    PubMed Central

    2014-01-01

    Background Host signals are being shown to have a major impact on the bacterial phenotype. One of them is the endogenously produced catecholamine stress hormones, which are also used therapeutically as inotropes. Recent work form our laboratories have found that stress hormones can markedly increase bacterial growth and virulence. This report reveals that Streptococcus pneumoniae, a commensal that can also be a major cause of community acquired and nosocomial pneumonia, is highly inotrope responsive. Therapeutic levels of the stress hormone norepinephrine increased pneumococcal growth via a mechanism involving provision of iron from serum-transferrin and inotrope uptake, as well as enhancing expression of key genes in central metabolism and virulence. Collectively, our data suggests that Streptococcus pneumoniae recognises host stress as an environmental cue to initiate growth and pathogenic processes. Results Effects of a clinically attainable concentration of norepinephrine on S. pneumoniae pathogenicity were explored using in vitro growth and virulence assays, and RT-PCR gene expression profiling of genes involved in metabolism and virulence. We found that norepinephrine was a potent stimulator of growth, via a mechanism involving norepinephrine-delivery of transferrin-iron and internalisation of the inotrope. Stress hormone exposure also markedly increased biofilm formation. Importantly, gene profiling showed that norepinephrine significantly enhanced expression of genes involved in central metabolism and host colonisation. Analysis of the response of the pneumococcal pspA and pspC mutants to the stress hormone showed them to have a central involvement in the catecholamine response mechanism. Conclusions Collectively, our evidence suggests that the pneumococcus has mechanisms to recognise and process host stress hormones to augment its virulence properties. The ability to respond to host stress signals may be important for the pneumococcal transition from

  4. Deciphering the Electron Transport Pathway for Graphene Oxide Reduction by Shewanella oneidensis MR-1 ▿†‡

    PubMed Central

    Jiao, Yongqin; Qian, Fang; Li, Yat; Wang, Gongming; Saltikov, Chad W.; Gralnick, Jeffrey A.

    2011-01-01

    We determined that graphene oxide reduction by Shewanella oneidensis MR-1 requires the Mtr respiratory pathway by analyzing a range of mutants lacking these proteins. Electron shuttling compounds increased the graphene oxide reduction rate 3- to 5-fold. These results may help facilitate the use of bacteria for large-scale graphene production. PMID:21602337

  5. Localized Hamiltonian control and its application to the reduction of chaotic transport of test particles in a Tokamak's plasma

    SciTech Connect

    Tronko, Natalia; Vittot, Michel

    2008-11-01

    Localized hamiltonian control theory gives the possibility to reduce the radial chaotic transport of plasma test-particles into the Tokamak, by creating the Internal Transport Barrier(ITB). We prove that the control term is of quadratic order in the perturbation of Hamiltonian. We apply this method to a phenomenological model of electric potential in magnetized plasma.

  6. Effects of exposure to simulated microgravity on neuronal catecholamine release and blood pressure responses to norepinephrine and angiotensin

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Ludwig, D. A.; Gray, B. D.; Vernikos, J.

    1998-01-01

    We tested the hypothesis that exposure to microgravity reduces the neuronal release of catecholamines and blood pressure responses to norepinephrine and angiotensin. Eight men underwent 30 days of 6 degrees head-down tilt (HDT) bedrest to simulate exposure to microgravity. Plasma norepinephrine and mean arterial blood pressure (MAP) were measured before and after a cold pressor test (CPT) and graded norepinephrine infusion (8, 16 and 32 ng/kg/min) on day 6 of a baseline control period (C6) and on days 14 and 27 of HDT. MAP and plasma angiotensin II (Ang-II) were measured during graded Ang-II infusion (1, 2 and 4 ng/kg/min) on C8 and days 16 and 29 of HDT. Baseline total circulating norepinephrine was reduced from 1017ng during the baseline control period to 610 ng at day 14 and 673ng at day 27 of HDT, confirming a hypoadrenergic state. An elevation of norepinephrine (+178 ng) to the CPT during the baseline control period was eliminated by HDT days 14 and 27. During norepinephrine infusion, similar elevations in plasma norepinephrine (7.7 pg/ml/ng/kg/min) caused similar elevations in MAP (0.12 mmHg/ng/kg/min) across all test days. Ang-II infusion produced higher levels of plasma Ang-II during HDT (47.3 pg/ml) than during baseline control (35.5 pg/ml), while producing similar corresponding elevations in blood pressure. While vascular responsiveness to norepinephrine appears unaffected, impaired neuronal release of norepinephrine and reduced vascular responsiveness to Ang-II might contribute to the lessened capacity to vasoconstrict after spaceflight. The time course of alterations indicates effects that occur within two weeks of exposure.

  7. Effect of spinal monoaminergic neuronal system dysfunction on pain threshold in rats, and the analgesic effect of serotonin and norepinephrine reuptake inhibitors.

    PubMed

    Tamano, Ryuta; Ishida, Mitsuhiro; Asaki, Toshiyuki; Hasegawa, Minoru; Shinohara, Shunji

    2016-02-26

    Dysfunction in the central serotonin (5-HT) and norepinephrine (NE) systems cause depression and pain. Descending spinal pain modulatory pathways are important in the analgesic mechanisms of antidepressants, particularly serotonin and norepinephrine reuptake inhibitors (SNRIs). While many non-clinical studies have demonstrated the roles of central monoaminergic systems in pain, there is little evidence to illuminate the direct contribution of spinal descending pain modulatory systems independently of depressive-like behavior. To examine the effects of dysfunction of spinal monoaminergic systems on pain sensitivity, we established a rat chronic pain model by administering lumbar-intrathecal reserpine to minimize its influence on brain. Lumbar-intrathecal reserpine evoked persistent mechanical hypersensitivity and corresponding reductions in spinal 5-HT and NE concentrations (from 767.2 to 241.6ng/g and from 455.9 to 41.7ng/g, respectively after reserpine 30nmol). Lumbar-intrathecal reserpine did not deplete brain monoamines or bring about depressive-like behavior in the forced swim test. Spinal monoamines depletion-induced pain sensitivity was ameliorated by lumbar-intrathecal administration of the SNRIs (duloxetine and milnacipran) in dose-dependent manners. These suggest that increased pain sensitivity could be induced by dysfunction solely of the descending pain modulatory system, regardless of depressive-like behavior, and lumbar-intrathecal administration of SNRIs could ameliorate the pain sensitivity which might be mediated by affecting the descending pain modulatory system in the spinal cord, not via their antidepressant effects. PMID:26806036

  8. Route and Regulation of Zinc, Cadmium, and Iron Transport in Rice Plants (Oryza sativa L.) during Vegetative Growth and Grain Filling: Metal Transporters, Metal Speciation, Grain Cd Reduction and Zn and Fe Biofortification

    PubMed Central

    Yoneyama, Tadakatsu; Ishikawa, Satoru; Fujimaki, Shu

    2015-01-01

    Zinc (Zn) and iron (Fe) are essential but are sometimes deficient in humans, while cadmium (Cd) is toxic if it accumulates in the liver and kidneys at high levels. All three are contained in the grains of rice, a staple cereal. Zn and Fe concentrations in rice grains harvested under different levels of soil/hydroponic metals are known to change only within a small range, while Cd concentrations show greater changes. To clarify the mechanisms underlying such different metal contents, we synthesized information on the routes of metal transport and accumulation in rice plants by examining metal speciation, metal transporters, and the xylem-to-phloem transport system. At grain-filling, Zn and Cd ascending in xylem sap are transferred to the phloem by the xylem-to-phloem transport system operating at stem nodes. Grain Fe is largely derived from the leaves by remobilization. Zn and Fe concentrations in phloem-sap and grains are regulated within a small range, while Cd concentrations vary depending on xylem supply. Transgenic techniques to increase concentrations of the metal chelators (nicotianamine, 2′-deoxymugineic acid) are useful in increasing grain Zn and Fe concentrations. The elimination of OsNRAMP5 Cd-uptake transporter and the enhancement of root cell vacuolar Cd sequestration reduce uptake and root-to-shoot transport, respectively, resulting in a reduction of grain Cd accumulation. PMID:26287170

  9. Route and Regulation of Zinc, Cadmium, and Iron Transport in Rice Plants (Oryza sativa L.) during Vegetative Growth and Grain Filling: Metal Transporters, Metal Speciation, Grain Cd Reduction and Zn and Fe Biofortification.

    PubMed

    Yoneyama, Tadakatsu; Ishikawa, Satoru; Fujimaki, Shu

    2015-01-01

    Zinc (Zn) and iron (Fe) are essential but are sometimes deficient in humans, while cadmium (Cd) is toxic if it accumulates in the liver and kidneys at high levels. All three are contained in the grains of rice, a staple cereal. Zn and Fe concentrations in rice grains harvested under different levels of soil/hydroponic metals are known to change only within a small range, while Cd concentrations show greater changes. To clarify the mechanisms underlying such different metal contents, we synthesized information on the routes of metal transport and accumulation in rice plants by examining metal speciation, metal transporters, and the xylem-to-phloem transport system. At grain-filling, Zn and Cd ascending in xylem sap are transferred to the phloem by the xylem-to-phloem transport system operating at stem nodes. Grain Fe is largely derived from the leaves by remobilization. Zn and Fe concentrations in phloem-sap and grains are regulated within a small range, while Cd concentrations vary depending on xylem supply. Transgenic techniques to increase concentrations of the metal chelators (nicotianamine, 2'-deoxymugineic acid) are useful in increasing grain Zn and Fe concentrations. The elimination of OsNRAMP5 Cd-uptake transporter and the enhancement of root cell vacuolar Cd sequestration reduce uptake and root-to-shoot transport, respectively, resulting in a reduction of grain Cd accumulation. PMID:26287170

  10. Effects of dopamine, norepinephrine and dobutamine on gastric mucosal pH of septic shock patients

    PubMed Central

    Wu, Yifen; Zhang, Ning; Wu, Yifu; Zheng, Yanping; You, Xiaoen; Cao, Zhuo; Xu, Yaqi

    2016-01-01

    The effect of different vasoactive drugs on the pH [intracellular pH (pHi)] of gastric mucosa in patients with septic shock was evaluated in the present study. According to the vasoactive drugs applied, 48 patients with septic shock were divided into 3 groups: A, B and C, with 16 cases each. Cases of group A were treated with dopamine, those of group B with norepinephrine while those of group C were treated with norepinephrine plus dobutamine. The changes of pH of gastric mucosa were observed before treatment (baseline) and 6, 12, 24 and 48 h after treatment, and the hemodynamic indicators were observed before treatment (baseline) and 6 h after administration. The gastric mucosal pH was not significantly different between two of the three groups before treatment (each at P>0.05). The gastric mucosal pH of group A did not change 6, 12, 24 and 48 h after treatment with drugs compared with the baseline (all at P>0.05), while the gastric mucosal pH in groups B and C were each statistically higher at the time points of 6, 12, 24 and 48 h after treatment with drugs compared with the respective baselines (all at P<0.05). Following treatment with drugs, the gastric mucosal pH of group C at all the time points of 6, 12, 24 and 48 h after treatment were significantly higher than those of groups A and B at the same time points after treatment, while there were some statistical differences between groups A and B at these time points (6, 12, 24 and 48 h after treatment; P<0.05). The hemodynamic indicators of the patients before treatment were not significantly different between two of the three groups (all at P>0.05). Compared with the baseline values, the mean arterial pressure and the cardiac index of each group after treatment were significantly increased, the pulmonary capillary wedge pressure and the central venous pressure of groups B and C significantly increased (all at P<0.05) and the heart rate of group A was significantly increased (P<0.05). In conclusion, the